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Preop pain perceptions drive outcomes after knee surgery
Adult athletes who underwent knee surgery and had higher levels of preoperative pain catastrophizing were significantly less likely to return to preinjury activity, based on data from 101 individuals.
Pain is highly subjective, and pain perception can play a role in postsurgical outcomes, but the relationships among preoperative pain perception and short-term outcomes including returning to sports have not been well-studied, wrote Joshua S. Everhart, MD, of The Ohio State University Wexner Medical Center, Columbus, and colleagues.
In a study published in the Journal of Science and Medicine in Sport, the researchers assessed 101 adult athletes who underwent knee surgery at a single center. The average age of the patients was 33 years, and 49 were women.
Pain perception and coping were assessed via the McGill Pain questionnaire (SF-MPQ), Pain Catastrophizing Scale (PCS), Pain Coping Measure (PCM), and the brief COPE subscales of acceptance, denial, positive reframing, and use of instrumental support.
Patients who were severe pain catastrophizers (defined as scores greater than 36 on the Pain Catastrophizing Scale) had increased odds of not returning to a similar level of sport (OR 11.3).
Higher scores on the brief COPE subscale of “use of instrumental support” (instruments designed to help patients cope with pain) had a protective effect on returning to preinjury activity (OR 0.72 per point increase). However, higher COPE-denial scores were significantly associated with lower odds of improvement in kinesiophobia (OR 0.43).
Patients with greater levels of problem-focused coping had significantly greater improvement in International Knee Documentation Committee (IKDC) scores, as did patients who were older and more active.
“Specific coping strategies appear to moderate the effect of pain perceptions on postoperative outcomes, with some coping strategies being protective and others being harmful,” the researchers said.
The findings were limited by several factors including the use of multiple comparisons, the inability to assess the impact of pain perception after knee rehabilitation independent of surgery, and the small number of some uncommon procedures, the researchers noted.
However, the results suggest that “recognition of pain perception and coping styles early on in treatment may help sports medicine providers identify patients at risk for an unsatisfactory subjective outcome,” they concluded.
The researchers had no financial conflicts to disclose.
SOURCE: Everhart JS et al. J Sci Med Sport. 2019. doi: 10.1016/j.jsams.2019.09.011.
Adult athletes who underwent knee surgery and had higher levels of preoperative pain catastrophizing were significantly less likely to return to preinjury activity, based on data from 101 individuals.
Pain is highly subjective, and pain perception can play a role in postsurgical outcomes, but the relationships among preoperative pain perception and short-term outcomes including returning to sports have not been well-studied, wrote Joshua S. Everhart, MD, of The Ohio State University Wexner Medical Center, Columbus, and colleagues.
In a study published in the Journal of Science and Medicine in Sport, the researchers assessed 101 adult athletes who underwent knee surgery at a single center. The average age of the patients was 33 years, and 49 were women.
Pain perception and coping were assessed via the McGill Pain questionnaire (SF-MPQ), Pain Catastrophizing Scale (PCS), Pain Coping Measure (PCM), and the brief COPE subscales of acceptance, denial, positive reframing, and use of instrumental support.
Patients who were severe pain catastrophizers (defined as scores greater than 36 on the Pain Catastrophizing Scale) had increased odds of not returning to a similar level of sport (OR 11.3).
Higher scores on the brief COPE subscale of “use of instrumental support” (instruments designed to help patients cope with pain) had a protective effect on returning to preinjury activity (OR 0.72 per point increase). However, higher COPE-denial scores were significantly associated with lower odds of improvement in kinesiophobia (OR 0.43).
Patients with greater levels of problem-focused coping had significantly greater improvement in International Knee Documentation Committee (IKDC) scores, as did patients who were older and more active.
“Specific coping strategies appear to moderate the effect of pain perceptions on postoperative outcomes, with some coping strategies being protective and others being harmful,” the researchers said.
The findings were limited by several factors including the use of multiple comparisons, the inability to assess the impact of pain perception after knee rehabilitation independent of surgery, and the small number of some uncommon procedures, the researchers noted.
However, the results suggest that “recognition of pain perception and coping styles early on in treatment may help sports medicine providers identify patients at risk for an unsatisfactory subjective outcome,” they concluded.
The researchers had no financial conflicts to disclose.
SOURCE: Everhart JS et al. J Sci Med Sport. 2019. doi: 10.1016/j.jsams.2019.09.011.
Adult athletes who underwent knee surgery and had higher levels of preoperative pain catastrophizing were significantly less likely to return to preinjury activity, based on data from 101 individuals.
Pain is highly subjective, and pain perception can play a role in postsurgical outcomes, but the relationships among preoperative pain perception and short-term outcomes including returning to sports have not been well-studied, wrote Joshua S. Everhart, MD, of The Ohio State University Wexner Medical Center, Columbus, and colleagues.
In a study published in the Journal of Science and Medicine in Sport, the researchers assessed 101 adult athletes who underwent knee surgery at a single center. The average age of the patients was 33 years, and 49 were women.
Pain perception and coping were assessed via the McGill Pain questionnaire (SF-MPQ), Pain Catastrophizing Scale (PCS), Pain Coping Measure (PCM), and the brief COPE subscales of acceptance, denial, positive reframing, and use of instrumental support.
Patients who were severe pain catastrophizers (defined as scores greater than 36 on the Pain Catastrophizing Scale) had increased odds of not returning to a similar level of sport (OR 11.3).
Higher scores on the brief COPE subscale of “use of instrumental support” (instruments designed to help patients cope with pain) had a protective effect on returning to preinjury activity (OR 0.72 per point increase). However, higher COPE-denial scores were significantly associated with lower odds of improvement in kinesiophobia (OR 0.43).
Patients with greater levels of problem-focused coping had significantly greater improvement in International Knee Documentation Committee (IKDC) scores, as did patients who were older and more active.
“Specific coping strategies appear to moderate the effect of pain perceptions on postoperative outcomes, with some coping strategies being protective and others being harmful,” the researchers said.
The findings were limited by several factors including the use of multiple comparisons, the inability to assess the impact of pain perception after knee rehabilitation independent of surgery, and the small number of some uncommon procedures, the researchers noted.
However, the results suggest that “recognition of pain perception and coping styles early on in treatment may help sports medicine providers identify patients at risk for an unsatisfactory subjective outcome,” they concluded.
The researchers had no financial conflicts to disclose.
SOURCE: Everhart JS et al. J Sci Med Sport. 2019. doi: 10.1016/j.jsams.2019.09.011.
FROM THE JOURNAL OF SCIENCE AND MEDICINE IN SPORT
FDA approves afamelanotide for treatment of rare condition with light-induced pain
The Food and Drug Administration has approved , a rare condition that causes extremely painful reactions when skin is exposed to light, according to an FDA announcement.
This is the first treatment approved to help patients with this condition increase their exposure to light, according to the release.
Afamelanotide, administered in a subcutaneous implant, is a melanocortin-1 receptor (MC1-R) agonist, which “increases the production of eumelanin in the skin independent of exposure to sunlight or artificial light sources,” the release says.
Approval is based on a pair of parallel-group clinical trials that compared the number of hours spent in sunlight in the treatment and placebo groups. The first trial enrolled 93 patients; 48 received afamelanotide. The treated patients spent a median of 61 hours in total over 180 days in direct sunlight between 10 a.m. and 6 p.m. on days with no pain, compared with 41 hours for patients taking placebo.
The second trial assessed the total number of hours over 270 days spent outdoors between 10 a.m. and 3 p.m. on days with no pain for which “most of the day” was spent in direct sunlight. In this study, 38 patients treated with afamelanotide spent a median total of 6 hours, compared with 0.75 hours among the remaining 36 who were taking a placebo.
The most common side effects include implant site reaction, nausea, and oropharyngeal pain. The implant should be administered only by trained professionals. Because afamelanotide may cause skin darkening, it’s recommended that patients should undergo twice-yearly skin examinations. Patients are also encouraged to maintain sun protection measures to help prevent phototoxic reactions.
“Today’s approval is one example of the FDA’s ongoing commitment to encourage industry innovation of therapies to treat rare diseases, and work with drug developers to make promising new therapies available to patients as safely and efficiently as possible,” said Julie Beitz, MD, director of FDA’s Center for Drug Evaluation and Research Office of Drug Evaluation III in the FDA release.
The Food and Drug Administration has approved , a rare condition that causes extremely painful reactions when skin is exposed to light, according to an FDA announcement.
This is the first treatment approved to help patients with this condition increase their exposure to light, according to the release.
Afamelanotide, administered in a subcutaneous implant, is a melanocortin-1 receptor (MC1-R) agonist, which “increases the production of eumelanin in the skin independent of exposure to sunlight or artificial light sources,” the release says.
Approval is based on a pair of parallel-group clinical trials that compared the number of hours spent in sunlight in the treatment and placebo groups. The first trial enrolled 93 patients; 48 received afamelanotide. The treated patients spent a median of 61 hours in total over 180 days in direct sunlight between 10 a.m. and 6 p.m. on days with no pain, compared with 41 hours for patients taking placebo.
The second trial assessed the total number of hours over 270 days spent outdoors between 10 a.m. and 3 p.m. on days with no pain for which “most of the day” was spent in direct sunlight. In this study, 38 patients treated with afamelanotide spent a median total of 6 hours, compared with 0.75 hours among the remaining 36 who were taking a placebo.
The most common side effects include implant site reaction, nausea, and oropharyngeal pain. The implant should be administered only by trained professionals. Because afamelanotide may cause skin darkening, it’s recommended that patients should undergo twice-yearly skin examinations. Patients are also encouraged to maintain sun protection measures to help prevent phototoxic reactions.
“Today’s approval is one example of the FDA’s ongoing commitment to encourage industry innovation of therapies to treat rare diseases, and work with drug developers to make promising new therapies available to patients as safely and efficiently as possible,” said Julie Beitz, MD, director of FDA’s Center for Drug Evaluation and Research Office of Drug Evaluation III in the FDA release.
The Food and Drug Administration has approved , a rare condition that causes extremely painful reactions when skin is exposed to light, according to an FDA announcement.
This is the first treatment approved to help patients with this condition increase their exposure to light, according to the release.
Afamelanotide, administered in a subcutaneous implant, is a melanocortin-1 receptor (MC1-R) agonist, which “increases the production of eumelanin in the skin independent of exposure to sunlight or artificial light sources,” the release says.
Approval is based on a pair of parallel-group clinical trials that compared the number of hours spent in sunlight in the treatment and placebo groups. The first trial enrolled 93 patients; 48 received afamelanotide. The treated patients spent a median of 61 hours in total over 180 days in direct sunlight between 10 a.m. and 6 p.m. on days with no pain, compared with 41 hours for patients taking placebo.
The second trial assessed the total number of hours over 270 days spent outdoors between 10 a.m. and 3 p.m. on days with no pain for which “most of the day” was spent in direct sunlight. In this study, 38 patients treated with afamelanotide spent a median total of 6 hours, compared with 0.75 hours among the remaining 36 who were taking a placebo.
The most common side effects include implant site reaction, nausea, and oropharyngeal pain. The implant should be administered only by trained professionals. Because afamelanotide may cause skin darkening, it’s recommended that patients should undergo twice-yearly skin examinations. Patients are also encouraged to maintain sun protection measures to help prevent phototoxic reactions.
“Today’s approval is one example of the FDA’s ongoing commitment to encourage industry innovation of therapies to treat rare diseases, and work with drug developers to make promising new therapies available to patients as safely and efficiently as possible,” said Julie Beitz, MD, director of FDA’s Center for Drug Evaluation and Research Office of Drug Evaluation III in the FDA release.
Consider centralized pain in patients with rheumatic disease
Las Vegas – A fibromyalgia survey may provide important information about the degree to which patients with rheumatic disease experience centralized pain. This information may guide treatment decisions, said Daniel J. Clauw, MD, professor of anesthesiology, rheumatology, and psychiatry and director of the Chronic Pain and Fatigue Research Center at the University of Michigan in Ann Arbor.
The questionnaire that Dr. Clauw uses is a patient self-report survey for the assessment of fibromyalgia based on criteria in the 2011 modification of the American College of Rheumatology preliminary diagnostic criteria for fibromyalgia. In it, he asks patients to report where they experience pain throughout the body and symptoms such as fatigue, sleep problems, and memory problems. The survey predicts outcomes of surgery for osteoarthritis better than x-rays, MRI scans, or psychological factors do, he said.
Physicians should ask every patient with chronic pain, including patients with OA, rheumatoid arthritis, or lupus, to complete the survey, Dr. Clauw said at the annual Perspectives in Rheumatic Diseases held by Global Academy for Medical Education. “This score will tell you the degree to which their central nervous system is augmenting or amplifying what is going on in their body,” he said. “And the higher their score is, the more you should treat them like you would someone with fibromyalgia, even if their underlying disease might be an autoimmune disease.”
Physicians should not use a cutoff of 13 points on the fibromyalgia measure to define whether a patient has the disease, as has been done in the past, he said. The threshold is arbitrary, he said. “We should not think about fibromyalgia as ‘yes’ or ‘no.’ We should think of the degree of fibromyalgia that people have.”
A poor relationship between pain and imaging
Some patients who have severe knee OA on imaging walk without pain. Other patients have normal x-rays, but severe pain. “There is a terrible relationship between what you see on a knee x-ray or an MRI and whether someone has pain,” Dr. Clauw said. Furthermore, the poor relationship between imaging and pain is common across chronic pain conditions, he said.
This phenomenon may occur because pain manifests in different ways, similar to there being multiple ways to adjust the volume of an electric guitar, he said. How hard the strings are strummed affects the volume. But so does the amplifier setting. “In these centralized pain conditions, the problem is an amplifier problem, not a guitar problem,” he said. “The amplifier, i.e., the central nervous system, is set too high.”
Researchers have found that people who have severe OA of the knee on x-ray but do not experience pain “have a very low amplifier setting,” he said. That is, they are nontender and less sensitive to pain. Most of these patients are men. “On average, men have a much lower amplifier setting than women,” he said. “This is also why ... women have 1.5 to 2 times the rate of any type of chronic pain than men, because on average women have a higher amplifier setting. ... In OA, at any given age, men and women have the exact same percentage of radiographic OA. But if you look at the clinical condition of OA, it is always two-thirds women, one-third men.”
Opioid responsiveness
To examine whether fibromyalgia survey results correlate with outcomes after knee and hip arthroplasty, Dr. Clauw and colleagues conducted a prospective, observational cohort study that included approximately 500 people. Patients completed the questionnaire on the day of surgery.
Patients with higher levels of fibromyalgia were less responsive to opioids. “For each 1-point increase in the fibromyalgia score, people needed about one more hydrocodone tablet in the first 24-48 hours to control their pain,” he said (Anesthesiology. 2013 Dec;119[6]:1434-43). In addition, each 1-point increase in the fibromyalgia score made people about 25% less likely to have a 50% improvement in knee pain level after 6 months (Arthritis Rheumatol. 2015 May;67[5]:1386-94). The correlations were independent of psychological factors. In addition, the associations were linear. “There was nothing magical about a fibromyalgia score of 13,” Dr. Clauw said.
Dr. Clauw is a coauthor of a study to be presented at the 2019 American College of Rheumatology/Association of Rheumatology Professionals annual meeting that found pain centralization in patients with RA is associated with poor response to disease-modifying antirheumatic drugs (DMARDs).
Prior studies in patients with RA have found that the degree of fibromyalgia is a better predictor of pain and disability than erythrocyte sedimentation rate or the number of swollen joints.
Diagnosed cases are the “tip of the iceberg”
Researchers at Dr. Clauw’s institution have identified dozens of patients undergoing knee surgery who met criteria for fibromyalgia but had not received the diagnosis. “This is at the University of Michigan, which is the epicenter for fibromyalgia research. If we are not seeing fibromyalgia superimposed on OA in our patients, no one is seeing it,” he said.
Patients with diagnosed fibromyalgia are “the tip of the iceberg,” he said. “There are far greater numbers of individuals whose primary diagnosis is OA, RA, lupus, ankylosing spondylitis, cancer pain, or sickle cell disease that have the same fundamental problem as fibromyalgia patients. But you do not see it because you label them as having an autoimmune disease or osteoarthritis. And that is at your peril and at their peril. Because treating that individual as if all of their pain and other symptoms are due to a problem out on the periphery will not make that person better.”
Patients with high levels of centralized pain may be less responsive to peripherally directed therapies such as surgery or injections, Dr. Clauw said. Pharmacologic options for patients with centralized pain include gabapentinoids (e.g., pregabalin and gabapentin), serotonin-norepinephrine reuptake inhibitors (e.g., duloxetine and milnacipran), and tricyclic compounds (e.g., amitriptyline and cyclobenzaprine), he said. “Opioids are going to be quite unlikely to help these individuals,” he said. “In fact, it is likely that opioids will make this kind of pain worse.”
Dr. Clauw is a consultant for Aptinyx, Daiichi Sankyo, Eli Lilly, Intec Pharma, Pfizer, Samumed, Theravance, Tonix, and Zynerba Pharma. He has received grant or research support from Aptinyx and Pfizer and is an expert witness.
Global Academy for Medical Education and this news organization are owned by the same parent company.
Las Vegas – A fibromyalgia survey may provide important information about the degree to which patients with rheumatic disease experience centralized pain. This information may guide treatment decisions, said Daniel J. Clauw, MD, professor of anesthesiology, rheumatology, and psychiatry and director of the Chronic Pain and Fatigue Research Center at the University of Michigan in Ann Arbor.
The questionnaire that Dr. Clauw uses is a patient self-report survey for the assessment of fibromyalgia based on criteria in the 2011 modification of the American College of Rheumatology preliminary diagnostic criteria for fibromyalgia. In it, he asks patients to report where they experience pain throughout the body and symptoms such as fatigue, sleep problems, and memory problems. The survey predicts outcomes of surgery for osteoarthritis better than x-rays, MRI scans, or psychological factors do, he said.
Physicians should ask every patient with chronic pain, including patients with OA, rheumatoid arthritis, or lupus, to complete the survey, Dr. Clauw said at the annual Perspectives in Rheumatic Diseases held by Global Academy for Medical Education. “This score will tell you the degree to which their central nervous system is augmenting or amplifying what is going on in their body,” he said. “And the higher their score is, the more you should treat them like you would someone with fibromyalgia, even if their underlying disease might be an autoimmune disease.”
Physicians should not use a cutoff of 13 points on the fibromyalgia measure to define whether a patient has the disease, as has been done in the past, he said. The threshold is arbitrary, he said. “We should not think about fibromyalgia as ‘yes’ or ‘no.’ We should think of the degree of fibromyalgia that people have.”
A poor relationship between pain and imaging
Some patients who have severe knee OA on imaging walk without pain. Other patients have normal x-rays, but severe pain. “There is a terrible relationship between what you see on a knee x-ray or an MRI and whether someone has pain,” Dr. Clauw said. Furthermore, the poor relationship between imaging and pain is common across chronic pain conditions, he said.
This phenomenon may occur because pain manifests in different ways, similar to there being multiple ways to adjust the volume of an electric guitar, he said. How hard the strings are strummed affects the volume. But so does the amplifier setting. “In these centralized pain conditions, the problem is an amplifier problem, not a guitar problem,” he said. “The amplifier, i.e., the central nervous system, is set too high.”
Researchers have found that people who have severe OA of the knee on x-ray but do not experience pain “have a very low amplifier setting,” he said. That is, they are nontender and less sensitive to pain. Most of these patients are men. “On average, men have a much lower amplifier setting than women,” he said. “This is also why ... women have 1.5 to 2 times the rate of any type of chronic pain than men, because on average women have a higher amplifier setting. ... In OA, at any given age, men and women have the exact same percentage of radiographic OA. But if you look at the clinical condition of OA, it is always two-thirds women, one-third men.”
Opioid responsiveness
To examine whether fibromyalgia survey results correlate with outcomes after knee and hip arthroplasty, Dr. Clauw and colleagues conducted a prospective, observational cohort study that included approximately 500 people. Patients completed the questionnaire on the day of surgery.
Patients with higher levels of fibromyalgia were less responsive to opioids. “For each 1-point increase in the fibromyalgia score, people needed about one more hydrocodone tablet in the first 24-48 hours to control their pain,” he said (Anesthesiology. 2013 Dec;119[6]:1434-43). In addition, each 1-point increase in the fibromyalgia score made people about 25% less likely to have a 50% improvement in knee pain level after 6 months (Arthritis Rheumatol. 2015 May;67[5]:1386-94). The correlations were independent of psychological factors. In addition, the associations were linear. “There was nothing magical about a fibromyalgia score of 13,” Dr. Clauw said.
Dr. Clauw is a coauthor of a study to be presented at the 2019 American College of Rheumatology/Association of Rheumatology Professionals annual meeting that found pain centralization in patients with RA is associated with poor response to disease-modifying antirheumatic drugs (DMARDs).
Prior studies in patients with RA have found that the degree of fibromyalgia is a better predictor of pain and disability than erythrocyte sedimentation rate or the number of swollen joints.
Diagnosed cases are the “tip of the iceberg”
Researchers at Dr. Clauw’s institution have identified dozens of patients undergoing knee surgery who met criteria for fibromyalgia but had not received the diagnosis. “This is at the University of Michigan, which is the epicenter for fibromyalgia research. If we are not seeing fibromyalgia superimposed on OA in our patients, no one is seeing it,” he said.
Patients with diagnosed fibromyalgia are “the tip of the iceberg,” he said. “There are far greater numbers of individuals whose primary diagnosis is OA, RA, lupus, ankylosing spondylitis, cancer pain, or sickle cell disease that have the same fundamental problem as fibromyalgia patients. But you do not see it because you label them as having an autoimmune disease or osteoarthritis. And that is at your peril and at their peril. Because treating that individual as if all of their pain and other symptoms are due to a problem out on the periphery will not make that person better.”
Patients with high levels of centralized pain may be less responsive to peripherally directed therapies such as surgery or injections, Dr. Clauw said. Pharmacologic options for patients with centralized pain include gabapentinoids (e.g., pregabalin and gabapentin), serotonin-norepinephrine reuptake inhibitors (e.g., duloxetine and milnacipran), and tricyclic compounds (e.g., amitriptyline and cyclobenzaprine), he said. “Opioids are going to be quite unlikely to help these individuals,” he said. “In fact, it is likely that opioids will make this kind of pain worse.”
Dr. Clauw is a consultant for Aptinyx, Daiichi Sankyo, Eli Lilly, Intec Pharma, Pfizer, Samumed, Theravance, Tonix, and Zynerba Pharma. He has received grant or research support from Aptinyx and Pfizer and is an expert witness.
Global Academy for Medical Education and this news organization are owned by the same parent company.
Las Vegas – A fibromyalgia survey may provide important information about the degree to which patients with rheumatic disease experience centralized pain. This information may guide treatment decisions, said Daniel J. Clauw, MD, professor of anesthesiology, rheumatology, and psychiatry and director of the Chronic Pain and Fatigue Research Center at the University of Michigan in Ann Arbor.
The questionnaire that Dr. Clauw uses is a patient self-report survey for the assessment of fibromyalgia based on criteria in the 2011 modification of the American College of Rheumatology preliminary diagnostic criteria for fibromyalgia. In it, he asks patients to report where they experience pain throughout the body and symptoms such as fatigue, sleep problems, and memory problems. The survey predicts outcomes of surgery for osteoarthritis better than x-rays, MRI scans, or psychological factors do, he said.
Physicians should ask every patient with chronic pain, including patients with OA, rheumatoid arthritis, or lupus, to complete the survey, Dr. Clauw said at the annual Perspectives in Rheumatic Diseases held by Global Academy for Medical Education. “This score will tell you the degree to which their central nervous system is augmenting or amplifying what is going on in their body,” he said. “And the higher their score is, the more you should treat them like you would someone with fibromyalgia, even if their underlying disease might be an autoimmune disease.”
Physicians should not use a cutoff of 13 points on the fibromyalgia measure to define whether a patient has the disease, as has been done in the past, he said. The threshold is arbitrary, he said. “We should not think about fibromyalgia as ‘yes’ or ‘no.’ We should think of the degree of fibromyalgia that people have.”
A poor relationship between pain and imaging
Some patients who have severe knee OA on imaging walk without pain. Other patients have normal x-rays, but severe pain. “There is a terrible relationship between what you see on a knee x-ray or an MRI and whether someone has pain,” Dr. Clauw said. Furthermore, the poor relationship between imaging and pain is common across chronic pain conditions, he said.
This phenomenon may occur because pain manifests in different ways, similar to there being multiple ways to adjust the volume of an electric guitar, he said. How hard the strings are strummed affects the volume. But so does the amplifier setting. “In these centralized pain conditions, the problem is an amplifier problem, not a guitar problem,” he said. “The amplifier, i.e., the central nervous system, is set too high.”
Researchers have found that people who have severe OA of the knee on x-ray but do not experience pain “have a very low amplifier setting,” he said. That is, they are nontender and less sensitive to pain. Most of these patients are men. “On average, men have a much lower amplifier setting than women,” he said. “This is also why ... women have 1.5 to 2 times the rate of any type of chronic pain than men, because on average women have a higher amplifier setting. ... In OA, at any given age, men and women have the exact same percentage of radiographic OA. But if you look at the clinical condition of OA, it is always two-thirds women, one-third men.”
Opioid responsiveness
To examine whether fibromyalgia survey results correlate with outcomes after knee and hip arthroplasty, Dr. Clauw and colleagues conducted a prospective, observational cohort study that included approximately 500 people. Patients completed the questionnaire on the day of surgery.
Patients with higher levels of fibromyalgia were less responsive to opioids. “For each 1-point increase in the fibromyalgia score, people needed about one more hydrocodone tablet in the first 24-48 hours to control their pain,” he said (Anesthesiology. 2013 Dec;119[6]:1434-43). In addition, each 1-point increase in the fibromyalgia score made people about 25% less likely to have a 50% improvement in knee pain level after 6 months (Arthritis Rheumatol. 2015 May;67[5]:1386-94). The correlations were independent of psychological factors. In addition, the associations were linear. “There was nothing magical about a fibromyalgia score of 13,” Dr. Clauw said.
Dr. Clauw is a coauthor of a study to be presented at the 2019 American College of Rheumatology/Association of Rheumatology Professionals annual meeting that found pain centralization in patients with RA is associated with poor response to disease-modifying antirheumatic drugs (DMARDs).
Prior studies in patients with RA have found that the degree of fibromyalgia is a better predictor of pain and disability than erythrocyte sedimentation rate or the number of swollen joints.
Diagnosed cases are the “tip of the iceberg”
Researchers at Dr. Clauw’s institution have identified dozens of patients undergoing knee surgery who met criteria for fibromyalgia but had not received the diagnosis. “This is at the University of Michigan, which is the epicenter for fibromyalgia research. If we are not seeing fibromyalgia superimposed on OA in our patients, no one is seeing it,” he said.
Patients with diagnosed fibromyalgia are “the tip of the iceberg,” he said. “There are far greater numbers of individuals whose primary diagnosis is OA, RA, lupus, ankylosing spondylitis, cancer pain, or sickle cell disease that have the same fundamental problem as fibromyalgia patients. But you do not see it because you label them as having an autoimmune disease or osteoarthritis. And that is at your peril and at their peril. Because treating that individual as if all of their pain and other symptoms are due to a problem out on the periphery will not make that person better.”
Patients with high levels of centralized pain may be less responsive to peripherally directed therapies such as surgery or injections, Dr. Clauw said. Pharmacologic options for patients with centralized pain include gabapentinoids (e.g., pregabalin and gabapentin), serotonin-norepinephrine reuptake inhibitors (e.g., duloxetine and milnacipran), and tricyclic compounds (e.g., amitriptyline and cyclobenzaprine), he said. “Opioids are going to be quite unlikely to help these individuals,” he said. “In fact, it is likely that opioids will make this kind of pain worse.”
Dr. Clauw is a consultant for Aptinyx, Daiichi Sankyo, Eli Lilly, Intec Pharma, Pfizer, Samumed, Theravance, Tonix, and Zynerba Pharma. He has received grant or research support from Aptinyx and Pfizer and is an expert witness.
Global Academy for Medical Education and this news organization are owned by the same parent company.
EXPERT ANALYSIS FROM PRD 2019
Persistent rash on the sole
A 52-year-old Chinese woman presented to a tertiary hospital in Singapore with a 3-month history of persistent and intermittently painful rashes over her right calf and foot (FIGURE). The patient had pancytopenia due to ongoing chemotherapy for metastatic nasopharyngeal carcinoma. She was systemically well and denied other dermatoses. Examination demonstrated scattered crops of tense hemorrhagic vesicles, each surrounded by a livid purpuric base, over the right plantar aspect of the foot, with areas of eschar over the right medial hallux. No allodynia, hyperaesthesia, or lymphadenopathy was noted.
A punch biopsy of an intact vesicle was performed.
WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?
Diagnosis:
Herpes zoster
Histopathologic examination showed full-thickness epidermal necrosis with ballooning degeneration resulting in an intra-epidermal blister. Multinucleated keratinocytes with nuclear moulding were seen within the blister cavity. Grocott-Gomori methenamine-silver (GMS), acid-fast, and Gram stains were negative. Granular immunoglobulin (Ig) G, IgM, and C3 were seen intramurally. DNA analysis of vesicular fluid was positive for varicella zoster virus (VZV). A diagnosis of herpes zoster (HZ) of the right S1 dermatome with primary obliterative vasculitis was established.
Immunocompromised people—those who have impaired T-cell immunity (eg, recipients of organ or hematopoietic stem-cell transplants), take immunosuppressive therapy, or have lymphoma, leukemia, or human immunodeficiency virus (HIV) infection—have an increased risk for HZ. For example, in patients with acquired immunodeficiency syndrome (AIDS), HZ uniquely manifests as recurrent shingles. An estimated 20% to 30% of HIV-infected patients will have more than 1 episode of HZ, which may involve the same or different dermatomes.1,2 Furthermore, HZ in this population is more commonly associated with atypical presentations.3
What an atypical presentation may look like
In immunocompromised patients, HZ may present with atypical cutaneous manifestations or with atypical generalized symptoms.
Atypical cutaneous manifestations, as in disseminated zoster, manifest with multiple hyperkeratotic papules (3-20 mm in diameter) that follow no dermatomal pattern. These lesions may be chronic, persisting for months or years, and may be associated with acyclovir-resistant strains of VZV.2,3 Another dermatologic variant is ecthymatous VZV, which manifests with multiple large (10-30 mm) punched-out ulcerations with a central black eschar and a peripheral rim of vesicles.4 Viral folliculitis—in which infection is limited to the hair follicle, with no associated blisters—has also been reported in atypical HZ.5
Our patient presented with hemorrhagic vesicles mimicking vasculitic lesions, which had persisted over a 3-month period with intermittent localized pain. It has been proposed that in atypical presentations, the reactivated VZV spreads transaxonally from adjacent nerves to the outermost adventitial layer of the arterial wall, leading to a vasculitic appearance of the vesicles.6 Viral-induced vasculitis may also result either directly from infection of the blood vessels or secondary to vascular damage from an inflammatory immune complex–mediated reaction, cell-mediated hypersensitivity, or inflammation due to immune dysregulation.7,8
Continue to: Differential includes vesiculobullous conditions
Differential includes vesiculobullous conditions
There are several important items to consider in the differential.
Cutaneous vasculitis, in severe cases, may manifest with vesicles or bullae that resemble the lesions seen in HZ. However, its unilateral nature and distribution distinguish it.
Angioinvasive fungal infections in immunocompromised patients may manifest with scattered ulceronecrotic lesions to purpuric vesiculobullous dermatoses.9 However, no fungal organisms were seen on GMS staining of the biopsied tissue.
Atypical hand-foot-and-mouth disease tends to affect adults and is associated with Coxsackievirus A6 infection.10 It may manifest as generalized vesiculobullous exanthem resembling varicella. The chronic nature and restricted extent of the patient’s rash made this diagnosis unlikely.
Successful management depends on timely identification
Although most cases of HZ can be diagnosed clinically, atypical rashes may require a biopsy and direct immunofluorescence assay for VZV antigen or a polymerase-chain-reaction (PCR) assay for VZV DNA in cells from the base of blisters. Therefore, it is important to consider the diagnosis of HZ in immunocompromised patients presenting with an atypical rash to avoid misdiagnosis and costly testing.
Continue to: Our patient was treated...
Our patient was treated with oral acyclovir 800 mg 5 times/day for 10 days, with prompt resolution of her rash.
CORRESPONDENCE
Joel Hua-Liang Lim, MBBS, MRCP, MMed, 1 Mandalay Road, Singapore 308205; [email protected]
1. LeBoit PE, Limova M, Yen TS, et al. Chronic verrucous varicella-zoster virus infection in patients with the acquired immunodeficiency syndrome (AIDS): histologic and molecular biologic findings. Am J Dermatopathol. 1992;14:1-7.
2. Gnann JW Jr. Varicella-zoster virus: atypical presentations and unusual complications. J Infect Dis. 2002;186(suppl 1):S91-S98.
3. Weinberg JM, Mysliwiec A, Turiansky GW, et al. Viral folliculitis: atypical presentations of herpes simplex, herpes zoster, and molluscum contagiosum. Arch Dermatol. 1997;133:983-986.
4. Gilson IH, Barnett JH, Conant MA, et al. Disseminated ecthymatous herpes varicella zoster virus infection in patients with acquired immunodeficiency syndrome. J Am Acad Dermatol. 1989;20:637-642.
5. Løkke BJ, Weismann K, Mathiesen L, et al. Atypical varicella-zoster infection in AIDS. Acta Derm Venereol. 1993;73:123-125.
6. Uhoda I, Piérard-Franchimont C, Piérard GE. Varicella-zoster virus vasculitis: a case of recurrent varicella without epidermal involvement. Dermatology. 2000;200:173-175.
7. Teng GG, Chatham WW. Vasculitis related to viral and other microbial agents. Best Pract Res Clin Rheumatol. 2015;29:226-243.
8. Nagel MA, Gilden D. Developments in varicella zoster virus vasculopathy. Curr Neurol Neurosci Rep. 2016;16:12.
9. Pfaller MA, Diekema DJ. Epidemiology of invasive mycoses in North America. Crit Rev Microbiol. 2010;36:1-53.
10. Lott JP, Liu K, Landry M-L, et al. Atypical hand-foot-and-mouth disease associated with coxsackievirus A6 infection. J Am Acad Dermatol. 2013;69:736-741.
A 52-year-old Chinese woman presented to a tertiary hospital in Singapore with a 3-month history of persistent and intermittently painful rashes over her right calf and foot (FIGURE). The patient had pancytopenia due to ongoing chemotherapy for metastatic nasopharyngeal carcinoma. She was systemically well and denied other dermatoses. Examination demonstrated scattered crops of tense hemorrhagic vesicles, each surrounded by a livid purpuric base, over the right plantar aspect of the foot, with areas of eschar over the right medial hallux. No allodynia, hyperaesthesia, or lymphadenopathy was noted.
A punch biopsy of an intact vesicle was performed.
WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?
Diagnosis:
Herpes zoster
Histopathologic examination showed full-thickness epidermal necrosis with ballooning degeneration resulting in an intra-epidermal blister. Multinucleated keratinocytes with nuclear moulding were seen within the blister cavity. Grocott-Gomori methenamine-silver (GMS), acid-fast, and Gram stains were negative. Granular immunoglobulin (Ig) G, IgM, and C3 were seen intramurally. DNA analysis of vesicular fluid was positive for varicella zoster virus (VZV). A diagnosis of herpes zoster (HZ) of the right S1 dermatome with primary obliterative vasculitis was established.
Immunocompromised people—those who have impaired T-cell immunity (eg, recipients of organ or hematopoietic stem-cell transplants), take immunosuppressive therapy, or have lymphoma, leukemia, or human immunodeficiency virus (HIV) infection—have an increased risk for HZ. For example, in patients with acquired immunodeficiency syndrome (AIDS), HZ uniquely manifests as recurrent shingles. An estimated 20% to 30% of HIV-infected patients will have more than 1 episode of HZ, which may involve the same or different dermatomes.1,2 Furthermore, HZ in this population is more commonly associated with atypical presentations.3
What an atypical presentation may look like
In immunocompromised patients, HZ may present with atypical cutaneous manifestations or with atypical generalized symptoms.
Atypical cutaneous manifestations, as in disseminated zoster, manifest with multiple hyperkeratotic papules (3-20 mm in diameter) that follow no dermatomal pattern. These lesions may be chronic, persisting for months or years, and may be associated with acyclovir-resistant strains of VZV.2,3 Another dermatologic variant is ecthymatous VZV, which manifests with multiple large (10-30 mm) punched-out ulcerations with a central black eschar and a peripheral rim of vesicles.4 Viral folliculitis—in which infection is limited to the hair follicle, with no associated blisters—has also been reported in atypical HZ.5
Our patient presented with hemorrhagic vesicles mimicking vasculitic lesions, which had persisted over a 3-month period with intermittent localized pain. It has been proposed that in atypical presentations, the reactivated VZV spreads transaxonally from adjacent nerves to the outermost adventitial layer of the arterial wall, leading to a vasculitic appearance of the vesicles.6 Viral-induced vasculitis may also result either directly from infection of the blood vessels or secondary to vascular damage from an inflammatory immune complex–mediated reaction, cell-mediated hypersensitivity, or inflammation due to immune dysregulation.7,8
Continue to: Differential includes vesiculobullous conditions
Differential includes vesiculobullous conditions
There are several important items to consider in the differential.
Cutaneous vasculitis, in severe cases, may manifest with vesicles or bullae that resemble the lesions seen in HZ. However, its unilateral nature and distribution distinguish it.
Angioinvasive fungal infections in immunocompromised patients may manifest with scattered ulceronecrotic lesions to purpuric vesiculobullous dermatoses.9 However, no fungal organisms were seen on GMS staining of the biopsied tissue.
Atypical hand-foot-and-mouth disease tends to affect adults and is associated with Coxsackievirus A6 infection.10 It may manifest as generalized vesiculobullous exanthem resembling varicella. The chronic nature and restricted extent of the patient’s rash made this diagnosis unlikely.
Successful management depends on timely identification
Although most cases of HZ can be diagnosed clinically, atypical rashes may require a biopsy and direct immunofluorescence assay for VZV antigen or a polymerase-chain-reaction (PCR) assay for VZV DNA in cells from the base of blisters. Therefore, it is important to consider the diagnosis of HZ in immunocompromised patients presenting with an atypical rash to avoid misdiagnosis and costly testing.
Continue to: Our patient was treated...
Our patient was treated with oral acyclovir 800 mg 5 times/day for 10 days, with prompt resolution of her rash.
CORRESPONDENCE
Joel Hua-Liang Lim, MBBS, MRCP, MMed, 1 Mandalay Road, Singapore 308205; [email protected]
A 52-year-old Chinese woman presented to a tertiary hospital in Singapore with a 3-month history of persistent and intermittently painful rashes over her right calf and foot (FIGURE). The patient had pancytopenia due to ongoing chemotherapy for metastatic nasopharyngeal carcinoma. She was systemically well and denied other dermatoses. Examination demonstrated scattered crops of tense hemorrhagic vesicles, each surrounded by a livid purpuric base, over the right plantar aspect of the foot, with areas of eschar over the right medial hallux. No allodynia, hyperaesthesia, or lymphadenopathy was noted.
A punch biopsy of an intact vesicle was performed.
WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?
Diagnosis:
Herpes zoster
Histopathologic examination showed full-thickness epidermal necrosis with ballooning degeneration resulting in an intra-epidermal blister. Multinucleated keratinocytes with nuclear moulding were seen within the blister cavity. Grocott-Gomori methenamine-silver (GMS), acid-fast, and Gram stains were negative. Granular immunoglobulin (Ig) G, IgM, and C3 were seen intramurally. DNA analysis of vesicular fluid was positive for varicella zoster virus (VZV). A diagnosis of herpes zoster (HZ) of the right S1 dermatome with primary obliterative vasculitis was established.
Immunocompromised people—those who have impaired T-cell immunity (eg, recipients of organ or hematopoietic stem-cell transplants), take immunosuppressive therapy, or have lymphoma, leukemia, or human immunodeficiency virus (HIV) infection—have an increased risk for HZ. For example, in patients with acquired immunodeficiency syndrome (AIDS), HZ uniquely manifests as recurrent shingles. An estimated 20% to 30% of HIV-infected patients will have more than 1 episode of HZ, which may involve the same or different dermatomes.1,2 Furthermore, HZ in this population is more commonly associated with atypical presentations.3
What an atypical presentation may look like
In immunocompromised patients, HZ may present with atypical cutaneous manifestations or with atypical generalized symptoms.
Atypical cutaneous manifestations, as in disseminated zoster, manifest with multiple hyperkeratotic papules (3-20 mm in diameter) that follow no dermatomal pattern. These lesions may be chronic, persisting for months or years, and may be associated with acyclovir-resistant strains of VZV.2,3 Another dermatologic variant is ecthymatous VZV, which manifests with multiple large (10-30 mm) punched-out ulcerations with a central black eschar and a peripheral rim of vesicles.4 Viral folliculitis—in which infection is limited to the hair follicle, with no associated blisters—has also been reported in atypical HZ.5
Our patient presented with hemorrhagic vesicles mimicking vasculitic lesions, which had persisted over a 3-month period with intermittent localized pain. It has been proposed that in atypical presentations, the reactivated VZV spreads transaxonally from adjacent nerves to the outermost adventitial layer of the arterial wall, leading to a vasculitic appearance of the vesicles.6 Viral-induced vasculitis may also result either directly from infection of the blood vessels or secondary to vascular damage from an inflammatory immune complex–mediated reaction, cell-mediated hypersensitivity, or inflammation due to immune dysregulation.7,8
Continue to: Differential includes vesiculobullous conditions
Differential includes vesiculobullous conditions
There are several important items to consider in the differential.
Cutaneous vasculitis, in severe cases, may manifest with vesicles or bullae that resemble the lesions seen in HZ. However, its unilateral nature and distribution distinguish it.
Angioinvasive fungal infections in immunocompromised patients may manifest with scattered ulceronecrotic lesions to purpuric vesiculobullous dermatoses.9 However, no fungal organisms were seen on GMS staining of the biopsied tissue.
Atypical hand-foot-and-mouth disease tends to affect adults and is associated with Coxsackievirus A6 infection.10 It may manifest as generalized vesiculobullous exanthem resembling varicella. The chronic nature and restricted extent of the patient’s rash made this diagnosis unlikely.
Successful management depends on timely identification
Although most cases of HZ can be diagnosed clinically, atypical rashes may require a biopsy and direct immunofluorescence assay for VZV antigen or a polymerase-chain-reaction (PCR) assay for VZV DNA in cells from the base of blisters. Therefore, it is important to consider the diagnosis of HZ in immunocompromised patients presenting with an atypical rash to avoid misdiagnosis and costly testing.
Continue to: Our patient was treated...
Our patient was treated with oral acyclovir 800 mg 5 times/day for 10 days, with prompt resolution of her rash.
CORRESPONDENCE
Joel Hua-Liang Lim, MBBS, MRCP, MMed, 1 Mandalay Road, Singapore 308205; [email protected]
1. LeBoit PE, Limova M, Yen TS, et al. Chronic verrucous varicella-zoster virus infection in patients with the acquired immunodeficiency syndrome (AIDS): histologic and molecular biologic findings. Am J Dermatopathol. 1992;14:1-7.
2. Gnann JW Jr. Varicella-zoster virus: atypical presentations and unusual complications. J Infect Dis. 2002;186(suppl 1):S91-S98.
3. Weinberg JM, Mysliwiec A, Turiansky GW, et al. Viral folliculitis: atypical presentations of herpes simplex, herpes zoster, and molluscum contagiosum. Arch Dermatol. 1997;133:983-986.
4. Gilson IH, Barnett JH, Conant MA, et al. Disseminated ecthymatous herpes varicella zoster virus infection in patients with acquired immunodeficiency syndrome. J Am Acad Dermatol. 1989;20:637-642.
5. Løkke BJ, Weismann K, Mathiesen L, et al. Atypical varicella-zoster infection in AIDS. Acta Derm Venereol. 1993;73:123-125.
6. Uhoda I, Piérard-Franchimont C, Piérard GE. Varicella-zoster virus vasculitis: a case of recurrent varicella without epidermal involvement. Dermatology. 2000;200:173-175.
7. Teng GG, Chatham WW. Vasculitis related to viral and other microbial agents. Best Pract Res Clin Rheumatol. 2015;29:226-243.
8. Nagel MA, Gilden D. Developments in varicella zoster virus vasculopathy. Curr Neurol Neurosci Rep. 2016;16:12.
9. Pfaller MA, Diekema DJ. Epidemiology of invasive mycoses in North America. Crit Rev Microbiol. 2010;36:1-53.
10. Lott JP, Liu K, Landry M-L, et al. Atypical hand-foot-and-mouth disease associated with coxsackievirus A6 infection. J Am Acad Dermatol. 2013;69:736-741.
1. LeBoit PE, Limova M, Yen TS, et al. Chronic verrucous varicella-zoster virus infection in patients with the acquired immunodeficiency syndrome (AIDS): histologic and molecular biologic findings. Am J Dermatopathol. 1992;14:1-7.
2. Gnann JW Jr. Varicella-zoster virus: atypical presentations and unusual complications. J Infect Dis. 2002;186(suppl 1):S91-S98.
3. Weinberg JM, Mysliwiec A, Turiansky GW, et al. Viral folliculitis: atypical presentations of herpes simplex, herpes zoster, and molluscum contagiosum. Arch Dermatol. 1997;133:983-986.
4. Gilson IH, Barnett JH, Conant MA, et al. Disseminated ecthymatous herpes varicella zoster virus infection in patients with acquired immunodeficiency syndrome. J Am Acad Dermatol. 1989;20:637-642.
5. Løkke BJ, Weismann K, Mathiesen L, et al. Atypical varicella-zoster infection in AIDS. Acta Derm Venereol. 1993;73:123-125.
6. Uhoda I, Piérard-Franchimont C, Piérard GE. Varicella-zoster virus vasculitis: a case of recurrent varicella without epidermal involvement. Dermatology. 2000;200:173-175.
7. Teng GG, Chatham WW. Vasculitis related to viral and other microbial agents. Best Pract Res Clin Rheumatol. 2015;29:226-243.
8. Nagel MA, Gilden D. Developments in varicella zoster virus vasculopathy. Curr Neurol Neurosci Rep. 2016;16:12.
9. Pfaller MA, Diekema DJ. Epidemiology of invasive mycoses in North America. Crit Rev Microbiol. 2010;36:1-53.
10. Lott JP, Liu K, Landry M-L, et al. Atypical hand-foot-and-mouth disease associated with coxsackievirus A6 infection. J Am Acad Dermatol. 2013;69:736-741.
Presentation is key to diagnosing salivary gland disorders
Making a diagnosis of a salivary gland disorder can be difficult. Common presentations, such as a painful or swollen gland, can be caused by numerous disorders of strikingly variable severity and consequences, including inflammatory, infectious, and neoplastic conditions, for which treatment can differ significantly, and referral for specialty care is sometimes necessary.
Yet it is the patient’s presentation that can aid you in making the diagnosis that will guide management. Consider that acute symptoms often result from infection, for example, and chronic or recurrent symptoms are caused more often by obstructive or nonobstructive inflammatory conditions and neoplasms. Diagnosis of an apparent neoplasm, prompted by clinical findings, is made using imaging and fine-needle aspiration (FNA) biopsy. Acute infection usually resolves with antibiotics and supportive management; calculi that cause persistent symptoms warrant referral for consideration of stone or gland removal; and malignant neoplasms usually require excision as well as neck dissection and chemotherapy or radiotherapy, or both—calling for multidisciplinary care.
In this article, we clarify what can be an imprecise and perplexing path from the presentation to diagnosis to treatment of disorders of the salivary glands. To begin, see “Geography of the salivary glands,” for an overview of the location, structure, and corresponding ducts of the component salivary glands (parotid, submandibular, sublingual, and minor glands).
SIDEBAR
Geography of the salivary glands
The salivary glands comprise the major paired parotid, submandibular, and sublingual glands, as well as minor salivary glands that line the oropharyngeal mucosa. Secretion of saliva is modulated by both autonomic and humoral factors.
The parotid gland sits between the mastoid process, the ramus of the mandible, and the styloid process, extend- ing from the external auditory meatus superiorly to below the angle of the mandible and into the neck inferiorly. The gland is surrounded by a tough capsule. Embedded within the gland is the facial nerve, which divides into its 5 branches within the substance of the gland. The parotid (Stensen’s) duct passes anteriorly before turning medially to pierce the buccinator muscle, opening onto the mucous membrane of the cheek opposite the second upper molar.
The submandibular gland comprises (1) a large superficial part that fills the space between the mandible and the floor of the mouth and (2) a small deep part that wraps around the posterior border of the mylohyoid muscle. The submandibular (Wharton’s) duct runs anteriorly to open onto the floor of the mouth, alongside the frenulum.
The sublingual gland, the smallest of the major salivary glands, lies anteriorly in the floor of the mouth, with many small ducts opening either into the submandibular duct or directly into the mouth.
Basic secretory units of salivary glands are clusters of cells, each called an acinus. These cells secrete a fluid that contains water, electrolytes, mucous, and enzymes, all of which flow out of the acini into collecting ducts. The saliva produced by the parotid is mainly serous; by the submandibular gland, mixed; and by the sublingual and minor salivary glands, mucoid.
Presentation helps establish the differential Dx
Ask: Are the glands swollen?
Painless salivary gland swelling has a variety of causes, including neoplasm, sialadenosis, and the eating disorders bulimia and anorexia nervosa. There is significant overlap of presentations among those causes (FIGURE). Pain accompanying swelling is uncommon but not unheard of.
Neoplasms. Tumors of the salivary gland are relatively uncommon, constituting approximately 2% of head and neck neoplasms; most (80%) occur in the parotid gland, and most of those are benign.1 Although benign and malignant salivary gland neoplasms do not usually present with pain, pain can be associated with a neoplasm secondary to suppuration, hemorrhage into a mass, or infiltration of a malignancy into adjacent tissue.
Benign tumors. The majority of benign tumors are pleomorphic adenomas of the parotid, accounting for approximately 60% of salivary gland neoplasms.1,2 Tumors localized to the submandibular gland are often (in 50% of cases) malignant, however.3
Benign tumors are typically slow-growing and, generally, painless. On examination, they are well-circumscribed, mobile, and nontender. Patients presenting late with a large tumor might, however, experience pain secondary to stretching of the parotid capsule or compression of local structures.
Continue to: Ultrasonograhpy (US) is an excellent...
Ultrasonography (US) is an excellent initial imaging choice for investigating a possible salivary gland tumor; US is combined with FNA, which is safe and highly reliable for differentiating neoplastic and non-neoplastic disorders.4 (Avoid open biopsy of a neoplasm because of the risk of tumor spillage.) In patients with suspected neoplasm, contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) should also be performed, because both modalities allow delineation of the tumor mass and demonstration of any infiltration of surrounding structures.
Treatment of benign neoplasms involves complete excision because, with some tumors, particularly pleomorphic adenomas, there is risk of malignant transformation over time. Superficial parotidectomy is the most common procedure, because most benign tumors occur in the superficial lobe of the parotid gland. Delicate dissection of the facial nerve is integral to the operation, although temporary facial nerve palsy will still occur in 5% to 10% of patients undergoing superficial parotidectomy for a benign tumor, with permanent injury occurring in fewer than 1%.5
Malignancy. Features of a tumor that raise concern of malignancy include6:
- rapid growth
- pain
- tethering to underlying structures or overlying skin
- firm mass
- associated cervical lymphadenopathy
- facial-nerve palsy.
The workup of a malignant tumor is the same as it is for a benign neoplasm: US-guided FNA, essential for diagnosis, and contrast-enhanced CT or MRI to delineate the tumor.
Malignant salivary gland neoplasms usually require excision as well as neck dissection and chemotherapy or radiotherapy, or both, necessitating a multidisciplinary approach. Also, there is potential for squamous-cell carcinoma and melanoma of the head to metastasize to salivary gland lymph nodes; it is important, therefore, to examine for, and elicit any history of, cutaneous malignancy of the scalp or face.
Continue to: Sialadenosis...
Sialadenosis presents with asymptomatic bilateral hypertrophy of the salivary glands—more commonly the parotids and rarely the submandibular glands. Swelling is persistent, symmetrical, painless, and of normal tone on palpation.
Causes of sialadenosis include alcoholism and, less commonly, diabetes mellitus and malnutrition; some cases are idiopathic. An autonomic neuropathy, causing excessive salivary acinar protein synthesis or failure of adequate secretion, or both, is common to alcoholism, diabetes, and malnutrition.7 Subsequent engorgement of acinar cells leads to clinical parotid hypertrophy.
Diagnosis is based on history and examination, as well as on the findings of US or CT, which will reveal bilateral gland enlargement and increased density. The glands appear dense because adipose cells are displaced by acinar cell hypertrophy; however, end-stage changes can result in the opposite appearance: a lucent enlargement caused by fatty infiltration.2 FNA is unnecessary, unless there is suspicion of neoplasm, as there would be in patients with asymmetrical parotid enlargement, pain, lymph node enlargement, or facial-nerve involvement. In patients with sialadenosis, in contrast, acinar cell hypertrophy alone will be present.
Treatment of sialadenosis is best aimed at rectifying the underlying medical condition, which might, over time, lead to some reduction in the size of the gland. There is no specific effective therapy for elimination of glandular swelling.
Bulimia and anorexia nervosa. Bulimia nervosa, the induction of vomiting after binge eating, can be associated with bilateral or occasionally unilateral parotid swelling. Anorexia, a form of self-starvation, can occur in association with bulimia, with patients also presenting with parotid swelling. Associated parotid swelling is similar to what is seen in sialadenosis: painless, persistent, and of nonpathologic consistency.
The pathophysiology of bulimia- and anorexia-associated parotid-gland swelling is identical to what is seen in sialadenosis: dysregulation of acinar cell sympathetic nerve supply that leads to enlargement of individual parenchymal cells.8 Contrast-enhanced CT can reveal increased vascularity associated with active bulimia. FNA and CT, however, are required only in patients in whom the diagnosis is not clear and when neoplasm is suspected.
Continue to: Treatment includes...
Treatment includes correcting electrolyte abnormalities and, more importantly, addressing underlying emotional issues to stop purging episodes. Psychiatric input and social support are invaluable. Parotid gland swelling generally improves with cessation of vomiting episodes.
Ask: Is the patient in pain?
Causes of salivary gland pain include sialolithiasis, sialadenitis, and recurrent parotitis of childhood. Pain occurs secondary to stretching of the fibrous capsule in which the parotid or submandibular gland is surrounded, compression of pain fibers by an expanding mass, or infiltration of nerves by neoplasia.
Sialolithiasis. Sialolithiasis, or salivary stones, are primarily calcium carbonate concentrations within the salivary ductal system. More than 80% occur in the submandibular gland or duct9 as a result of production of mixed mucoid and serous saliva and a tortuous duct path.
Patients usually present with a history of intermittent swelling and pain of the involved gland associated with eating. Increased production of saliva during meals, which then passes through a partially obstructed salivary duct, leads to salivary retention and glandular swelling. Thus, a recurring pattern can develop, with varying periods of remission,7 eventually leading to an acute suppurative process or sialadenitis (described below). Chronic salivary disease can also be caused by stricture of a duct or, rarely, external compression by a tumor mass.
Examination often reveals an enlarged and often tender gland; conversely, chronic disease can lead to gland atrophy. Usually, only minimal saliva is able to be expressed from an obstructed duct. For a submandibular duct stone, bimanual palpation might reveal its position if it is located distally in the floor of the mouth; a proximal stone might not be palpable.
Continue to: Although US is operator-dependent...
Although US is operator-dependent, it is the imaging modality of choice for identifying sialolithiasis10 because it can identify gland architecture, duct dilation, and both radiolucent and radiopaque stones. For patients in whom US findings are normal despite a convincing clinical presentation of sialolithiasis, CT should be performed because small stones can be missed on US.11
Supportive measures for sialolithiasis are listed in the TABLE. Reserve antibiotics for patients who have signs or symptoms of infection, including pyrexia, trismus, and malaise. A beta-lactam antibiotic, such as amoxicillin–clavulanate, 875 mg orally bid, or a cephalosporin, such as cephalexin, 500 mg orally qid, are appropriate first-line options. Clindamycin, 300 mg orally tid, or metronidazole, 500 mg orally tid, are acceptable alternatives. When signs or symptoms are persistent or recurrent, refer the patient for a surgical opinion.
Stones located in the floor of the mouth are usually excised through an intraoral approach. In the past, gland excision was advocated when a sialolith was found more proximally within the gland parenchyma. More recently, however, sialendoscopy, involving insertion of a small, semirigid endoscope into the salivary duct, has been shown safe and effective for removing a stone; successful removal, in as many as 80% of cases, increases to 90% when performed using a minimally invasive surgical technique.12 Although sialendoscopy is effective, the technique cannot always treat the underlying abnormality of the salivary gland; gland excision is therefore warranted in some cases.
Last, extracorporeal shock wave therapy is aimed at fragmenting salivary stones before retrieval. Results are variable, however, and treatment should be guided by an otolaryngologist.13,14
Sialadenitis (bacterial and viral infection). Acute suppurative sialadenitis occurs secondary to retrograde ductal bacterial infection. The parotid gland is most frequently involved,15 although submandibular sialadenitis is not uncommon. Patients usually present with sudden-onset unilateral, painful swelling.
Continue to: Pathophysiology involves...
Pathophysiology involves dehydration or decreased oral intake leading to salivary stasis and subsequent bacterial migration into the gland. Medically debilitated and postoperative patients are therefore at greater risk; so are patients with diabetes mellitus, poor oral hygiene, Sjögren’s syndrome, hypothyroidism, or renal failure.16 Certain medications, including anticholinergics, can also predispose to hyposalivation.17
(As discussed, sialolithiasis and stricture of salivary ducts can also cause acute bacterial infection; in such cases, however, the typical presentation is one of chronic or recurrent infection.)
Examination might reveal an exquisitely tender, indurated, and inflamed gland; pus can often be expressed from the respective intraoral orifice. Any expressed pus should be sent for culture to guide antibiotic therapy.
Treatment should focus on hydration, oral hygiene, and antibiotics, while reversing or minimizing any underlying contributing medical condition. Warm compresses applied to the involved gland, massage, and sialagogues, such as lemon drops or sugar-free lollipops, can stimulate salivary flow and prevent stasis.
More than 80% of infections are caused by Staphylococcus aureus17; anaerobic and mixed infections have also been recognized.A beta-lactam penicillin, such as amoxicillin-clavulanate, is the antibiotic of choice. A patient who is systemically unwell should be treated as an inpatient with nafcillin and metronidazole. Methicillin-resistant S aureus must also be considered in patients with comorbid disease, such as diabetes mellitus or intravenous drug use, or in patients residing in an area of substantial incidence of methicillin-resistant S aureus. In those cases, substitute vancomycin or linezolid for nafcillin.18
Continue to: Less commonly...
Less commonly, abscess can form, with the patient presenting as systemically unwell with a fluctuant mass. If the diagnosis is unclear or the patient does not improve, abscess can be confirmed by US. Expedient surgical review and inpatient admission can then be arranged.
Unlike bacterial sialadenitis, causes of viral sialadenitis are often bilateral. Mumps (a paramyxovirus) is the most common viral cause, affecting primarily children < 15 years.19 The parotid glands are most often involved, with inflammation and edema causing significant pain because of increasing intraparotid pressure as expansion of the gland is limited by its tense fibrous capsule. Complications of mumps include orchitis, meningitis, pancreatitis, and oophoritis.
Mumps is highly contagious; it is spread through contact with airborne saliva droplets, with viral entry through the nose or mouth, followed by proliferation in the salivary glands or on surface epithelium of the respiratory tract.7 Diagnosis is confirmed by viral serology. A positive test of serum immunoglobulin M confirms the diagnosis, but this test should not be performed until 3 days after onset of symptoms because a false-negative result is otherwise possible.20 Immunoglobulin G serologic testing can further aid diagnosis; the titer is measured approximately 4 days after onset of symptoms and again 2 to 3 weeks later. A 4-fold rise in titer confirms mumps.
Other viral infections that can cause sialadenitis include Epstein-Barr virus, cytomegalovirus, human immunodeficiency virus, coxsackievirus, and influenza. Treatment is supportive: analgesia, hydration, oral hygiene, and rest. Inflammation might take weeks to resolve, but expect complete resolution. For a patient who has significant trismus, poor oral intake, or a potentially threatened airway, inpatient care should be provided.
Recurrent parotitis of childhood is an inflammatory condition that usually affects one, but at times both, parotid glands. It is characterized by episodes of painful swelling. Incidence peaks at 3 to 6 years of age.7 Episodes can be frequent, occurring 1 to 5 times a year and lasting 3 to 7 days—sometimes longer—and usually resolving without treatment.
Continue to: The precise etiology...
The precise etiology of recurrent parotitis of childhood is unclear; possibly, saliva aggregates to form obstructive mucous plugs, thus causing stasis and swelling of the gland. As pressure builds, spontaneous plug extrusion occurs and symptoms resolve, provided infection is not a factor. US demonstrates multiple round, hypoechoic areas consistent with duct dilation, and surrounding infiltration by lymphocytes.1
Supportive care—adequate hydration, gland massage, warm compresses, and sialogogues—are mainstays of treatment. Fever and malaise warrant treatment with oral antibiotics. Sialadenoscopy, which can be considered in children with frequent episodes, can decrease the frequency and severity of episodes.21 The condition usually resolves spontaneously at puberty.
Ask: Does the patient have dry mouth?
In-depth review of xerostomia is beyond the scope of this article. Causes include Sjögren's syndrome, immunoglobulin G4-related sialadenitis, sarcoidosis, radiation therapy, diabetes, chronic infection, and medications—in particular those with anticholinergic effects.
Treatment of xerostomia includes saliva substitutes, sialagogues, and, for oral candidiasis, antifungals. Muscarinic cholinergic stimulators, such as pilocarpine, 5 mg qid have been used with some success22; patients should be advised of potential adverse effects with these agents, including sweating, urinary frequency, flushing, and chills.
CORRESPONDENCE
Shankar Haran, MBBS, ENT Department, Townsville Hospital, 100 Angus Smith Dr, Douglas, Queensland, Australia 4814; [email protected].
1. de Oliveira FA, Duarte EC, Taveira CT, et al. Salivary gland tumor: a review of 599 cases in a Brazilian population. Head Neck Pathol. 2009;3:271-275.
2. Spiro RH. Salivary neoplasms: overview of a 35-year experience with 2,807 patients. Head Neck Surg. 1986;8:177-184.
3. Bova R. A guide to salivary gland disorders. Medicine Today. 2006;7:44-48.
4. Zhang S, Bao R, Bagby J, et al. Fine needle aspiration of salivary glands: 5-year experience from a single academic center. Acta Cytol. 2009;53:375-382.
5. Bova R, Saylor A, Coman WB. Parotidectomy: review of treatment and outcomes. ANZ J Surg. 2004;74:563-568.
6. Sood S, McGurk M, Vaz F. Management of salivary gland tumours: United Kingdom National Multidisciplinary Guidelines. J Laryngol Otol. 2016;130:S142-S149.
7. Mandel L. Salivary gland disorders. Med Clin North Am. 2014;98:1407-1449.
8. Mandel L, Abai S. Diagnosing bulimia nervosa with parotid gland swelling. J Am Dent Assoc. 2004;135:613–616.
9. Lustmann J, Regev E, Melamed Y. Sialolithiasis. A survey on 245 patients and a review of literature. Int J Oral Maxillofac Surg. 1990;19:135–138.
10. Vogl TJ, Al-Nawas B, Beutner D, et al. Updated S2K AWMF guideline for the diagnosis and follow-up of obstructive sialadenitis—relevance for radiologic imaging. Rofo. 2014;186:843-846.
11. Schwarz D, Kabbasch C, Scheer M, et al. Comparative analysis of sialendoscopy, sonography, and CBCT in the detection of sialolithiasis. Laryngoscope. 2015;125:1098–1101.
12. Atienza G, López-Cedrún JL. Management of obstructive salivary disorders by sialendoscopy: a systematic review. Br J Oral Maxillofac Surg. 2015;53:507-519.
13. Escudier MP, Brown JE, Putcha V, et al. Factors influencing the outcome of extracorporeal shock wave lithotripsy in the management of salivary calculi. Laryngoscope. 2010;120:1545-1549.
14. Koch M, Schapher M, Mantsopoulos K, et al. Multimodal treatment in difficult sialolithiasis: Role of extracorporeal shock-wave lithotripsy and intraductal pneumatic lithotripsy. Laryngoscope. 2018;128:E332-E338.
15. McQuone SJ. Acute viral and bacterial infections of the salivary glands. Otolaryngol Clin North Am. 1999;32:793-811.
16. O’Neil C, Sidhu S. Salivary gland disorders. Australian Doctor. 2011;28:19-25.
17. Mandel L. Differentiating acute suppurative parotitis from acute exacerbation of a chronic parotitis: case reports. J Oral Maxillofac Surg. 2008;66:1964-1968.
18. Chow AW. Suppurative parotitis in adults. UpToDate.com. www.uptodate.com/contents/suppurative-parotitis-in-adults. Accessed September 25, 2019.
19. Katz SL, Gershon AA, Hotez PJ. Infectious Diseases of Children. New York, NY: Mosby Year Book; 1998:280-289.
20. Krause CH, Molyneaux PJ, Ho-Yen DO, et al. Comparison of mumps-IgM ELISAs in acute infection. J Clin Virol. 2007;38:153-156.
21. Quenin S, Plouin-Gaudon I, Marchal F, et al. Juvenile recurrent parotitis: sialendoscopic approach. Arch Otolaryngol Head Neck Surg. 2008;134:715-719.
22. Papas AS, Sherrer YS, Charney M, et al. Successful treatment of dry mouth and dry eye symptoms in Sjögren’s syndrome patients with oral pilocarpine: a randomized, placebo-controlled, dose-adjustment study. J Clin Rheumatol. 2004;10:169-177.
Making a diagnosis of a salivary gland disorder can be difficult. Common presentations, such as a painful or swollen gland, can be caused by numerous disorders of strikingly variable severity and consequences, including inflammatory, infectious, and neoplastic conditions, for which treatment can differ significantly, and referral for specialty care is sometimes necessary.
Yet it is the patient’s presentation that can aid you in making the diagnosis that will guide management. Consider that acute symptoms often result from infection, for example, and chronic or recurrent symptoms are caused more often by obstructive or nonobstructive inflammatory conditions and neoplasms. Diagnosis of an apparent neoplasm, prompted by clinical findings, is made using imaging and fine-needle aspiration (FNA) biopsy. Acute infection usually resolves with antibiotics and supportive management; calculi that cause persistent symptoms warrant referral for consideration of stone or gland removal; and malignant neoplasms usually require excision as well as neck dissection and chemotherapy or radiotherapy, or both—calling for multidisciplinary care.
In this article, we clarify what can be an imprecise and perplexing path from the presentation to diagnosis to treatment of disorders of the salivary glands. To begin, see “Geography of the salivary glands,” for an overview of the location, structure, and corresponding ducts of the component salivary glands (parotid, submandibular, sublingual, and minor glands).
SIDEBAR
Geography of the salivary glands
The salivary glands comprise the major paired parotid, submandibular, and sublingual glands, as well as minor salivary glands that line the oropharyngeal mucosa. Secretion of saliva is modulated by both autonomic and humoral factors.
The parotid gland sits between the mastoid process, the ramus of the mandible, and the styloid process, extend- ing from the external auditory meatus superiorly to below the angle of the mandible and into the neck inferiorly. The gland is surrounded by a tough capsule. Embedded within the gland is the facial nerve, which divides into its 5 branches within the substance of the gland. The parotid (Stensen’s) duct passes anteriorly before turning medially to pierce the buccinator muscle, opening onto the mucous membrane of the cheek opposite the second upper molar.
The submandibular gland comprises (1) a large superficial part that fills the space between the mandible and the floor of the mouth and (2) a small deep part that wraps around the posterior border of the mylohyoid muscle. The submandibular (Wharton’s) duct runs anteriorly to open onto the floor of the mouth, alongside the frenulum.
The sublingual gland, the smallest of the major salivary glands, lies anteriorly in the floor of the mouth, with many small ducts opening either into the submandibular duct or directly into the mouth.
Basic secretory units of salivary glands are clusters of cells, each called an acinus. These cells secrete a fluid that contains water, electrolytes, mucous, and enzymes, all of which flow out of the acini into collecting ducts. The saliva produced by the parotid is mainly serous; by the submandibular gland, mixed; and by the sublingual and minor salivary glands, mucoid.
Presentation helps establish the differential Dx
Ask: Are the glands swollen?
Painless salivary gland swelling has a variety of causes, including neoplasm, sialadenosis, and the eating disorders bulimia and anorexia nervosa. There is significant overlap of presentations among those causes (FIGURE). Pain accompanying swelling is uncommon but not unheard of.
Neoplasms. Tumors of the salivary gland are relatively uncommon, constituting approximately 2% of head and neck neoplasms; most (80%) occur in the parotid gland, and most of those are benign.1 Although benign and malignant salivary gland neoplasms do not usually present with pain, pain can be associated with a neoplasm secondary to suppuration, hemorrhage into a mass, or infiltration of a malignancy into adjacent tissue.
Benign tumors. The majority of benign tumors are pleomorphic adenomas of the parotid, accounting for approximately 60% of salivary gland neoplasms.1,2 Tumors localized to the submandibular gland are often (in 50% of cases) malignant, however.3
Benign tumors are typically slow-growing and, generally, painless. On examination, they are well-circumscribed, mobile, and nontender. Patients presenting late with a large tumor might, however, experience pain secondary to stretching of the parotid capsule or compression of local structures.
Continue to: Ultrasonograhpy (US) is an excellent...
Ultrasonography (US) is an excellent initial imaging choice for investigating a possible salivary gland tumor; US is combined with FNA, which is safe and highly reliable for differentiating neoplastic and non-neoplastic disorders.4 (Avoid open biopsy of a neoplasm because of the risk of tumor spillage.) In patients with suspected neoplasm, contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) should also be performed, because both modalities allow delineation of the tumor mass and demonstration of any infiltration of surrounding structures.
Treatment of benign neoplasms involves complete excision because, with some tumors, particularly pleomorphic adenomas, there is risk of malignant transformation over time. Superficial parotidectomy is the most common procedure, because most benign tumors occur in the superficial lobe of the parotid gland. Delicate dissection of the facial nerve is integral to the operation, although temporary facial nerve palsy will still occur in 5% to 10% of patients undergoing superficial parotidectomy for a benign tumor, with permanent injury occurring in fewer than 1%.5
Malignancy. Features of a tumor that raise concern of malignancy include6:
- rapid growth
- pain
- tethering to underlying structures or overlying skin
- firm mass
- associated cervical lymphadenopathy
- facial-nerve palsy.
The workup of a malignant tumor is the same as it is for a benign neoplasm: US-guided FNA, essential for diagnosis, and contrast-enhanced CT or MRI to delineate the tumor.
Malignant salivary gland neoplasms usually require excision as well as neck dissection and chemotherapy or radiotherapy, or both, necessitating a multidisciplinary approach. Also, there is potential for squamous-cell carcinoma and melanoma of the head to metastasize to salivary gland lymph nodes; it is important, therefore, to examine for, and elicit any history of, cutaneous malignancy of the scalp or face.
Continue to: Sialadenosis...
Sialadenosis presents with asymptomatic bilateral hypertrophy of the salivary glands—more commonly the parotids and rarely the submandibular glands. Swelling is persistent, symmetrical, painless, and of normal tone on palpation.
Causes of sialadenosis include alcoholism and, less commonly, diabetes mellitus and malnutrition; some cases are idiopathic. An autonomic neuropathy, causing excessive salivary acinar protein synthesis or failure of adequate secretion, or both, is common to alcoholism, diabetes, and malnutrition.7 Subsequent engorgement of acinar cells leads to clinical parotid hypertrophy.
Diagnosis is based on history and examination, as well as on the findings of US or CT, which will reveal bilateral gland enlargement and increased density. The glands appear dense because adipose cells are displaced by acinar cell hypertrophy; however, end-stage changes can result in the opposite appearance: a lucent enlargement caused by fatty infiltration.2 FNA is unnecessary, unless there is suspicion of neoplasm, as there would be in patients with asymmetrical parotid enlargement, pain, lymph node enlargement, or facial-nerve involvement. In patients with sialadenosis, in contrast, acinar cell hypertrophy alone will be present.
Treatment of sialadenosis is best aimed at rectifying the underlying medical condition, which might, over time, lead to some reduction in the size of the gland. There is no specific effective therapy for elimination of glandular swelling.
Bulimia and anorexia nervosa. Bulimia nervosa, the induction of vomiting after binge eating, can be associated with bilateral or occasionally unilateral parotid swelling. Anorexia, a form of self-starvation, can occur in association with bulimia, with patients also presenting with parotid swelling. Associated parotid swelling is similar to what is seen in sialadenosis: painless, persistent, and of nonpathologic consistency.
The pathophysiology of bulimia- and anorexia-associated parotid-gland swelling is identical to what is seen in sialadenosis: dysregulation of acinar cell sympathetic nerve supply that leads to enlargement of individual parenchymal cells.8 Contrast-enhanced CT can reveal increased vascularity associated with active bulimia. FNA and CT, however, are required only in patients in whom the diagnosis is not clear and when neoplasm is suspected.
Continue to: Treatment includes...
Treatment includes correcting electrolyte abnormalities and, more importantly, addressing underlying emotional issues to stop purging episodes. Psychiatric input and social support are invaluable. Parotid gland swelling generally improves with cessation of vomiting episodes.
Ask: Is the patient in pain?
Causes of salivary gland pain include sialolithiasis, sialadenitis, and recurrent parotitis of childhood. Pain occurs secondary to stretching of the fibrous capsule in which the parotid or submandibular gland is surrounded, compression of pain fibers by an expanding mass, or infiltration of nerves by neoplasia.
Sialolithiasis. Sialolithiasis, or salivary stones, are primarily calcium carbonate concentrations within the salivary ductal system. More than 80% occur in the submandibular gland or duct9 as a result of production of mixed mucoid and serous saliva and a tortuous duct path.
Patients usually present with a history of intermittent swelling and pain of the involved gland associated with eating. Increased production of saliva during meals, which then passes through a partially obstructed salivary duct, leads to salivary retention and glandular swelling. Thus, a recurring pattern can develop, with varying periods of remission,7 eventually leading to an acute suppurative process or sialadenitis (described below). Chronic salivary disease can also be caused by stricture of a duct or, rarely, external compression by a tumor mass.
Examination often reveals an enlarged and often tender gland; conversely, chronic disease can lead to gland atrophy. Usually, only minimal saliva is able to be expressed from an obstructed duct. For a submandibular duct stone, bimanual palpation might reveal its position if it is located distally in the floor of the mouth; a proximal stone might not be palpable.
Continue to: Although US is operator-dependent...
Although US is operator-dependent, it is the imaging modality of choice for identifying sialolithiasis10 because it can identify gland architecture, duct dilation, and both radiolucent and radiopaque stones. For patients in whom US findings are normal despite a convincing clinical presentation of sialolithiasis, CT should be performed because small stones can be missed on US.11
Supportive measures for sialolithiasis are listed in the TABLE. Reserve antibiotics for patients who have signs or symptoms of infection, including pyrexia, trismus, and malaise. A beta-lactam antibiotic, such as amoxicillin–clavulanate, 875 mg orally bid, or a cephalosporin, such as cephalexin, 500 mg orally qid, are appropriate first-line options. Clindamycin, 300 mg orally tid, or metronidazole, 500 mg orally tid, are acceptable alternatives. When signs or symptoms are persistent or recurrent, refer the patient for a surgical opinion.
Stones located in the floor of the mouth are usually excised through an intraoral approach. In the past, gland excision was advocated when a sialolith was found more proximally within the gland parenchyma. More recently, however, sialendoscopy, involving insertion of a small, semirigid endoscope into the salivary duct, has been shown safe and effective for removing a stone; successful removal, in as many as 80% of cases, increases to 90% when performed using a minimally invasive surgical technique.12 Although sialendoscopy is effective, the technique cannot always treat the underlying abnormality of the salivary gland; gland excision is therefore warranted in some cases.
Last, extracorporeal shock wave therapy is aimed at fragmenting salivary stones before retrieval. Results are variable, however, and treatment should be guided by an otolaryngologist.13,14
Sialadenitis (bacterial and viral infection). Acute suppurative sialadenitis occurs secondary to retrograde ductal bacterial infection. The parotid gland is most frequently involved,15 although submandibular sialadenitis is not uncommon. Patients usually present with sudden-onset unilateral, painful swelling.
Continue to: Pathophysiology involves...
Pathophysiology involves dehydration or decreased oral intake leading to salivary stasis and subsequent bacterial migration into the gland. Medically debilitated and postoperative patients are therefore at greater risk; so are patients with diabetes mellitus, poor oral hygiene, Sjögren’s syndrome, hypothyroidism, or renal failure.16 Certain medications, including anticholinergics, can also predispose to hyposalivation.17
(As discussed, sialolithiasis and stricture of salivary ducts can also cause acute bacterial infection; in such cases, however, the typical presentation is one of chronic or recurrent infection.)
Examination might reveal an exquisitely tender, indurated, and inflamed gland; pus can often be expressed from the respective intraoral orifice. Any expressed pus should be sent for culture to guide antibiotic therapy.
Treatment should focus on hydration, oral hygiene, and antibiotics, while reversing or minimizing any underlying contributing medical condition. Warm compresses applied to the involved gland, massage, and sialagogues, such as lemon drops or sugar-free lollipops, can stimulate salivary flow and prevent stasis.
More than 80% of infections are caused by Staphylococcus aureus17; anaerobic and mixed infections have also been recognized.A beta-lactam penicillin, such as amoxicillin-clavulanate, is the antibiotic of choice. A patient who is systemically unwell should be treated as an inpatient with nafcillin and metronidazole. Methicillin-resistant S aureus must also be considered in patients with comorbid disease, such as diabetes mellitus or intravenous drug use, or in patients residing in an area of substantial incidence of methicillin-resistant S aureus. In those cases, substitute vancomycin or linezolid for nafcillin.18
Continue to: Less commonly...
Less commonly, abscess can form, with the patient presenting as systemically unwell with a fluctuant mass. If the diagnosis is unclear or the patient does not improve, abscess can be confirmed by US. Expedient surgical review and inpatient admission can then be arranged.
Unlike bacterial sialadenitis, causes of viral sialadenitis are often bilateral. Mumps (a paramyxovirus) is the most common viral cause, affecting primarily children < 15 years.19 The parotid glands are most often involved, with inflammation and edema causing significant pain because of increasing intraparotid pressure as expansion of the gland is limited by its tense fibrous capsule. Complications of mumps include orchitis, meningitis, pancreatitis, and oophoritis.
Mumps is highly contagious; it is spread through contact with airborne saliva droplets, with viral entry through the nose or mouth, followed by proliferation in the salivary glands or on surface epithelium of the respiratory tract.7 Diagnosis is confirmed by viral serology. A positive test of serum immunoglobulin M confirms the diagnosis, but this test should not be performed until 3 days after onset of symptoms because a false-negative result is otherwise possible.20 Immunoglobulin G serologic testing can further aid diagnosis; the titer is measured approximately 4 days after onset of symptoms and again 2 to 3 weeks later. A 4-fold rise in titer confirms mumps.
Other viral infections that can cause sialadenitis include Epstein-Barr virus, cytomegalovirus, human immunodeficiency virus, coxsackievirus, and influenza. Treatment is supportive: analgesia, hydration, oral hygiene, and rest. Inflammation might take weeks to resolve, but expect complete resolution. For a patient who has significant trismus, poor oral intake, or a potentially threatened airway, inpatient care should be provided.
Recurrent parotitis of childhood is an inflammatory condition that usually affects one, but at times both, parotid glands. It is characterized by episodes of painful swelling. Incidence peaks at 3 to 6 years of age.7 Episodes can be frequent, occurring 1 to 5 times a year and lasting 3 to 7 days—sometimes longer—and usually resolving without treatment.
Continue to: The precise etiology...
The precise etiology of recurrent parotitis of childhood is unclear; possibly, saliva aggregates to form obstructive mucous plugs, thus causing stasis and swelling of the gland. As pressure builds, spontaneous plug extrusion occurs and symptoms resolve, provided infection is not a factor. US demonstrates multiple round, hypoechoic areas consistent with duct dilation, and surrounding infiltration by lymphocytes.1
Supportive care—adequate hydration, gland massage, warm compresses, and sialogogues—are mainstays of treatment. Fever and malaise warrant treatment with oral antibiotics. Sialadenoscopy, which can be considered in children with frequent episodes, can decrease the frequency and severity of episodes.21 The condition usually resolves spontaneously at puberty.
Ask: Does the patient have dry mouth?
In-depth review of xerostomia is beyond the scope of this article. Causes include Sjögren's syndrome, immunoglobulin G4-related sialadenitis, sarcoidosis, radiation therapy, diabetes, chronic infection, and medications—in particular those with anticholinergic effects.
Treatment of xerostomia includes saliva substitutes, sialagogues, and, for oral candidiasis, antifungals. Muscarinic cholinergic stimulators, such as pilocarpine, 5 mg qid have been used with some success22; patients should be advised of potential adverse effects with these agents, including sweating, urinary frequency, flushing, and chills.
CORRESPONDENCE
Shankar Haran, MBBS, ENT Department, Townsville Hospital, 100 Angus Smith Dr, Douglas, Queensland, Australia 4814; [email protected].
Making a diagnosis of a salivary gland disorder can be difficult. Common presentations, such as a painful or swollen gland, can be caused by numerous disorders of strikingly variable severity and consequences, including inflammatory, infectious, and neoplastic conditions, for which treatment can differ significantly, and referral for specialty care is sometimes necessary.
Yet it is the patient’s presentation that can aid you in making the diagnosis that will guide management. Consider that acute symptoms often result from infection, for example, and chronic or recurrent symptoms are caused more often by obstructive or nonobstructive inflammatory conditions and neoplasms. Diagnosis of an apparent neoplasm, prompted by clinical findings, is made using imaging and fine-needle aspiration (FNA) biopsy. Acute infection usually resolves with antibiotics and supportive management; calculi that cause persistent symptoms warrant referral for consideration of stone or gland removal; and malignant neoplasms usually require excision as well as neck dissection and chemotherapy or radiotherapy, or both—calling for multidisciplinary care.
In this article, we clarify what can be an imprecise and perplexing path from the presentation to diagnosis to treatment of disorders of the salivary glands. To begin, see “Geography of the salivary glands,” for an overview of the location, structure, and corresponding ducts of the component salivary glands (parotid, submandibular, sublingual, and minor glands).
SIDEBAR
Geography of the salivary glands
The salivary glands comprise the major paired parotid, submandibular, and sublingual glands, as well as minor salivary glands that line the oropharyngeal mucosa. Secretion of saliva is modulated by both autonomic and humoral factors.
The parotid gland sits between the mastoid process, the ramus of the mandible, and the styloid process, extend- ing from the external auditory meatus superiorly to below the angle of the mandible and into the neck inferiorly. The gland is surrounded by a tough capsule. Embedded within the gland is the facial nerve, which divides into its 5 branches within the substance of the gland. The parotid (Stensen’s) duct passes anteriorly before turning medially to pierce the buccinator muscle, opening onto the mucous membrane of the cheek opposite the second upper molar.
The submandibular gland comprises (1) a large superficial part that fills the space between the mandible and the floor of the mouth and (2) a small deep part that wraps around the posterior border of the mylohyoid muscle. The submandibular (Wharton’s) duct runs anteriorly to open onto the floor of the mouth, alongside the frenulum.
The sublingual gland, the smallest of the major salivary glands, lies anteriorly in the floor of the mouth, with many small ducts opening either into the submandibular duct or directly into the mouth.
Basic secretory units of salivary glands are clusters of cells, each called an acinus. These cells secrete a fluid that contains water, electrolytes, mucous, and enzymes, all of which flow out of the acini into collecting ducts. The saliva produced by the parotid is mainly serous; by the submandibular gland, mixed; and by the sublingual and minor salivary glands, mucoid.
Presentation helps establish the differential Dx
Ask: Are the glands swollen?
Painless salivary gland swelling has a variety of causes, including neoplasm, sialadenosis, and the eating disorders bulimia and anorexia nervosa. There is significant overlap of presentations among those causes (FIGURE). Pain accompanying swelling is uncommon but not unheard of.
Neoplasms. Tumors of the salivary gland are relatively uncommon, constituting approximately 2% of head and neck neoplasms; most (80%) occur in the parotid gland, and most of those are benign.1 Although benign and malignant salivary gland neoplasms do not usually present with pain, pain can be associated with a neoplasm secondary to suppuration, hemorrhage into a mass, or infiltration of a malignancy into adjacent tissue.
Benign tumors. The majority of benign tumors are pleomorphic adenomas of the parotid, accounting for approximately 60% of salivary gland neoplasms.1,2 Tumors localized to the submandibular gland are often (in 50% of cases) malignant, however.3
Benign tumors are typically slow-growing and, generally, painless. On examination, they are well-circumscribed, mobile, and nontender. Patients presenting late with a large tumor might, however, experience pain secondary to stretching of the parotid capsule or compression of local structures.
Continue to: Ultrasonograhpy (US) is an excellent...
Ultrasonography (US) is an excellent initial imaging choice for investigating a possible salivary gland tumor; US is combined with FNA, which is safe and highly reliable for differentiating neoplastic and non-neoplastic disorders.4 (Avoid open biopsy of a neoplasm because of the risk of tumor spillage.) In patients with suspected neoplasm, contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) should also be performed, because both modalities allow delineation of the tumor mass and demonstration of any infiltration of surrounding structures.
Treatment of benign neoplasms involves complete excision because, with some tumors, particularly pleomorphic adenomas, there is risk of malignant transformation over time. Superficial parotidectomy is the most common procedure, because most benign tumors occur in the superficial lobe of the parotid gland. Delicate dissection of the facial nerve is integral to the operation, although temporary facial nerve palsy will still occur in 5% to 10% of patients undergoing superficial parotidectomy for a benign tumor, with permanent injury occurring in fewer than 1%.5
Malignancy. Features of a tumor that raise concern of malignancy include6:
- rapid growth
- pain
- tethering to underlying structures or overlying skin
- firm mass
- associated cervical lymphadenopathy
- facial-nerve palsy.
The workup of a malignant tumor is the same as it is for a benign neoplasm: US-guided FNA, essential for diagnosis, and contrast-enhanced CT or MRI to delineate the tumor.
Malignant salivary gland neoplasms usually require excision as well as neck dissection and chemotherapy or radiotherapy, or both, necessitating a multidisciplinary approach. Also, there is potential for squamous-cell carcinoma and melanoma of the head to metastasize to salivary gland lymph nodes; it is important, therefore, to examine for, and elicit any history of, cutaneous malignancy of the scalp or face.
Continue to: Sialadenosis...
Sialadenosis presents with asymptomatic bilateral hypertrophy of the salivary glands—more commonly the parotids and rarely the submandibular glands. Swelling is persistent, symmetrical, painless, and of normal tone on palpation.
Causes of sialadenosis include alcoholism and, less commonly, diabetes mellitus and malnutrition; some cases are idiopathic. An autonomic neuropathy, causing excessive salivary acinar protein synthesis or failure of adequate secretion, or both, is common to alcoholism, diabetes, and malnutrition.7 Subsequent engorgement of acinar cells leads to clinical parotid hypertrophy.
Diagnosis is based on history and examination, as well as on the findings of US or CT, which will reveal bilateral gland enlargement and increased density. The glands appear dense because adipose cells are displaced by acinar cell hypertrophy; however, end-stage changes can result in the opposite appearance: a lucent enlargement caused by fatty infiltration.2 FNA is unnecessary, unless there is suspicion of neoplasm, as there would be in patients with asymmetrical parotid enlargement, pain, lymph node enlargement, or facial-nerve involvement. In patients with sialadenosis, in contrast, acinar cell hypertrophy alone will be present.
Treatment of sialadenosis is best aimed at rectifying the underlying medical condition, which might, over time, lead to some reduction in the size of the gland. There is no specific effective therapy for elimination of glandular swelling.
Bulimia and anorexia nervosa. Bulimia nervosa, the induction of vomiting after binge eating, can be associated with bilateral or occasionally unilateral parotid swelling. Anorexia, a form of self-starvation, can occur in association with bulimia, with patients also presenting with parotid swelling. Associated parotid swelling is similar to what is seen in sialadenosis: painless, persistent, and of nonpathologic consistency.
The pathophysiology of bulimia- and anorexia-associated parotid-gland swelling is identical to what is seen in sialadenosis: dysregulation of acinar cell sympathetic nerve supply that leads to enlargement of individual parenchymal cells.8 Contrast-enhanced CT can reveal increased vascularity associated with active bulimia. FNA and CT, however, are required only in patients in whom the diagnosis is not clear and when neoplasm is suspected.
Continue to: Treatment includes...
Treatment includes correcting electrolyte abnormalities and, more importantly, addressing underlying emotional issues to stop purging episodes. Psychiatric input and social support are invaluable. Parotid gland swelling generally improves with cessation of vomiting episodes.
Ask: Is the patient in pain?
Causes of salivary gland pain include sialolithiasis, sialadenitis, and recurrent parotitis of childhood. Pain occurs secondary to stretching of the fibrous capsule in which the parotid or submandibular gland is surrounded, compression of pain fibers by an expanding mass, or infiltration of nerves by neoplasia.
Sialolithiasis. Sialolithiasis, or salivary stones, are primarily calcium carbonate concentrations within the salivary ductal system. More than 80% occur in the submandibular gland or duct9 as a result of production of mixed mucoid and serous saliva and a tortuous duct path.
Patients usually present with a history of intermittent swelling and pain of the involved gland associated with eating. Increased production of saliva during meals, which then passes through a partially obstructed salivary duct, leads to salivary retention and glandular swelling. Thus, a recurring pattern can develop, with varying periods of remission,7 eventually leading to an acute suppurative process or sialadenitis (described below). Chronic salivary disease can also be caused by stricture of a duct or, rarely, external compression by a tumor mass.
Examination often reveals an enlarged and often tender gland; conversely, chronic disease can lead to gland atrophy. Usually, only minimal saliva is able to be expressed from an obstructed duct. For a submandibular duct stone, bimanual palpation might reveal its position if it is located distally in the floor of the mouth; a proximal stone might not be palpable.
Continue to: Although US is operator-dependent...
Although US is operator-dependent, it is the imaging modality of choice for identifying sialolithiasis10 because it can identify gland architecture, duct dilation, and both radiolucent and radiopaque stones. For patients in whom US findings are normal despite a convincing clinical presentation of sialolithiasis, CT should be performed because small stones can be missed on US.11
Supportive measures for sialolithiasis are listed in the TABLE. Reserve antibiotics for patients who have signs or symptoms of infection, including pyrexia, trismus, and malaise. A beta-lactam antibiotic, such as amoxicillin–clavulanate, 875 mg orally bid, or a cephalosporin, such as cephalexin, 500 mg orally qid, are appropriate first-line options. Clindamycin, 300 mg orally tid, or metronidazole, 500 mg orally tid, are acceptable alternatives. When signs or symptoms are persistent or recurrent, refer the patient for a surgical opinion.
Stones located in the floor of the mouth are usually excised through an intraoral approach. In the past, gland excision was advocated when a sialolith was found more proximally within the gland parenchyma. More recently, however, sialendoscopy, involving insertion of a small, semirigid endoscope into the salivary duct, has been shown safe and effective for removing a stone; successful removal, in as many as 80% of cases, increases to 90% when performed using a minimally invasive surgical technique.12 Although sialendoscopy is effective, the technique cannot always treat the underlying abnormality of the salivary gland; gland excision is therefore warranted in some cases.
Last, extracorporeal shock wave therapy is aimed at fragmenting salivary stones before retrieval. Results are variable, however, and treatment should be guided by an otolaryngologist.13,14
Sialadenitis (bacterial and viral infection). Acute suppurative sialadenitis occurs secondary to retrograde ductal bacterial infection. The parotid gland is most frequently involved,15 although submandibular sialadenitis is not uncommon. Patients usually present with sudden-onset unilateral, painful swelling.
Continue to: Pathophysiology involves...
Pathophysiology involves dehydration or decreased oral intake leading to salivary stasis and subsequent bacterial migration into the gland. Medically debilitated and postoperative patients are therefore at greater risk; so are patients with diabetes mellitus, poor oral hygiene, Sjögren’s syndrome, hypothyroidism, or renal failure.16 Certain medications, including anticholinergics, can also predispose to hyposalivation.17
(As discussed, sialolithiasis and stricture of salivary ducts can also cause acute bacterial infection; in such cases, however, the typical presentation is one of chronic or recurrent infection.)
Examination might reveal an exquisitely tender, indurated, and inflamed gland; pus can often be expressed from the respective intraoral orifice. Any expressed pus should be sent for culture to guide antibiotic therapy.
Treatment should focus on hydration, oral hygiene, and antibiotics, while reversing or minimizing any underlying contributing medical condition. Warm compresses applied to the involved gland, massage, and sialagogues, such as lemon drops or sugar-free lollipops, can stimulate salivary flow and prevent stasis.
More than 80% of infections are caused by Staphylococcus aureus17; anaerobic and mixed infections have also been recognized.A beta-lactam penicillin, such as amoxicillin-clavulanate, is the antibiotic of choice. A patient who is systemically unwell should be treated as an inpatient with nafcillin and metronidazole. Methicillin-resistant S aureus must also be considered in patients with comorbid disease, such as diabetes mellitus or intravenous drug use, or in patients residing in an area of substantial incidence of methicillin-resistant S aureus. In those cases, substitute vancomycin or linezolid for nafcillin.18
Continue to: Less commonly...
Less commonly, abscess can form, with the patient presenting as systemically unwell with a fluctuant mass. If the diagnosis is unclear or the patient does not improve, abscess can be confirmed by US. Expedient surgical review and inpatient admission can then be arranged.
Unlike bacterial sialadenitis, causes of viral sialadenitis are often bilateral. Mumps (a paramyxovirus) is the most common viral cause, affecting primarily children < 15 years.19 The parotid glands are most often involved, with inflammation and edema causing significant pain because of increasing intraparotid pressure as expansion of the gland is limited by its tense fibrous capsule. Complications of mumps include orchitis, meningitis, pancreatitis, and oophoritis.
Mumps is highly contagious; it is spread through contact with airborne saliva droplets, with viral entry through the nose or mouth, followed by proliferation in the salivary glands or on surface epithelium of the respiratory tract.7 Diagnosis is confirmed by viral serology. A positive test of serum immunoglobulin M confirms the diagnosis, but this test should not be performed until 3 days after onset of symptoms because a false-negative result is otherwise possible.20 Immunoglobulin G serologic testing can further aid diagnosis; the titer is measured approximately 4 days after onset of symptoms and again 2 to 3 weeks later. A 4-fold rise in titer confirms mumps.
Other viral infections that can cause sialadenitis include Epstein-Barr virus, cytomegalovirus, human immunodeficiency virus, coxsackievirus, and influenza. Treatment is supportive: analgesia, hydration, oral hygiene, and rest. Inflammation might take weeks to resolve, but expect complete resolution. For a patient who has significant trismus, poor oral intake, or a potentially threatened airway, inpatient care should be provided.
Recurrent parotitis of childhood is an inflammatory condition that usually affects one, but at times both, parotid glands. It is characterized by episodes of painful swelling. Incidence peaks at 3 to 6 years of age.7 Episodes can be frequent, occurring 1 to 5 times a year and lasting 3 to 7 days—sometimes longer—and usually resolving without treatment.
Continue to: The precise etiology...
The precise etiology of recurrent parotitis of childhood is unclear; possibly, saliva aggregates to form obstructive mucous plugs, thus causing stasis and swelling of the gland. As pressure builds, spontaneous plug extrusion occurs and symptoms resolve, provided infection is not a factor. US demonstrates multiple round, hypoechoic areas consistent with duct dilation, and surrounding infiltration by lymphocytes.1
Supportive care—adequate hydration, gland massage, warm compresses, and sialogogues—are mainstays of treatment. Fever and malaise warrant treatment with oral antibiotics. Sialadenoscopy, which can be considered in children with frequent episodes, can decrease the frequency and severity of episodes.21 The condition usually resolves spontaneously at puberty.
Ask: Does the patient have dry mouth?
In-depth review of xerostomia is beyond the scope of this article. Causes include Sjögren's syndrome, immunoglobulin G4-related sialadenitis, sarcoidosis, radiation therapy, diabetes, chronic infection, and medications—in particular those with anticholinergic effects.
Treatment of xerostomia includes saliva substitutes, sialagogues, and, for oral candidiasis, antifungals. Muscarinic cholinergic stimulators, such as pilocarpine, 5 mg qid have been used with some success22; patients should be advised of potential adverse effects with these agents, including sweating, urinary frequency, flushing, and chills.
CORRESPONDENCE
Shankar Haran, MBBS, ENT Department, Townsville Hospital, 100 Angus Smith Dr, Douglas, Queensland, Australia 4814; [email protected].
1. de Oliveira FA, Duarte EC, Taveira CT, et al. Salivary gland tumor: a review of 599 cases in a Brazilian population. Head Neck Pathol. 2009;3:271-275.
2. Spiro RH. Salivary neoplasms: overview of a 35-year experience with 2,807 patients. Head Neck Surg. 1986;8:177-184.
3. Bova R. A guide to salivary gland disorders. Medicine Today. 2006;7:44-48.
4. Zhang S, Bao R, Bagby J, et al. Fine needle aspiration of salivary glands: 5-year experience from a single academic center. Acta Cytol. 2009;53:375-382.
5. Bova R, Saylor A, Coman WB. Parotidectomy: review of treatment and outcomes. ANZ J Surg. 2004;74:563-568.
6. Sood S, McGurk M, Vaz F. Management of salivary gland tumours: United Kingdom National Multidisciplinary Guidelines. J Laryngol Otol. 2016;130:S142-S149.
7. Mandel L. Salivary gland disorders. Med Clin North Am. 2014;98:1407-1449.
8. Mandel L, Abai S. Diagnosing bulimia nervosa with parotid gland swelling. J Am Dent Assoc. 2004;135:613–616.
9. Lustmann J, Regev E, Melamed Y. Sialolithiasis. A survey on 245 patients and a review of literature. Int J Oral Maxillofac Surg. 1990;19:135–138.
10. Vogl TJ, Al-Nawas B, Beutner D, et al. Updated S2K AWMF guideline for the diagnosis and follow-up of obstructive sialadenitis—relevance for radiologic imaging. Rofo. 2014;186:843-846.
11. Schwarz D, Kabbasch C, Scheer M, et al. Comparative analysis of sialendoscopy, sonography, and CBCT in the detection of sialolithiasis. Laryngoscope. 2015;125:1098–1101.
12. Atienza G, López-Cedrún JL. Management of obstructive salivary disorders by sialendoscopy: a systematic review. Br J Oral Maxillofac Surg. 2015;53:507-519.
13. Escudier MP, Brown JE, Putcha V, et al. Factors influencing the outcome of extracorporeal shock wave lithotripsy in the management of salivary calculi. Laryngoscope. 2010;120:1545-1549.
14. Koch M, Schapher M, Mantsopoulos K, et al. Multimodal treatment in difficult sialolithiasis: Role of extracorporeal shock-wave lithotripsy and intraductal pneumatic lithotripsy. Laryngoscope. 2018;128:E332-E338.
15. McQuone SJ. Acute viral and bacterial infections of the salivary glands. Otolaryngol Clin North Am. 1999;32:793-811.
16. O’Neil C, Sidhu S. Salivary gland disorders. Australian Doctor. 2011;28:19-25.
17. Mandel L. Differentiating acute suppurative parotitis from acute exacerbation of a chronic parotitis: case reports. J Oral Maxillofac Surg. 2008;66:1964-1968.
18. Chow AW. Suppurative parotitis in adults. UpToDate.com. www.uptodate.com/contents/suppurative-parotitis-in-adults. Accessed September 25, 2019.
19. Katz SL, Gershon AA, Hotez PJ. Infectious Diseases of Children. New York, NY: Mosby Year Book; 1998:280-289.
20. Krause CH, Molyneaux PJ, Ho-Yen DO, et al. Comparison of mumps-IgM ELISAs in acute infection. J Clin Virol. 2007;38:153-156.
21. Quenin S, Plouin-Gaudon I, Marchal F, et al. Juvenile recurrent parotitis: sialendoscopic approach. Arch Otolaryngol Head Neck Surg. 2008;134:715-719.
22. Papas AS, Sherrer YS, Charney M, et al. Successful treatment of dry mouth and dry eye symptoms in Sjögren’s syndrome patients with oral pilocarpine: a randomized, placebo-controlled, dose-adjustment study. J Clin Rheumatol. 2004;10:169-177.
1. de Oliveira FA, Duarte EC, Taveira CT, et al. Salivary gland tumor: a review of 599 cases in a Brazilian population. Head Neck Pathol. 2009;3:271-275.
2. Spiro RH. Salivary neoplasms: overview of a 35-year experience with 2,807 patients. Head Neck Surg. 1986;8:177-184.
3. Bova R. A guide to salivary gland disorders. Medicine Today. 2006;7:44-48.
4. Zhang S, Bao R, Bagby J, et al. Fine needle aspiration of salivary glands: 5-year experience from a single academic center. Acta Cytol. 2009;53:375-382.
5. Bova R, Saylor A, Coman WB. Parotidectomy: review of treatment and outcomes. ANZ J Surg. 2004;74:563-568.
6. Sood S, McGurk M, Vaz F. Management of salivary gland tumours: United Kingdom National Multidisciplinary Guidelines. J Laryngol Otol. 2016;130:S142-S149.
7. Mandel L. Salivary gland disorders. Med Clin North Am. 2014;98:1407-1449.
8. Mandel L, Abai S. Diagnosing bulimia nervosa with parotid gland swelling. J Am Dent Assoc. 2004;135:613–616.
9. Lustmann J, Regev E, Melamed Y. Sialolithiasis. A survey on 245 patients and a review of literature. Int J Oral Maxillofac Surg. 1990;19:135–138.
10. Vogl TJ, Al-Nawas B, Beutner D, et al. Updated S2K AWMF guideline for the diagnosis and follow-up of obstructive sialadenitis—relevance for radiologic imaging. Rofo. 2014;186:843-846.
11. Schwarz D, Kabbasch C, Scheer M, et al. Comparative analysis of sialendoscopy, sonography, and CBCT in the detection of sialolithiasis. Laryngoscope. 2015;125:1098–1101.
12. Atienza G, López-Cedrún JL. Management of obstructive salivary disorders by sialendoscopy: a systematic review. Br J Oral Maxillofac Surg. 2015;53:507-519.
13. Escudier MP, Brown JE, Putcha V, et al. Factors influencing the outcome of extracorporeal shock wave lithotripsy in the management of salivary calculi. Laryngoscope. 2010;120:1545-1549.
14. Koch M, Schapher M, Mantsopoulos K, et al. Multimodal treatment in difficult sialolithiasis: Role of extracorporeal shock-wave lithotripsy and intraductal pneumatic lithotripsy. Laryngoscope. 2018;128:E332-E338.
15. McQuone SJ. Acute viral and bacterial infections of the salivary glands. Otolaryngol Clin North Am. 1999;32:793-811.
16. O’Neil C, Sidhu S. Salivary gland disorders. Australian Doctor. 2011;28:19-25.
17. Mandel L. Differentiating acute suppurative parotitis from acute exacerbation of a chronic parotitis: case reports. J Oral Maxillofac Surg. 2008;66:1964-1968.
18. Chow AW. Suppurative parotitis in adults. UpToDate.com. www.uptodate.com/contents/suppurative-parotitis-in-adults. Accessed September 25, 2019.
19. Katz SL, Gershon AA, Hotez PJ. Infectious Diseases of Children. New York, NY: Mosby Year Book; 1998:280-289.
20. Krause CH, Molyneaux PJ, Ho-Yen DO, et al. Comparison of mumps-IgM ELISAs in acute infection. J Clin Virol. 2007;38:153-156.
21. Quenin S, Plouin-Gaudon I, Marchal F, et al. Juvenile recurrent parotitis: sialendoscopic approach. Arch Otolaryngol Head Neck Surg. 2008;134:715-719.
22. Papas AS, Sherrer YS, Charney M, et al. Successful treatment of dry mouth and dry eye symptoms in Sjögren’s syndrome patients with oral pilocarpine: a randomized, placebo-controlled, dose-adjustment study. J Clin Rheumatol. 2004;10:169-177.
PRACTICE RECOMMENDATIONS
› Use ultrasonography for initial imaging of a salivary gland. A
› Refer patients with the following findings for further specialty evaluation: abscess, inflammation unresponsive to medical care, recurrent or chronic symptoms, suspected neoplasm (for excision), and suspected sialolithiasis. A
Strength of recommendation (SOR)
A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series
Painful ulcers on gingiva, tongue, and buccal mucosa
A 29-year-old man with no prior history of mouth sores abruptly developed many 1- to 1.5-mm blisters on the gingiva (FIGURE 1A),tongue (FIGURE 1B), and buccal mucosa (FIGURE 1C), which evolved into small erosions accompanied by a low-grade fever 5 days prior to presentation. The patient had no history of any dermatologic conditions or systemic illnesses and was taking no medication.
WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?
Diagnosis: Acute primary herpetic gingivostomatitis
Herpes simplex virus (HSV) is the causative agent for acute primary herpetic gingivostomatitis.1 HSV-1 is primarily responsible for oral mucosal infections, while HSV-2 is implicated in most genital and cutaneous lower body lesions.1 Herpetic gingivostomatitis often presents as a sudden vesiculoulcerative eruption anywhere in the mouth, including the perioral skin, vermillion border, gingiva, tongue, or buccal mucosa.2 Associated symptoms include malaise, headache, fever, and cervical lymphadenopathy; however, most occurrences are subclinical or asymptomatic.2
A diagnosis that’s more common in children. Primary HSV occurs in people who have not previously been exposed to the virus. While it is an infection that classically presents in childhood, it is not limited to this group. Manifestations often are more severe in adults.1
Following an incubation period of a few days to 3 weeks, the primary infection typically lasts 10 to 14 days.1,2 Recurrence is highly variable and generally less severe than primary infection, with grouped vesicles often recurring in the same spot with each recurrence on the vermillion border of the lip. Triggers for reactivation include immunosuppression, pregnancy, fever, UV radiation, or trauma.1,2
Differential includes other conditions with mucosal lesions
Acute herpetic gingivostomatitis must be distinguished from other disease processes that cause ulcerative mucosal lesions.
Aphthous stomatitis (canker sores) is the most common ulcerative disease of the oral mucosa.3 It presents as painful, punched-out, shallow ulcers with a yellowish gray pseudomembranous center and surrounding erythema.3 No definitive etiology has been established; however, aphthae often occur after trauma.
Continue to: Herpangina...
Herpangina is caused by coxsackie A virus and primarily is seen in infants and children younger than 5.4 The papulovesicular lesions primarily affect the posterior oral cavity, including the soft palate, anterior tonsillar pillars, and uvula.4
Allergic contact dermatitis is precipitated by contact with an allergen and presents with pain or pruritus. Lesions are erythematous with vesicles, erosions, ulcers, or hyperkeratosis that gradually resolve after withdrawal of the causative allergen.5
Pemphigus vulgaris. Oral ulcerations of the buccal mucosa and gingiva are the first manifestation of pemphigus vulgaris in the majority of patients, with skin blisters occurring months to years later over areas exposed to frictional stress.6 Skin sloughs may be seen in response to frictional stress (Nikolsky sign).6
The new Dx gold standard is PCR
Acute herpetic gingivostomatitis usually is diagnosed by history and hallmark clinical signs and symptoms.1 In this case, our patient presented with a sudden eruption of painful blisters on multiple areas of the oral mucosa associated with fever. The diagnosis can be confirmed by viral culture, serology with anti-HSV IgM and IgG, Tzanck preparation, immunofluorescence, and polymerase chain reaction (PCR).1 Viral culture has been the gold standard for mucosal HSV diagnosis; however, PCR is emerging as the new gold standard because of its unrivaled sensitivity, specificity, and rapid turnaround time.7,8 Specimens for PCR are submitted using a swab of infected cells placed in the same viral transport medium used for HSV cultures.
Our patient’s culture was positive for HSV-1.
Continue to: Prompt use of antivirals is key
Prompt use of antivirals is key
Treatment of acute HSV gingivostomatitis involves symptomatic management with topical anesthetics, oral analgesics, and normal saline rinses.1 Acyclovir is an established therapy; however, it has poor bioavailability and gastrointestinal absorption.1 Valacyclovir has improved bioavailability and is well tolerated.1 For primary herpes gingivostomatitis, we favor 1 g twice daily for 7 days.1 Our patient responded well to this valacyclovir regimen and healed completely in 1 week.
CORRESPONDENCE
Robert T. Brodell, MD, 2500 N State St, Jackson, MS 39216; [email protected]
1. Ajar AH, Chauvin PJ. Acute herpetic gingivostomatitis in adults: a review of 13 cases, including diagnosis and management. J Can Dent Assoc. 2002;68:247-251.
2. George AK, Anil S. Acute herpetic gingivostomatitis associated with herpes simplex virus 2: report of a case. J Int Oral Health. 2014;6:99-102.
3. Akintoye SO, Greenburg MS. Recurrent aphthous stomatitis. Dent Clin N Am. 2014;58:281-297.
4. Scott LA, Stone MS. Viral exanthems. Dermatol Online J. 2003;9:4.
5. Feller L, Wood NH, Khammissa RA, et al. Review: allergic contact stomatitis. Oral Surg Oral Med Oral Pathol Oral Radiol. 2017;123:559-565.
6. Bascones-Martinez A, Munoz-Corcuera M, Bascones-Ilundain C, et al. Oral manifestations of pemphigus vulgaris: clinical presentation, differential diagnosis and management. J Clin Exp Dermatol Res. 2010;1:112.
7. LeGoff J, Péré H, Bélec L. Diagnosis of genital herpes simplex virus infection in the clinical laboratory. Virol J. 2014;11:83.
8. Centers for Disease Control and Prevention. Genital HSV infections. www.cdc.gov/std/tg2015/herpes.htm. Updated June 4, 2015. Accessed September 26, 2019.
A 29-year-old man with no prior history of mouth sores abruptly developed many 1- to 1.5-mm blisters on the gingiva (FIGURE 1A),tongue (FIGURE 1B), and buccal mucosa (FIGURE 1C), which evolved into small erosions accompanied by a low-grade fever 5 days prior to presentation. The patient had no history of any dermatologic conditions or systemic illnesses and was taking no medication.
WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?
Diagnosis: Acute primary herpetic gingivostomatitis
Herpes simplex virus (HSV) is the causative agent for acute primary herpetic gingivostomatitis.1 HSV-1 is primarily responsible for oral mucosal infections, while HSV-2 is implicated in most genital and cutaneous lower body lesions.1 Herpetic gingivostomatitis often presents as a sudden vesiculoulcerative eruption anywhere in the mouth, including the perioral skin, vermillion border, gingiva, tongue, or buccal mucosa.2 Associated symptoms include malaise, headache, fever, and cervical lymphadenopathy; however, most occurrences are subclinical or asymptomatic.2
A diagnosis that’s more common in children. Primary HSV occurs in people who have not previously been exposed to the virus. While it is an infection that classically presents in childhood, it is not limited to this group. Manifestations often are more severe in adults.1
Following an incubation period of a few days to 3 weeks, the primary infection typically lasts 10 to 14 days.1,2 Recurrence is highly variable and generally less severe than primary infection, with grouped vesicles often recurring in the same spot with each recurrence on the vermillion border of the lip. Triggers for reactivation include immunosuppression, pregnancy, fever, UV radiation, or trauma.1,2
Differential includes other conditions with mucosal lesions
Acute herpetic gingivostomatitis must be distinguished from other disease processes that cause ulcerative mucosal lesions.
Aphthous stomatitis (canker sores) is the most common ulcerative disease of the oral mucosa.3 It presents as painful, punched-out, shallow ulcers with a yellowish gray pseudomembranous center and surrounding erythema.3 No definitive etiology has been established; however, aphthae often occur after trauma.
Continue to: Herpangina...
Herpangina is caused by coxsackie A virus and primarily is seen in infants and children younger than 5.4 The papulovesicular lesions primarily affect the posterior oral cavity, including the soft palate, anterior tonsillar pillars, and uvula.4
Allergic contact dermatitis is precipitated by contact with an allergen and presents with pain or pruritus. Lesions are erythematous with vesicles, erosions, ulcers, or hyperkeratosis that gradually resolve after withdrawal of the causative allergen.5
Pemphigus vulgaris. Oral ulcerations of the buccal mucosa and gingiva are the first manifestation of pemphigus vulgaris in the majority of patients, with skin blisters occurring months to years later over areas exposed to frictional stress.6 Skin sloughs may be seen in response to frictional stress (Nikolsky sign).6
The new Dx gold standard is PCR
Acute herpetic gingivostomatitis usually is diagnosed by history and hallmark clinical signs and symptoms.1 In this case, our patient presented with a sudden eruption of painful blisters on multiple areas of the oral mucosa associated with fever. The diagnosis can be confirmed by viral culture, serology with anti-HSV IgM and IgG, Tzanck preparation, immunofluorescence, and polymerase chain reaction (PCR).1 Viral culture has been the gold standard for mucosal HSV diagnosis; however, PCR is emerging as the new gold standard because of its unrivaled sensitivity, specificity, and rapid turnaround time.7,8 Specimens for PCR are submitted using a swab of infected cells placed in the same viral transport medium used for HSV cultures.
Our patient’s culture was positive for HSV-1.
Continue to: Prompt use of antivirals is key
Prompt use of antivirals is key
Treatment of acute HSV gingivostomatitis involves symptomatic management with topical anesthetics, oral analgesics, and normal saline rinses.1 Acyclovir is an established therapy; however, it has poor bioavailability and gastrointestinal absorption.1 Valacyclovir has improved bioavailability and is well tolerated.1 For primary herpes gingivostomatitis, we favor 1 g twice daily for 7 days.1 Our patient responded well to this valacyclovir regimen and healed completely in 1 week.
CORRESPONDENCE
Robert T. Brodell, MD, 2500 N State St, Jackson, MS 39216; [email protected]
A 29-year-old man with no prior history of mouth sores abruptly developed many 1- to 1.5-mm blisters on the gingiva (FIGURE 1A),tongue (FIGURE 1B), and buccal mucosa (FIGURE 1C), which evolved into small erosions accompanied by a low-grade fever 5 days prior to presentation. The patient had no history of any dermatologic conditions or systemic illnesses and was taking no medication.
WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?
Diagnosis: Acute primary herpetic gingivostomatitis
Herpes simplex virus (HSV) is the causative agent for acute primary herpetic gingivostomatitis.1 HSV-1 is primarily responsible for oral mucosal infections, while HSV-2 is implicated in most genital and cutaneous lower body lesions.1 Herpetic gingivostomatitis often presents as a sudden vesiculoulcerative eruption anywhere in the mouth, including the perioral skin, vermillion border, gingiva, tongue, or buccal mucosa.2 Associated symptoms include malaise, headache, fever, and cervical lymphadenopathy; however, most occurrences are subclinical or asymptomatic.2
A diagnosis that’s more common in children. Primary HSV occurs in people who have not previously been exposed to the virus. While it is an infection that classically presents in childhood, it is not limited to this group. Manifestations often are more severe in adults.1
Following an incubation period of a few days to 3 weeks, the primary infection typically lasts 10 to 14 days.1,2 Recurrence is highly variable and generally less severe than primary infection, with grouped vesicles often recurring in the same spot with each recurrence on the vermillion border of the lip. Triggers for reactivation include immunosuppression, pregnancy, fever, UV radiation, or trauma.1,2
Differential includes other conditions with mucosal lesions
Acute herpetic gingivostomatitis must be distinguished from other disease processes that cause ulcerative mucosal lesions.
Aphthous stomatitis (canker sores) is the most common ulcerative disease of the oral mucosa.3 It presents as painful, punched-out, shallow ulcers with a yellowish gray pseudomembranous center and surrounding erythema.3 No definitive etiology has been established; however, aphthae often occur after trauma.
Continue to: Herpangina...
Herpangina is caused by coxsackie A virus and primarily is seen in infants and children younger than 5.4 The papulovesicular lesions primarily affect the posterior oral cavity, including the soft palate, anterior tonsillar pillars, and uvula.4
Allergic contact dermatitis is precipitated by contact with an allergen and presents with pain or pruritus. Lesions are erythematous with vesicles, erosions, ulcers, or hyperkeratosis that gradually resolve after withdrawal of the causative allergen.5
Pemphigus vulgaris. Oral ulcerations of the buccal mucosa and gingiva are the first manifestation of pemphigus vulgaris in the majority of patients, with skin blisters occurring months to years later over areas exposed to frictional stress.6 Skin sloughs may be seen in response to frictional stress (Nikolsky sign).6
The new Dx gold standard is PCR
Acute herpetic gingivostomatitis usually is diagnosed by history and hallmark clinical signs and symptoms.1 In this case, our patient presented with a sudden eruption of painful blisters on multiple areas of the oral mucosa associated with fever. The diagnosis can be confirmed by viral culture, serology with anti-HSV IgM and IgG, Tzanck preparation, immunofluorescence, and polymerase chain reaction (PCR).1 Viral culture has been the gold standard for mucosal HSV diagnosis; however, PCR is emerging as the new gold standard because of its unrivaled sensitivity, specificity, and rapid turnaround time.7,8 Specimens for PCR are submitted using a swab of infected cells placed in the same viral transport medium used for HSV cultures.
Our patient’s culture was positive for HSV-1.
Continue to: Prompt use of antivirals is key
Prompt use of antivirals is key
Treatment of acute HSV gingivostomatitis involves symptomatic management with topical anesthetics, oral analgesics, and normal saline rinses.1 Acyclovir is an established therapy; however, it has poor bioavailability and gastrointestinal absorption.1 Valacyclovir has improved bioavailability and is well tolerated.1 For primary herpes gingivostomatitis, we favor 1 g twice daily for 7 days.1 Our patient responded well to this valacyclovir regimen and healed completely in 1 week.
CORRESPONDENCE
Robert T. Brodell, MD, 2500 N State St, Jackson, MS 39216; [email protected]
1. Ajar AH, Chauvin PJ. Acute herpetic gingivostomatitis in adults: a review of 13 cases, including diagnosis and management. J Can Dent Assoc. 2002;68:247-251.
2. George AK, Anil S. Acute herpetic gingivostomatitis associated with herpes simplex virus 2: report of a case. J Int Oral Health. 2014;6:99-102.
3. Akintoye SO, Greenburg MS. Recurrent aphthous stomatitis. Dent Clin N Am. 2014;58:281-297.
4. Scott LA, Stone MS. Viral exanthems. Dermatol Online J. 2003;9:4.
5. Feller L, Wood NH, Khammissa RA, et al. Review: allergic contact stomatitis. Oral Surg Oral Med Oral Pathol Oral Radiol. 2017;123:559-565.
6. Bascones-Martinez A, Munoz-Corcuera M, Bascones-Ilundain C, et al. Oral manifestations of pemphigus vulgaris: clinical presentation, differential diagnosis and management. J Clin Exp Dermatol Res. 2010;1:112.
7. LeGoff J, Péré H, Bélec L. Diagnosis of genital herpes simplex virus infection in the clinical laboratory. Virol J. 2014;11:83.
8. Centers for Disease Control and Prevention. Genital HSV infections. www.cdc.gov/std/tg2015/herpes.htm. Updated June 4, 2015. Accessed September 26, 2019.
1. Ajar AH, Chauvin PJ. Acute herpetic gingivostomatitis in adults: a review of 13 cases, including diagnosis and management. J Can Dent Assoc. 2002;68:247-251.
2. George AK, Anil S. Acute herpetic gingivostomatitis associated with herpes simplex virus 2: report of a case. J Int Oral Health. 2014;6:99-102.
3. Akintoye SO, Greenburg MS. Recurrent aphthous stomatitis. Dent Clin N Am. 2014;58:281-297.
4. Scott LA, Stone MS. Viral exanthems. Dermatol Online J. 2003;9:4.
5. Feller L, Wood NH, Khammissa RA, et al. Review: allergic contact stomatitis. Oral Surg Oral Med Oral Pathol Oral Radiol. 2017;123:559-565.
6. Bascones-Martinez A, Munoz-Corcuera M, Bascones-Ilundain C, et al. Oral manifestations of pemphigus vulgaris: clinical presentation, differential diagnosis and management. J Clin Exp Dermatol Res. 2010;1:112.
7. LeGoff J, Péré H, Bélec L. Diagnosis of genital herpes simplex virus infection in the clinical laboratory. Virol J. 2014;11:83.
8. Centers for Disease Control and Prevention. Genital HSV infections. www.cdc.gov/std/tg2015/herpes.htm. Updated June 4, 2015. Accessed September 26, 2019.
20-year-old male college basketball prospect • wrist pain after falling on wrist • normal ROM • pain with active/passive wrist extension • Dx?
THE CASE
A 20-year-old man presented to our family medicine clinic with right wrist pain 4 days after falling on his wrist and hand while playing basketball. He denied any other previous injury or trauma. The pain was unchanged since the injury occurred.
Examination demonstrated mild edema over the palmar and ulnar aspect of the patient’s right wrist with no apparent ecchymosis. He had normal range of motion of his right wrist and hand. However, he experienced pain with active and passive wrist extension and ulnar deviation. There was significant tenderness in the palmar and ulnar aspects of his right wrist just distal to the ulnar styloid process.
THE DIAGNOSIS
Standard plain x-rays of the right wrist revealed an isolated fracture of the body of the triquetrum (FIGURE 1). Since the patient refused to have a cast placed, his wrist was immobilized with a wrist brace. By Day 16 post injury, the pain and edema had improved significantly. After talking with the patient about the potential risks and benefits of continuing to play basketball—and despite our recommendation that he not play—he decided to continue playing since he was a college basketball prospect.
At 4 weeks post injury, x-rays demonstrated mild interval healing (FIGURE 2). At the 8-week visit, the patient had only very mild pain and tenderness, and x-ray images showed improvement (FIGURE 3). Within a few months, his symptoms resolved completely. No further imaging was performed.
DISCUSSION
In general, carpal fractures are uncommon.1 The triquetrum is the second most commonly injured carpal bone, involved in up to 18% of all carpal fractures.2,3 Triquetrum fractures most commonly occur as isolated injuries and are typically classified in 2 general categories: avulsion fractures (dorsal cortex or volar cortex) and fractures of the triquetrum body.4-8 Isolated avulsion fractures of the triquetral dorsal cortex are relatively common, occurring in about 95% of triquetrum injuries.4-9 Isolated fractures of the triquetrum body are less common, occurring in about 4% of triquetrum injuries, and can go unnoticed on conventional x-rays.4-9
Basketball presents a unique risk for hand or wrist fracture due to its high-impact nature, hard playing surfaces, and frequent use of the hands for dribbling, shooting, rebounding, and passing the ball.
In a retrospective study of sports-related fractures conducted at the Royal Infirmary of Edinburgh, basketball had the highest incidence of carpal injuries compared with other sports, including football, rugby, skiing, snowboarding, and ice-skating.4 Similarly, a retrospective study conducted at the University of California, Los Angeles, found that of all Division 1 collegiate athletes at the school, basketball players had the highest incidence of primary fractures, and the most common fracture location was the hand.10
Continue to: An injury that's easy to miss
An injury that’s easy to miss
Because the incidence of hand and wrist injuries is high among basketball players, it is imperative that triquetrum body fractures are not missed or misdiagnosed as more common hand and wrist injuries, such as triquetral dorsal avulsion fractures.
Our patient, who had an isolated triquetrum body fracture, presented with focal tenderness on the palmar and ulnar aspects of his wrist and pain with ulnar deviation. Since triquetral body fractures often have a clinical presentation quite similar to that of triquetral dorsal avulsion fractures, patients presenting with symptoms of wrist tenderness and pain should be treated with a high degree of clinical suspicion.
With our patient, anteroposterior and lateral x-rays were sufficient to demonstrate an isolated triquetrum body fracture; however, triquetral fractures can be missed in up to 20% of x-rays.4 Both magnetic resonance imaging and computerized tomography are useful in diagnosing occult triquetrum fractures and should be used to confirm clinical suspicion when traditional x-rays are inconclusive.11,12
Management varies
Management of isolated triquetrum body fractures varies depending on the fracture pattern and the status of bone consolidation. Triquetral body fractures typically heal well; it’s very rare that there is a nonunion. As our patient’s fracture was nondisplaced and stable, brace immobilization for 4 weeks was sufficient to facilitate healing and restore long-term hand and wrist functionality. This course of treatment is consistent with other cases of nondisplaced triquetrum body fractures reported in the literature.13
Long-term outcomes. The literature is sparse regarding the long-term functional outcome of nonsurgical treatment for nondisplaced triquetrum body fractures. Multiple carpal fractures, displaced triquetrum body fractures, and persistent pain for multiple months after nonsurgical management all indicate the need for referral to orthopedic surgery. In instances of fracture displacement or nonunion, management tends to be surgical, with open reduction and internal fixation (ORIF) used in multiple cases of nonunion for isolated triquetrum body fractures.3,14 Any diagnostic imaging that reveals displacement, malunion, or nonunion of the fracture is an indication for referral to an orthopedic surgeon.
Continue to: Return to play
Return to play. There is no evidence-based return-to-play recommendation for patients with a triquetrum fracture. However, our patient continued to play basketball through the early stages of injury management because he was a collegiate prospect. While medical, social, and economic factors should be considered when discussing treatment options with athletes, injuries should be managed so that there is no long-term loss of function or risk of injury exacerbation. When discussing early return from injury with athletes who have outside pressure to return to play, it’s important to make them aware of the associated long- and short-term risks.15
THE TAKEAWAY
Management of an isolated triquetrum body fracture is typically straightforward; however, if the fracture is displaced, refer the patient to an orthopedic surgeon as ORIF may be required. For this reason, it’s important to be able to promptly identify isolated triquetrum body fractures and to avoid confusing them with triquetrum dorsal avulsion fractures.
Depending on the sport played and the severity of the injury, athletes with conservatively managed nondisplaced triquetral body fractures may be candidates for early return to play. Nonetheless, athletes should understand both the short- and the long-term risks of playing with an injury, and they should never be advised to continue playing with an injury if it jeopardizes their well-being or the long-term functionality of the affected body part.
CORRESPONDENCE
Morteza Khodaee, MD, MPH, University of Colorado School of Medicine, AFW Clinic, 3055 Roslyn Street, Denver, CO 80238; [email protected]
1. Suh N, Ek ET, Wolfe SW. Carpal fractures. J Hand Surg Am. 2014;39:785-791.
2. Hey HW, Chong AK, Murphy D. Prevalence of carpal fracture in Singapore. J Hand Surg Am. 2011;36:278-283.
3. Al Rashid M, Rasoli S, Khan WS. Non-union of isolated displaced triquetral body fracture—a case report. Ortop Traumatol Rehabil. 2012;14:71-74.
4. Becce F, Theumann N, Bollmann C, et al. Dorsal fractures of the triquetrum: MRI findings with an emphasis on dorsal carpal ligament injuries. AJR Am J Roentgenol. 2013;200:608-617.
5. Court-Brown CM, Wood AM, Aitken S. The epidemiology of acute sports-related fractures in adults. Injury. 2008;39:1365-1372.
6. Urch EY, Lee SK. Carpal fractures other than scaphoid. Clin Sports Med. 2015;34:51-67.
7. deWeber K. Triquetrum fractures. UpToDate. 2016. www.uptodate.com/contents/triquetrum-fractures. Accessed September 3, 2019.
8. Höcker K, Menschik A. Chip fractures of the triquetrum. Mechanism, classification and results. J Hand Surg Br. 1994;19:584-588.
9. Jarraya M, Hayashi D, Roemer FW, et al. Radiographically occult and subtle fractures: a pictorial review. Radiol Res Pract. 2013;2013:370169.
10. Hame SL, LaFemina JM, McAllister DR, et al. Fractures in the collegiate athlete. Am J Sports Med. 2004;32:446-451.
11. Hindman BW, Kulik WJ, Lee G, et al. Occult fractures of the carpals and metacarpals: demonstration by CT. AJR Am J Roentgenol. 1989;153:529-532.
12. Pierre-Jerome C, Moncayo V, Albastaki U, et al. Multiple occult wrist bone injuries and joint effusions: prevalence and distribution on MRI. Emerg Radiol. 2010;17:179-184.
13. Yildirim C, Akmaz I, Keklikçi K, et al. An unusual combined fracture pattern of the triquetrum. J Hand Surg Eur Vol. 2008;33:385-386.
14. Rasoli S, Ricks M, Packer G. Isolated displaced non-union of a triquetral body fracture: a case report. J Med Case Rep. 2012;6:54.
15. Strickland JW. Considerations for the treatment of the injured athlete. Clin Sports Med. 1998;17:397-400.
THE CASE
A 20-year-old man presented to our family medicine clinic with right wrist pain 4 days after falling on his wrist and hand while playing basketball. He denied any other previous injury or trauma. The pain was unchanged since the injury occurred.
Examination demonstrated mild edema over the palmar and ulnar aspect of the patient’s right wrist with no apparent ecchymosis. He had normal range of motion of his right wrist and hand. However, he experienced pain with active and passive wrist extension and ulnar deviation. There was significant tenderness in the palmar and ulnar aspects of his right wrist just distal to the ulnar styloid process.
THE DIAGNOSIS
Standard plain x-rays of the right wrist revealed an isolated fracture of the body of the triquetrum (FIGURE 1). Since the patient refused to have a cast placed, his wrist was immobilized with a wrist brace. By Day 16 post injury, the pain and edema had improved significantly. After talking with the patient about the potential risks and benefits of continuing to play basketball—and despite our recommendation that he not play—he decided to continue playing since he was a college basketball prospect.
At 4 weeks post injury, x-rays demonstrated mild interval healing (FIGURE 2). At the 8-week visit, the patient had only very mild pain and tenderness, and x-ray images showed improvement (FIGURE 3). Within a few months, his symptoms resolved completely. No further imaging was performed.
DISCUSSION
In general, carpal fractures are uncommon.1 The triquetrum is the second most commonly injured carpal bone, involved in up to 18% of all carpal fractures.2,3 Triquetrum fractures most commonly occur as isolated injuries and are typically classified in 2 general categories: avulsion fractures (dorsal cortex or volar cortex) and fractures of the triquetrum body.4-8 Isolated avulsion fractures of the triquetral dorsal cortex are relatively common, occurring in about 95% of triquetrum injuries.4-9 Isolated fractures of the triquetrum body are less common, occurring in about 4% of triquetrum injuries, and can go unnoticed on conventional x-rays.4-9
Basketball presents a unique risk for hand or wrist fracture due to its high-impact nature, hard playing surfaces, and frequent use of the hands for dribbling, shooting, rebounding, and passing the ball.
In a retrospective study of sports-related fractures conducted at the Royal Infirmary of Edinburgh, basketball had the highest incidence of carpal injuries compared with other sports, including football, rugby, skiing, snowboarding, and ice-skating.4 Similarly, a retrospective study conducted at the University of California, Los Angeles, found that of all Division 1 collegiate athletes at the school, basketball players had the highest incidence of primary fractures, and the most common fracture location was the hand.10
Continue to: An injury that's easy to miss
An injury that’s easy to miss
Because the incidence of hand and wrist injuries is high among basketball players, it is imperative that triquetrum body fractures are not missed or misdiagnosed as more common hand and wrist injuries, such as triquetral dorsal avulsion fractures.
Our patient, who had an isolated triquetrum body fracture, presented with focal tenderness on the palmar and ulnar aspects of his wrist and pain with ulnar deviation. Since triquetral body fractures often have a clinical presentation quite similar to that of triquetral dorsal avulsion fractures, patients presenting with symptoms of wrist tenderness and pain should be treated with a high degree of clinical suspicion.
With our patient, anteroposterior and lateral x-rays were sufficient to demonstrate an isolated triquetrum body fracture; however, triquetral fractures can be missed in up to 20% of x-rays.4 Both magnetic resonance imaging and computerized tomography are useful in diagnosing occult triquetrum fractures and should be used to confirm clinical suspicion when traditional x-rays are inconclusive.11,12
Management varies
Management of isolated triquetrum body fractures varies depending on the fracture pattern and the status of bone consolidation. Triquetral body fractures typically heal well; it’s very rare that there is a nonunion. As our patient’s fracture was nondisplaced and stable, brace immobilization for 4 weeks was sufficient to facilitate healing and restore long-term hand and wrist functionality. This course of treatment is consistent with other cases of nondisplaced triquetrum body fractures reported in the literature.13
Long-term outcomes. The literature is sparse regarding the long-term functional outcome of nonsurgical treatment for nondisplaced triquetrum body fractures. Multiple carpal fractures, displaced triquetrum body fractures, and persistent pain for multiple months after nonsurgical management all indicate the need for referral to orthopedic surgery. In instances of fracture displacement or nonunion, management tends to be surgical, with open reduction and internal fixation (ORIF) used in multiple cases of nonunion for isolated triquetrum body fractures.3,14 Any diagnostic imaging that reveals displacement, malunion, or nonunion of the fracture is an indication for referral to an orthopedic surgeon.
Continue to: Return to play
Return to play. There is no evidence-based return-to-play recommendation for patients with a triquetrum fracture. However, our patient continued to play basketball through the early stages of injury management because he was a collegiate prospect. While medical, social, and economic factors should be considered when discussing treatment options with athletes, injuries should be managed so that there is no long-term loss of function or risk of injury exacerbation. When discussing early return from injury with athletes who have outside pressure to return to play, it’s important to make them aware of the associated long- and short-term risks.15
THE TAKEAWAY
Management of an isolated triquetrum body fracture is typically straightforward; however, if the fracture is displaced, refer the patient to an orthopedic surgeon as ORIF may be required. For this reason, it’s important to be able to promptly identify isolated triquetrum body fractures and to avoid confusing them with triquetrum dorsal avulsion fractures.
Depending on the sport played and the severity of the injury, athletes with conservatively managed nondisplaced triquetral body fractures may be candidates for early return to play. Nonetheless, athletes should understand both the short- and the long-term risks of playing with an injury, and they should never be advised to continue playing with an injury if it jeopardizes their well-being or the long-term functionality of the affected body part.
CORRESPONDENCE
Morteza Khodaee, MD, MPH, University of Colorado School of Medicine, AFW Clinic, 3055 Roslyn Street, Denver, CO 80238; [email protected]
THE CASE
A 20-year-old man presented to our family medicine clinic with right wrist pain 4 days after falling on his wrist and hand while playing basketball. He denied any other previous injury or trauma. The pain was unchanged since the injury occurred.
Examination demonstrated mild edema over the palmar and ulnar aspect of the patient’s right wrist with no apparent ecchymosis. He had normal range of motion of his right wrist and hand. However, he experienced pain with active and passive wrist extension and ulnar deviation. There was significant tenderness in the palmar and ulnar aspects of his right wrist just distal to the ulnar styloid process.
THE DIAGNOSIS
Standard plain x-rays of the right wrist revealed an isolated fracture of the body of the triquetrum (FIGURE 1). Since the patient refused to have a cast placed, his wrist was immobilized with a wrist brace. By Day 16 post injury, the pain and edema had improved significantly. After talking with the patient about the potential risks and benefits of continuing to play basketball—and despite our recommendation that he not play—he decided to continue playing since he was a college basketball prospect.
At 4 weeks post injury, x-rays demonstrated mild interval healing (FIGURE 2). At the 8-week visit, the patient had only very mild pain and tenderness, and x-ray images showed improvement (FIGURE 3). Within a few months, his symptoms resolved completely. No further imaging was performed.
DISCUSSION
In general, carpal fractures are uncommon.1 The triquetrum is the second most commonly injured carpal bone, involved in up to 18% of all carpal fractures.2,3 Triquetrum fractures most commonly occur as isolated injuries and are typically classified in 2 general categories: avulsion fractures (dorsal cortex or volar cortex) and fractures of the triquetrum body.4-8 Isolated avulsion fractures of the triquetral dorsal cortex are relatively common, occurring in about 95% of triquetrum injuries.4-9 Isolated fractures of the triquetrum body are less common, occurring in about 4% of triquetrum injuries, and can go unnoticed on conventional x-rays.4-9
Basketball presents a unique risk for hand or wrist fracture due to its high-impact nature, hard playing surfaces, and frequent use of the hands for dribbling, shooting, rebounding, and passing the ball.
In a retrospective study of sports-related fractures conducted at the Royal Infirmary of Edinburgh, basketball had the highest incidence of carpal injuries compared with other sports, including football, rugby, skiing, snowboarding, and ice-skating.4 Similarly, a retrospective study conducted at the University of California, Los Angeles, found that of all Division 1 collegiate athletes at the school, basketball players had the highest incidence of primary fractures, and the most common fracture location was the hand.10
Continue to: An injury that's easy to miss
An injury that’s easy to miss
Because the incidence of hand and wrist injuries is high among basketball players, it is imperative that triquetrum body fractures are not missed or misdiagnosed as more common hand and wrist injuries, such as triquetral dorsal avulsion fractures.
Our patient, who had an isolated triquetrum body fracture, presented with focal tenderness on the palmar and ulnar aspects of his wrist and pain with ulnar deviation. Since triquetral body fractures often have a clinical presentation quite similar to that of triquetral dorsal avulsion fractures, patients presenting with symptoms of wrist tenderness and pain should be treated with a high degree of clinical suspicion.
With our patient, anteroposterior and lateral x-rays were sufficient to demonstrate an isolated triquetrum body fracture; however, triquetral fractures can be missed in up to 20% of x-rays.4 Both magnetic resonance imaging and computerized tomography are useful in diagnosing occult triquetrum fractures and should be used to confirm clinical suspicion when traditional x-rays are inconclusive.11,12
Management varies
Management of isolated triquetrum body fractures varies depending on the fracture pattern and the status of bone consolidation. Triquetral body fractures typically heal well; it’s very rare that there is a nonunion. As our patient’s fracture was nondisplaced and stable, brace immobilization for 4 weeks was sufficient to facilitate healing and restore long-term hand and wrist functionality. This course of treatment is consistent with other cases of nondisplaced triquetrum body fractures reported in the literature.13
Long-term outcomes. The literature is sparse regarding the long-term functional outcome of nonsurgical treatment for nondisplaced triquetrum body fractures. Multiple carpal fractures, displaced triquetrum body fractures, and persistent pain for multiple months after nonsurgical management all indicate the need for referral to orthopedic surgery. In instances of fracture displacement or nonunion, management tends to be surgical, with open reduction and internal fixation (ORIF) used in multiple cases of nonunion for isolated triquetrum body fractures.3,14 Any diagnostic imaging that reveals displacement, malunion, or nonunion of the fracture is an indication for referral to an orthopedic surgeon.
Continue to: Return to play
Return to play. There is no evidence-based return-to-play recommendation for patients with a triquetrum fracture. However, our patient continued to play basketball through the early stages of injury management because he was a collegiate prospect. While medical, social, and economic factors should be considered when discussing treatment options with athletes, injuries should be managed so that there is no long-term loss of function or risk of injury exacerbation. When discussing early return from injury with athletes who have outside pressure to return to play, it’s important to make them aware of the associated long- and short-term risks.15
THE TAKEAWAY
Management of an isolated triquetrum body fracture is typically straightforward; however, if the fracture is displaced, refer the patient to an orthopedic surgeon as ORIF may be required. For this reason, it’s important to be able to promptly identify isolated triquetrum body fractures and to avoid confusing them with triquetrum dorsal avulsion fractures.
Depending on the sport played and the severity of the injury, athletes with conservatively managed nondisplaced triquetral body fractures may be candidates for early return to play. Nonetheless, athletes should understand both the short- and the long-term risks of playing with an injury, and they should never be advised to continue playing with an injury if it jeopardizes their well-being or the long-term functionality of the affected body part.
CORRESPONDENCE
Morteza Khodaee, MD, MPH, University of Colorado School of Medicine, AFW Clinic, 3055 Roslyn Street, Denver, CO 80238; [email protected]
1. Suh N, Ek ET, Wolfe SW. Carpal fractures. J Hand Surg Am. 2014;39:785-791.
2. Hey HW, Chong AK, Murphy D. Prevalence of carpal fracture in Singapore. J Hand Surg Am. 2011;36:278-283.
3. Al Rashid M, Rasoli S, Khan WS. Non-union of isolated displaced triquetral body fracture—a case report. Ortop Traumatol Rehabil. 2012;14:71-74.
4. Becce F, Theumann N, Bollmann C, et al. Dorsal fractures of the triquetrum: MRI findings with an emphasis on dorsal carpal ligament injuries. AJR Am J Roentgenol. 2013;200:608-617.
5. Court-Brown CM, Wood AM, Aitken S. The epidemiology of acute sports-related fractures in adults. Injury. 2008;39:1365-1372.
6. Urch EY, Lee SK. Carpal fractures other than scaphoid. Clin Sports Med. 2015;34:51-67.
7. deWeber K. Triquetrum fractures. UpToDate. 2016. www.uptodate.com/contents/triquetrum-fractures. Accessed September 3, 2019.
8. Höcker K, Menschik A. Chip fractures of the triquetrum. Mechanism, classification and results. J Hand Surg Br. 1994;19:584-588.
9. Jarraya M, Hayashi D, Roemer FW, et al. Radiographically occult and subtle fractures: a pictorial review. Radiol Res Pract. 2013;2013:370169.
10. Hame SL, LaFemina JM, McAllister DR, et al. Fractures in the collegiate athlete. Am J Sports Med. 2004;32:446-451.
11. Hindman BW, Kulik WJ, Lee G, et al. Occult fractures of the carpals and metacarpals: demonstration by CT. AJR Am J Roentgenol. 1989;153:529-532.
12. Pierre-Jerome C, Moncayo V, Albastaki U, et al. Multiple occult wrist bone injuries and joint effusions: prevalence and distribution on MRI. Emerg Radiol. 2010;17:179-184.
13. Yildirim C, Akmaz I, Keklikçi K, et al. An unusual combined fracture pattern of the triquetrum. J Hand Surg Eur Vol. 2008;33:385-386.
14. Rasoli S, Ricks M, Packer G. Isolated displaced non-union of a triquetral body fracture: a case report. J Med Case Rep. 2012;6:54.
15. Strickland JW. Considerations for the treatment of the injured athlete. Clin Sports Med. 1998;17:397-400.
1. Suh N, Ek ET, Wolfe SW. Carpal fractures. J Hand Surg Am. 2014;39:785-791.
2. Hey HW, Chong AK, Murphy D. Prevalence of carpal fracture in Singapore. J Hand Surg Am. 2011;36:278-283.
3. Al Rashid M, Rasoli S, Khan WS. Non-union of isolated displaced triquetral body fracture—a case report. Ortop Traumatol Rehabil. 2012;14:71-74.
4. Becce F, Theumann N, Bollmann C, et al. Dorsal fractures of the triquetrum: MRI findings with an emphasis on dorsal carpal ligament injuries. AJR Am J Roentgenol. 2013;200:608-617.
5. Court-Brown CM, Wood AM, Aitken S. The epidemiology of acute sports-related fractures in adults. Injury. 2008;39:1365-1372.
6. Urch EY, Lee SK. Carpal fractures other than scaphoid. Clin Sports Med. 2015;34:51-67.
7. deWeber K. Triquetrum fractures. UpToDate. 2016. www.uptodate.com/contents/triquetrum-fractures. Accessed September 3, 2019.
8. Höcker K, Menschik A. Chip fractures of the triquetrum. Mechanism, classification and results. J Hand Surg Br. 1994;19:584-588.
9. Jarraya M, Hayashi D, Roemer FW, et al. Radiographically occult and subtle fractures: a pictorial review. Radiol Res Pract. 2013;2013:370169.
10. Hame SL, LaFemina JM, McAllister DR, et al. Fractures in the collegiate athlete. Am J Sports Med. 2004;32:446-451.
11. Hindman BW, Kulik WJ, Lee G, et al. Occult fractures of the carpals and metacarpals: demonstration by CT. AJR Am J Roentgenol. 1989;153:529-532.
12. Pierre-Jerome C, Moncayo V, Albastaki U, et al. Multiple occult wrist bone injuries and joint effusions: prevalence and distribution on MRI. Emerg Radiol. 2010;17:179-184.
13. Yildirim C, Akmaz I, Keklikçi K, et al. An unusual combined fracture pattern of the triquetrum. J Hand Surg Eur Vol. 2008;33:385-386.
14. Rasoli S, Ricks M, Packer G. Isolated displaced non-union of a triquetral body fracture: a case report. J Med Case Rep. 2012;6:54.
15. Strickland JW. Considerations for the treatment of the injured athlete. Clin Sports Med. 1998;17:397-400.
Novel research aims to improve ED care in sickle cell disease
Several initiatives are in the works to improve the management of patients with sickle cell disease in the ED, experts said at a recent webinar held by the National Heart, Lung, and Blood Institute.
In 2014, the NHLBI released evidence-based guidelines for the management of patients with sickle cell disease. The expert panel provided recommendations on the treatment of acute complications of sickle cell disease, many of which are common reasons for ED visits.
Optimizing the treatment of acute complications, namely vasoocclusive crisis, is essential to ensure improved long-term outcomes, explained Paula Tanabe, PhD, of Duke University, Durham, N.C.
Pain management
While the majority of pain-related ED visits in sickle cell are the result of vasoocclusive crisis, other causes, such as acute chest syndrome, abdominal catastrophes, and splenic sequestration, are also important.
The hallmark of pain management in this population is rapid and aggressive treatment with intravenous opioids. The use of individualized doses is also important, but if not available, an sickle cell disease–specific pain protocol can be used, she explained.
Recent evidence has confirmed the benefit of using an individualized (patient-specific) dosing protocol. Dr. Tanabe reported the results of a randomized pilot study that compared two pain protocols for patients undergoing a vasoocclusive episode in the ED.
“The reason we pursued this project is to generate additional evidence beyond the expert panel,” she said.
The primary outcome of the study was the difference in pain scores from arrival to discharge between patients receiving an individualized or weight-based dosing protocol. Secondary outcomes included safety, pain experience, and side effects, among others.
The researchers found that patients who received an individualized protocol had significantly lower pain scores, compared with a standard weight-based protocol (between-protocol pain score difference, 15.6 plus or minus 5.0; P = .002).
Additionally, patients in the individualized dosing arm were admitted less often than those in the weight-based arm (P = .03), Dr. Tanabe reported.
The findings from the previous study formed the basis for an ongoing study that is further examining the impact of patient-specific dosing in patients who present with a vasoocclusive episode. The COMPARE VOE study is currently enrolling patients and is being funded by NHLBI.
The NHLBI also provides funding to eight Sickle Cell Disease Implementation Consortium sites throughout the United States. The objective of this grant funding is to help implement NHLBI recommendations in the emergency setting.
Quality improvement
“One area [that] we want to improve is how quickly we administer [analgesic therapy] to patients when they are experiencing a vasoocclusive episode,” said Caroline Freiermuth, MD, of the University of Cincinnati.
Some common barriers to delivering rapid analgesia in this setting include difficulties in obtaining intravenous access, high patient volumes, lack of education, and provider biases, she explained.
With respect to high patient volumes, one strategy that may help overcome this barrier is to triage patients as Emergency Severity Index level 2, allowing for accelerated room placement.
Sickle cell patients undergoing vasoocclusive crisis meet the criteria for level 2 based on morbidity, degree of pain, and the level of resources often required.
Another important strategy is improving education related to sickle cell disease, particularly the high morbidity and mortality seen in these patients, Dr. Freiermuth said.
“The median lifespan for patients with HbSS disease is in the 40s, basically half of the lifespan of a typical American,” she said.
At present, acute chest syndrome is the principal cause of death in patients with sickle cell disease, and most frequently occurs during a vasoocclusive episode. As a result, screening for this complication is essential to reduce mortality in the emergency setting.
Dr. Freiermuth explained that one of the best ways to prevent acute chest syndrome is to encourage the use of incentive spirometry in patients undergoing a vasoocclusive episode.
In order to increase the likelihood of obtaining intravenous access, the use of ultrasound may help guide placement. Educating nurses on the proper use of ultrasound-guided placement of intravenous catheters is one practical approach, she said.
Alternatively, opioid analgesia can be administered subcutaneously. Benefits of subcutaneous delivery include comparable pharmacokinetics, less pain, and a reduced likelihood of sterile abscesses that are often seen with intramuscular administration.
Dr. Freiermuth outlined the quality-improvement initiative being tested at her institution, which involves the administration of parenteral opioid therapy during triage for sickle cell patients undergoing a suspected vasoocclusive crisis. The initiative was developed with input from both the emergency and hematology departments at the site.
Early results have shown no significant changes using this approach, but the data is still preliminary. Initial feedback has revealed that time to room placement has been the greatest barrier, she reported.
Dr. Tanabe reported grant/research support from the National Institutes of Health and the Agency for Healthcare Research and Quality. Dr. Freiermuth reported research support from Pfizer.
Several initiatives are in the works to improve the management of patients with sickle cell disease in the ED, experts said at a recent webinar held by the National Heart, Lung, and Blood Institute.
In 2014, the NHLBI released evidence-based guidelines for the management of patients with sickle cell disease. The expert panel provided recommendations on the treatment of acute complications of sickle cell disease, many of which are common reasons for ED visits.
Optimizing the treatment of acute complications, namely vasoocclusive crisis, is essential to ensure improved long-term outcomes, explained Paula Tanabe, PhD, of Duke University, Durham, N.C.
Pain management
While the majority of pain-related ED visits in sickle cell are the result of vasoocclusive crisis, other causes, such as acute chest syndrome, abdominal catastrophes, and splenic sequestration, are also important.
The hallmark of pain management in this population is rapid and aggressive treatment with intravenous opioids. The use of individualized doses is also important, but if not available, an sickle cell disease–specific pain protocol can be used, she explained.
Recent evidence has confirmed the benefit of using an individualized (patient-specific) dosing protocol. Dr. Tanabe reported the results of a randomized pilot study that compared two pain protocols for patients undergoing a vasoocclusive episode in the ED.
“The reason we pursued this project is to generate additional evidence beyond the expert panel,” she said.
The primary outcome of the study was the difference in pain scores from arrival to discharge between patients receiving an individualized or weight-based dosing protocol. Secondary outcomes included safety, pain experience, and side effects, among others.
The researchers found that patients who received an individualized protocol had significantly lower pain scores, compared with a standard weight-based protocol (between-protocol pain score difference, 15.6 plus or minus 5.0; P = .002).
Additionally, patients in the individualized dosing arm were admitted less often than those in the weight-based arm (P = .03), Dr. Tanabe reported.
The findings from the previous study formed the basis for an ongoing study that is further examining the impact of patient-specific dosing in patients who present with a vasoocclusive episode. The COMPARE VOE study is currently enrolling patients and is being funded by NHLBI.
The NHLBI also provides funding to eight Sickle Cell Disease Implementation Consortium sites throughout the United States. The objective of this grant funding is to help implement NHLBI recommendations in the emergency setting.
Quality improvement
“One area [that] we want to improve is how quickly we administer [analgesic therapy] to patients when they are experiencing a vasoocclusive episode,” said Caroline Freiermuth, MD, of the University of Cincinnati.
Some common barriers to delivering rapid analgesia in this setting include difficulties in obtaining intravenous access, high patient volumes, lack of education, and provider biases, she explained.
With respect to high patient volumes, one strategy that may help overcome this barrier is to triage patients as Emergency Severity Index level 2, allowing for accelerated room placement.
Sickle cell patients undergoing vasoocclusive crisis meet the criteria for level 2 based on morbidity, degree of pain, and the level of resources often required.
Another important strategy is improving education related to sickle cell disease, particularly the high morbidity and mortality seen in these patients, Dr. Freiermuth said.
“The median lifespan for patients with HbSS disease is in the 40s, basically half of the lifespan of a typical American,” she said.
At present, acute chest syndrome is the principal cause of death in patients with sickle cell disease, and most frequently occurs during a vasoocclusive episode. As a result, screening for this complication is essential to reduce mortality in the emergency setting.
Dr. Freiermuth explained that one of the best ways to prevent acute chest syndrome is to encourage the use of incentive spirometry in patients undergoing a vasoocclusive episode.
In order to increase the likelihood of obtaining intravenous access, the use of ultrasound may help guide placement. Educating nurses on the proper use of ultrasound-guided placement of intravenous catheters is one practical approach, she said.
Alternatively, opioid analgesia can be administered subcutaneously. Benefits of subcutaneous delivery include comparable pharmacokinetics, less pain, and a reduced likelihood of sterile abscesses that are often seen with intramuscular administration.
Dr. Freiermuth outlined the quality-improvement initiative being tested at her institution, which involves the administration of parenteral opioid therapy during triage for sickle cell patients undergoing a suspected vasoocclusive crisis. The initiative was developed with input from both the emergency and hematology departments at the site.
Early results have shown no significant changes using this approach, but the data is still preliminary. Initial feedback has revealed that time to room placement has been the greatest barrier, she reported.
Dr. Tanabe reported grant/research support from the National Institutes of Health and the Agency for Healthcare Research and Quality. Dr. Freiermuth reported research support from Pfizer.
Several initiatives are in the works to improve the management of patients with sickle cell disease in the ED, experts said at a recent webinar held by the National Heart, Lung, and Blood Institute.
In 2014, the NHLBI released evidence-based guidelines for the management of patients with sickle cell disease. The expert panel provided recommendations on the treatment of acute complications of sickle cell disease, many of which are common reasons for ED visits.
Optimizing the treatment of acute complications, namely vasoocclusive crisis, is essential to ensure improved long-term outcomes, explained Paula Tanabe, PhD, of Duke University, Durham, N.C.
Pain management
While the majority of pain-related ED visits in sickle cell are the result of vasoocclusive crisis, other causes, such as acute chest syndrome, abdominal catastrophes, and splenic sequestration, are also important.
The hallmark of pain management in this population is rapid and aggressive treatment with intravenous opioids. The use of individualized doses is also important, but if not available, an sickle cell disease–specific pain protocol can be used, she explained.
Recent evidence has confirmed the benefit of using an individualized (patient-specific) dosing protocol. Dr. Tanabe reported the results of a randomized pilot study that compared two pain protocols for patients undergoing a vasoocclusive episode in the ED.
“The reason we pursued this project is to generate additional evidence beyond the expert panel,” she said.
The primary outcome of the study was the difference in pain scores from arrival to discharge between patients receiving an individualized or weight-based dosing protocol. Secondary outcomes included safety, pain experience, and side effects, among others.
The researchers found that patients who received an individualized protocol had significantly lower pain scores, compared with a standard weight-based protocol (between-protocol pain score difference, 15.6 plus or minus 5.0; P = .002).
Additionally, patients in the individualized dosing arm were admitted less often than those in the weight-based arm (P = .03), Dr. Tanabe reported.
The findings from the previous study formed the basis for an ongoing study that is further examining the impact of patient-specific dosing in patients who present with a vasoocclusive episode. The COMPARE VOE study is currently enrolling patients and is being funded by NHLBI.
The NHLBI also provides funding to eight Sickle Cell Disease Implementation Consortium sites throughout the United States. The objective of this grant funding is to help implement NHLBI recommendations in the emergency setting.
Quality improvement
“One area [that] we want to improve is how quickly we administer [analgesic therapy] to patients when they are experiencing a vasoocclusive episode,” said Caroline Freiermuth, MD, of the University of Cincinnati.
Some common barriers to delivering rapid analgesia in this setting include difficulties in obtaining intravenous access, high patient volumes, lack of education, and provider biases, she explained.
With respect to high patient volumes, one strategy that may help overcome this barrier is to triage patients as Emergency Severity Index level 2, allowing for accelerated room placement.
Sickle cell patients undergoing vasoocclusive crisis meet the criteria for level 2 based on morbidity, degree of pain, and the level of resources often required.
Another important strategy is improving education related to sickle cell disease, particularly the high morbidity and mortality seen in these patients, Dr. Freiermuth said.
“The median lifespan for patients with HbSS disease is in the 40s, basically half of the lifespan of a typical American,” she said.
At present, acute chest syndrome is the principal cause of death in patients with sickle cell disease, and most frequently occurs during a vasoocclusive episode. As a result, screening for this complication is essential to reduce mortality in the emergency setting.
Dr. Freiermuth explained that one of the best ways to prevent acute chest syndrome is to encourage the use of incentive spirometry in patients undergoing a vasoocclusive episode.
In order to increase the likelihood of obtaining intravenous access, the use of ultrasound may help guide placement. Educating nurses on the proper use of ultrasound-guided placement of intravenous catheters is one practical approach, she said.
Alternatively, opioid analgesia can be administered subcutaneously. Benefits of subcutaneous delivery include comparable pharmacokinetics, less pain, and a reduced likelihood of sterile abscesses that are often seen with intramuscular administration.
Dr. Freiermuth outlined the quality-improvement initiative being tested at her institution, which involves the administration of parenteral opioid therapy during triage for sickle cell patients undergoing a suspected vasoocclusive crisis. The initiative was developed with input from both the emergency and hematology departments at the site.
Early results have shown no significant changes using this approach, but the data is still preliminary. Initial feedback has revealed that time to room placement has been the greatest barrier, she reported.
Dr. Tanabe reported grant/research support from the National Institutes of Health and the Agency for Healthcare Research and Quality. Dr. Freiermuth reported research support from Pfizer.
REPORTING FROM AN NIH WEBINAR
A few pearls can help prepare the mind
We need to recognize the diverse problems that patients with potential multisystem disease can develop, lobby when necessary for them to be seen promptly by the relevant specialists, and initiate appropriate diagnostic testing and management in less-urgent scenarios. Most of us need frequent refreshers on the clinical manifestations of these disorders so that we can recognize them when they appear unannounced in our exam rooms.
The caregiver with a prepared mind is more likely to experience the diagnostic epiphany, and then use point-of-care references to hone in on the details. With many patients and clinical conundrums, the basics matter.
Dr. Chester Oddis, in this issue of the Journal, reviews the basics of several primary muscle disorders. He discusses, in a case-based format extracted from his recent Medicine Grand Rounds presentation at Cleveland Clinic, nuances of specific diagnoses and the clinical progression of diseases that are critical to be aware of in order to recognize and manage them, and expeditiously refer the patient to our appropriate subspecialty colleagues.
Major challenges exist in recognizing the inflammatory myopathies and their mimics early in their course. These are serious but uncommon entities, and in part because patients and physicians often attribute their early symptoms to more-common causes, diagnosis can be elusive—until the possibility is considered. We hope that Dr. Oddis’s article will make it easier to rapidly recognize these muscle disorders.
Patients often struggle to explain their symptoms of early muscle dysfunction. Since patients often verbalize their fatigue as “feeling weak,” we often misconstrue complaints of true muscle weakness (like difficulty walking up steps) as being due to fatigue. Add in some anemia from chronic inflammation and some “liver test” abnormalities, and it is easy to see how the recognition of true muscle weakness can be delayed.
We can tease muscle weakness from fatigue or dyspnea by asking the patient to specifically and functionally describe their “weakness,” and then by asking pointed questions: “Do you have difficulty getting up from the toilet without using your arms? Do you have trouble brushing your hair or teeth?” Physical examination can clearly help here, but without routine examination of muscle strength in normal fragile elderly patients, the degree of muscle weakness can be difficult to assess. Likewise challenging is detecting the early onset of weakness by examination in a 280-lb power-lifter.
Obtaining an accurate functional and behavioral history is often critical to the early recognition of muscle disease. Muscle pain, as Dr. Oddis notes, is not a characteristic feature of many myopathies, whereas, paradoxically, the coexistence of new-onset symmetrical small-joint pain (especially with arthritis) along with muscle weakness can be a powerful clue to the diagnosis of an inflammatory myopathy.
An elevated creatine kinase (CK) level generally points directly to a muscle disease, although some neurologic disorders are associated with elevations in CK, and the entity of benign “hyperCKemia” must be recognized and not overmanaged. The latter becomes a problem when laboratory tests are allowed to drive the diagnostic evaluation in a vacuum of clinical details.
A more common scenario is the misinterpretation of common laboratory test abnormalities in the setting of a patient with “fatigue” or generalized weakness who has elevations in aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Although AST and ALT are often called “liver function tests,” these enzymes are also abundant in skeletal muscle, and since they are included on routine biochemical panels, their elevation often leads to liver imaging and sometimes even biopsy before anyone recognizes muscle disease as the cause of the patient’s symptoms and laboratory test abnormalities. Hence, a muscle source (or hemolysis) should at least be considered when AST and ALT are elevated in the absence of elevated alkaline phosphatase or gamma-glutamyl transferase.
When evaluating innumerable clinical scenarios, experienced clinicians can most certainly generate similar principles of diagnostic reasoning, based on having a few fundamental facts at their fingertips. Increasing the chances of having a prepared mind when confronted with a patient with a less-than-straightforward set of symptoms is one of my major arguments in support of continuing to read and generate internal medicine teaching literature and to attend and participate in clinical teaching conferences such as Medicine Grand Rounds. It is also why we will continue to appreciate and publish presentations like this one in the Journal.
I don’t expect to retain all the details from these and similar papers, and I know we all carry virtually infinite databases in our pockets. But keeping a few clinical pearls outside of my specialty in my head comes in handy. Having a prepared mind makes it much easier to converse with patients, to promptly initiate appropriate testing, plans, and consultations, and to then decide what to search for on my smartphone between patients.
We need to recognize the diverse problems that patients with potential multisystem disease can develop, lobby when necessary for them to be seen promptly by the relevant specialists, and initiate appropriate diagnostic testing and management in less-urgent scenarios. Most of us need frequent refreshers on the clinical manifestations of these disorders so that we can recognize them when they appear unannounced in our exam rooms.
The caregiver with a prepared mind is more likely to experience the diagnostic epiphany, and then use point-of-care references to hone in on the details. With many patients and clinical conundrums, the basics matter.
Dr. Chester Oddis, in this issue of the Journal, reviews the basics of several primary muscle disorders. He discusses, in a case-based format extracted from his recent Medicine Grand Rounds presentation at Cleveland Clinic, nuances of specific diagnoses and the clinical progression of diseases that are critical to be aware of in order to recognize and manage them, and expeditiously refer the patient to our appropriate subspecialty colleagues.
Major challenges exist in recognizing the inflammatory myopathies and their mimics early in their course. These are serious but uncommon entities, and in part because patients and physicians often attribute their early symptoms to more-common causes, diagnosis can be elusive—until the possibility is considered. We hope that Dr. Oddis’s article will make it easier to rapidly recognize these muscle disorders.
Patients often struggle to explain their symptoms of early muscle dysfunction. Since patients often verbalize their fatigue as “feeling weak,” we often misconstrue complaints of true muscle weakness (like difficulty walking up steps) as being due to fatigue. Add in some anemia from chronic inflammation and some “liver test” abnormalities, and it is easy to see how the recognition of true muscle weakness can be delayed.
We can tease muscle weakness from fatigue or dyspnea by asking the patient to specifically and functionally describe their “weakness,” and then by asking pointed questions: “Do you have difficulty getting up from the toilet without using your arms? Do you have trouble brushing your hair or teeth?” Physical examination can clearly help here, but without routine examination of muscle strength in normal fragile elderly patients, the degree of muscle weakness can be difficult to assess. Likewise challenging is detecting the early onset of weakness by examination in a 280-lb power-lifter.
Obtaining an accurate functional and behavioral history is often critical to the early recognition of muscle disease. Muscle pain, as Dr. Oddis notes, is not a characteristic feature of many myopathies, whereas, paradoxically, the coexistence of new-onset symmetrical small-joint pain (especially with arthritis) along with muscle weakness can be a powerful clue to the diagnosis of an inflammatory myopathy.
An elevated creatine kinase (CK) level generally points directly to a muscle disease, although some neurologic disorders are associated with elevations in CK, and the entity of benign “hyperCKemia” must be recognized and not overmanaged. The latter becomes a problem when laboratory tests are allowed to drive the diagnostic evaluation in a vacuum of clinical details.
A more common scenario is the misinterpretation of common laboratory test abnormalities in the setting of a patient with “fatigue” or generalized weakness who has elevations in aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Although AST and ALT are often called “liver function tests,” these enzymes are also abundant in skeletal muscle, and since they are included on routine biochemical panels, their elevation often leads to liver imaging and sometimes even biopsy before anyone recognizes muscle disease as the cause of the patient’s symptoms and laboratory test abnormalities. Hence, a muscle source (or hemolysis) should at least be considered when AST and ALT are elevated in the absence of elevated alkaline phosphatase or gamma-glutamyl transferase.
When evaluating innumerable clinical scenarios, experienced clinicians can most certainly generate similar principles of diagnostic reasoning, based on having a few fundamental facts at their fingertips. Increasing the chances of having a prepared mind when confronted with a patient with a less-than-straightforward set of symptoms is one of my major arguments in support of continuing to read and generate internal medicine teaching literature and to attend and participate in clinical teaching conferences such as Medicine Grand Rounds. It is also why we will continue to appreciate and publish presentations like this one in the Journal.
I don’t expect to retain all the details from these and similar papers, and I know we all carry virtually infinite databases in our pockets. But keeping a few clinical pearls outside of my specialty in my head comes in handy. Having a prepared mind makes it much easier to converse with patients, to promptly initiate appropriate testing, plans, and consultations, and to then decide what to search for on my smartphone between patients.
We need to recognize the diverse problems that patients with potential multisystem disease can develop, lobby when necessary for them to be seen promptly by the relevant specialists, and initiate appropriate diagnostic testing and management in less-urgent scenarios. Most of us need frequent refreshers on the clinical manifestations of these disorders so that we can recognize them when they appear unannounced in our exam rooms.
The caregiver with a prepared mind is more likely to experience the diagnostic epiphany, and then use point-of-care references to hone in on the details. With many patients and clinical conundrums, the basics matter.
Dr. Chester Oddis, in this issue of the Journal, reviews the basics of several primary muscle disorders. He discusses, in a case-based format extracted from his recent Medicine Grand Rounds presentation at Cleveland Clinic, nuances of specific diagnoses and the clinical progression of diseases that are critical to be aware of in order to recognize and manage them, and expeditiously refer the patient to our appropriate subspecialty colleagues.
Major challenges exist in recognizing the inflammatory myopathies and their mimics early in their course. These are serious but uncommon entities, and in part because patients and physicians often attribute their early symptoms to more-common causes, diagnosis can be elusive—until the possibility is considered. We hope that Dr. Oddis’s article will make it easier to rapidly recognize these muscle disorders.
Patients often struggle to explain their symptoms of early muscle dysfunction. Since patients often verbalize their fatigue as “feeling weak,” we often misconstrue complaints of true muscle weakness (like difficulty walking up steps) as being due to fatigue. Add in some anemia from chronic inflammation and some “liver test” abnormalities, and it is easy to see how the recognition of true muscle weakness can be delayed.
We can tease muscle weakness from fatigue or dyspnea by asking the patient to specifically and functionally describe their “weakness,” and then by asking pointed questions: “Do you have difficulty getting up from the toilet without using your arms? Do you have trouble brushing your hair or teeth?” Physical examination can clearly help here, but without routine examination of muscle strength in normal fragile elderly patients, the degree of muscle weakness can be difficult to assess. Likewise challenging is detecting the early onset of weakness by examination in a 280-lb power-lifter.
Obtaining an accurate functional and behavioral history is often critical to the early recognition of muscle disease. Muscle pain, as Dr. Oddis notes, is not a characteristic feature of many myopathies, whereas, paradoxically, the coexistence of new-onset symmetrical small-joint pain (especially with arthritis) along with muscle weakness can be a powerful clue to the diagnosis of an inflammatory myopathy.
An elevated creatine kinase (CK) level generally points directly to a muscle disease, although some neurologic disorders are associated with elevations in CK, and the entity of benign “hyperCKemia” must be recognized and not overmanaged. The latter becomes a problem when laboratory tests are allowed to drive the diagnostic evaluation in a vacuum of clinical details.
A more common scenario is the misinterpretation of common laboratory test abnormalities in the setting of a patient with “fatigue” or generalized weakness who has elevations in aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Although AST and ALT are often called “liver function tests,” these enzymes are also abundant in skeletal muscle, and since they are included on routine biochemical panels, their elevation often leads to liver imaging and sometimes even biopsy before anyone recognizes muscle disease as the cause of the patient’s symptoms and laboratory test abnormalities. Hence, a muscle source (or hemolysis) should at least be considered when AST and ALT are elevated in the absence of elevated alkaline phosphatase or gamma-glutamyl transferase.
When evaluating innumerable clinical scenarios, experienced clinicians can most certainly generate similar principles of diagnostic reasoning, based on having a few fundamental facts at their fingertips. Increasing the chances of having a prepared mind when confronted with a patient with a less-than-straightforward set of symptoms is one of my major arguments in support of continuing to read and generate internal medicine teaching literature and to attend and participate in clinical teaching conferences such as Medicine Grand Rounds. It is also why we will continue to appreciate and publish presentations like this one in the Journal.
I don’t expect to retain all the details from these and similar papers, and I know we all carry virtually infinite databases in our pockets. But keeping a few clinical pearls outside of my specialty in my head comes in handy. Having a prepared mind makes it much easier to converse with patients, to promptly initiate appropriate testing, plans, and consultations, and to then decide what to search for on my smartphone between patients.
Myopathy for the general internist: Statins and much more
Myopathies can present with a wide variety of symptoms, so patients with muscle weakness are often seen initially by a general practitioner. Nonrheumatologists should be able to evaluate a patient presenting with muscle weakness or myalgia and be aware of red flags indicating potentially dangerous syndromes that require a prompt, thorough investigation.
This article reviews selected causes of muscle weakness, such as statin-induced and autoimmune disorders, and systemic features of inflammatory myopathies beyond myositis, such as dermatologic and pulmonary manifestations.
FOCUSING THE EVALUATION
The evaluation of a patient presenting with muscle weakness should include several assessments:
Temporal progression. Was the onset of symptoms rapid or insidious? Patterns of onset may give clues to etiology, including the possibility of an associated autoimmune condition.
Location of muscle weakness. Are symptoms global or localized? And if localized, are they proximal or distal? Proximal weakness can be manifested by difficulty rising from a chair (hip muscles) or combing one’s hair (shoulder muscles), whereas distal weakness can involve difficulty standing on toes (gastrocnemius and soleus muscles) or performing fine motor activities (intrinsic hand muscles).
Symmetry. A focal or asymmetric pattern often has a neurologic etiology, but this could also be consistent with inclusion body myositis.
Other symptoms. Arthritis, rash, and swallowing problems point to a possible underlying rheumatologic disease. Weight gain or loss may indicate a thyroid disorder.
Family history. Some patients report that others in their family have this pattern of weakness, indicating a likely genetic myopathy. If the patient reports a relative with multiple sclerosis, lupus erythematosus, rheumatoid arthritis, or another autoimmune disease, then an immune-mediated myopathy should be considered.
Medications should be reviewed, particularly statins.
CASE 1: SLOWLY PROGRESSIVE WEAKNESS
A 65-year-old man presented with the insidious onset of muscle weakness and episodes of falling. On review of his medical record, his serum creatine kinase (CK) levels were elevated at various periods at 2 to 4 times the upper limit of normal. Electromyography (EMG) previously showed a myopathic pattern, and a muscle biopsy was abnormal, consistent with endomysial inflammation (term is consistent with “polymyositis”). He was treated for polymyositis for several years with prednisone alone, with steroids plus methotrexate, and with combined immunosuppression including methotrexate and azathioprine, but with no improvement. Eventually, another muscle biopsy revealed inclusion bodies with rimmed vacuoles, consistent with inclusion body myositis.
Inclusion body myositis
Inclusion body myositis is the most common myopathy in middle-aged to elderly people, especially men. These patients are often told “You are just getting old,” but they have a defined condition. It should also be considered in patients failing to respond to treatment or with those with “refractory” polymyositis.
The onset of muscle weakness is insidious and painless, and the weakness progresses slowly. The pattern is distal and asymmetric (eg, foot drop), and muscle atrophy typically affects the forearm flexors, quadriceps, and intrinsic muscles of the hands.1
Magnetic resonance imaging may show marked muscle atrophy. Unfortunately, no treatment has shown efficacy, and most neuromuscular and rheumatology experts do not treat inclusion body myositis with immunosuppressive drugs.
CASE 2: MILD MYALGIA WITHOUT WEAKNESS
A black 52-year-old man was referred because of myalgia and a CK level of 862 U/L (reference range < 200). His physician wanted to start him on a statin but was hesitant to do so without first consulting a rheumatologist.
The patient had a long history of mild arthralgias and myalgias without muscle weakness. He had dyslipidemia and hypertension. He reported no family history of myopathy and no illicit drug use. He was formerly an athlete. Medications included a thiazide diuretic and a beta-blocker. On examination, his muscles were strong (rated 5 on a scale of 5) in the upper and lower extremities, without atrophy.
His records showed that his CK levels had risen and fallen repeatedly over the past few years, ranging from 600 to 1,100 U/L. On further questioning, he reported that when he had joined the army 30 years previously, a physician had recommended he undergo a liver biopsy in view of elevated liver function tests, but that he had refused because he felt fine.
Currently, his gamma-glutamyl transpeptidase levels were normal.
Idiopathic ‘hyperCKemia’
So-called idiopathic hyperCKemia is not a form of myositis but merely a laboratory result outside the “normal” range. Reference ranges are based predominantly on measurements in white people and on an assumption that the distribution is Gaussian (bell-shaped). A normal CK level is usually defined as less than 200 U/L. Using this standard, up to 20% of men and 5% of women have hyperCKemia.2
However, CK levels vary by sex and ethnicity, with mean levels highest in black men, followed by black women, white men, and white women. The mean level in black men is higher than the standard cutoff point for normal, and especially in this population, there is wide fluctuation around the mean, leading to hyperCKemia quite frequently in black men. Exercise and manual labor also drive up CK levels.3–5
Idiopathic hyperCKemia is benign. D’Adda et al6 followed 55 patients for a mean of 7.5 years. CK levels normalized in 12 patients or at least decreased in 24. Most remained symptom-free or had minimal symptoms.
Idiopathic hyperCKemia: Bottom line
Before prescribing a statin, determine the baseline CK level. If slightly elevated (ie, up to 3 to 5 times the upper limit of normal, or even higher) in the setting of normal muscle strength, there is no need for electromyography or muscle biopsy, and the patient can certainly receive a statin. Most of these patients do not need to see a rheumatologist but can simply have their CK and muscle strength monitored.
CLASSIFYING MYOSITIS
Myositis (idiopathic inflammatory myopathy) is a heterogeneous group of autoimmune syndromes of unknown cause characterized by chronic muscle weakness and inflammation of striated muscle. These syndromes likely arise as a result of genetic predisposition and an environmental or infectious “hit.”
Myositis is rare, with an incidence of 5 to 10 cases per million per year and an estimated prevalence of 50 to 90 cases per million. It has 2 incidence peaks: 1 in childhood (age 5–15) and another in adult midlife (age 30–50). Women are affected 2 to 3 times more often than men, with black women most commonly affected.
Myositis is traditionally classified as follows:
- Adult polymyositis
- Adult dermatomyositis
- Juvenile myositis (dermatomyositis much more frequent than polymyositis)
- Malignancy-associated myositis (usually dermatomyositis)
- Myositis overlapping with another autoimmune disease
- Inclusion body myositis.
However, polymyositis is less common than we originally thought, and the term necrotizing myopathy is now used in many patients, as noted in the case studies below. Further, myositis overlap syndromes are being increasingly diagnosed, likely related to the emergence of autoantibodies and clinical “syndromes” associated with these autoantibody subsets (discussed in cases below).
Dermatomyositis
Dermatomyositis is characterized by muscle weakness and a rash that can be obvious or subtle. Classic skin lesions are Gottron papules, which are raised, flat-topped red or purplish lesions over the knuckles, elbows, or knees.
Lesions may be confused with those of psoriasis. There can also be a V-neck rash over the anterior chest or upper back (“shawl sign”) or a rash over the lateral thigh (“holster sign”). A facial rash may occur, but unlike lupus, dermatomyositis does not spare the nasolabial area. However, the V-neck rash can be similar to that seen in lupus.
Dermatomyositis may cause muscle pain, perhaps related to muscle ischemia, whereas polymyositis and necrotizing myopathy are often painless. However, pain is also associated with fibromyalgia, which may be seen in many autoimmune conditions. It is important not to overtreat rheumatologic diseases with immunosuppression to try to control pain if the pain is actually caused by fibromyalgia.
Polymyositis mimics
Hypothyroid myopathy can present as classic polymyositis. The serum CK may be elevated, and there may be myalgias, muscle hypertrophy with stiffness, weakness, cramps, and even features of a proximal myopathy, and rhabdomyolysis. The electromyogram can be normal or myopathic. Results of muscle biopsy are often normal but may show focal necrosis and mild inflammatory infiltrates, thus mimicking that seen with inflammatory myopathy.7
Drug-induced or toxic myopathies can also mimic polymyositis. Statins are among the most commonly prescribed drugs in the United States, with more than 35 million people taking them. Statins are generally well tolerated but have a broad spectrum of toxicity, ranging from myalgias to life-threatening rhabdomyolysis. Myalgias lead to about 5% to 10% of patients refusing to take a statin or stopping it on their own.
Myalgias affect up to 20% of statin users in clinical practice.8,9 A small cross-sectional study10 of 1,000 patients in a primary care setting found that the risk of muscle complaints in statin users was 1.5 times higher than in nonstatin users, similar to findings in other studies.
My strategy for managing a patient with possible statin-induced myopathy is illustrated in Figure 1.
CASE 3: WEAKNESS, VERY HIGH CK ON A STATIN
In March 2010, a 67-year-old woman presented with muscle weakness. She had a history of hypertension, hyperlipidemia, and, more than 10 years previously, uterine cancer. In 2004, she was given atorvastatin for dyslipidemia. Four years later, she developed lower-extremity weakness, which her doctor attributed to normal aging. A year after that, she found it difficult to walk up steps and lift her arms overhead. In June 2009, she stopped taking the atorvastatin on her own, but the weakness did not improve.
In September 2009, she returned to her doctor, who found her CK level was 6,473 U/L but believed it to be an error, so the test was repeated, with a result of 9,375 U/L. She had no rash or joint involvement.
She was admitted to the hospital and underwent muscle biopsy, which showed myonecrosis with no inflammation or vasculitis. She was treated with prednisone 60 mg/day, and her elevated CK level and weakness improved.
Immune-mediated necrotizing myopathy associated with statins
The hallmark of necrotizing myopathy is myonecrosis without significant inflammation.12 This pattern contrasts with that of polymyositis, which is characterized by lymphocytic inflammation.
Although statins became available in the United States in 1987, immune-mediated necrotizing myopathy associated with statins was first described only in 2010. In that report, Grable-Esposito et al13 described 25 patients from 2 neuromuscular centers seen between 2000 and 2008 who had elevated CK and proximal weakness during or after statin use, both of which persisted despite stopping the statin. Patients improved with immunosuppressive agents but had a relapse when steroids were stopped or tapered, a pattern typical in autoimmune disease.
Autoantibody defines subgroup of necrotizing myopathy
Also in 2010, Christopher-Stine et al14 reported an antibody associated with necrotizing myopathy. Of 38 patients with the condition, 16 were found to have an abnormal “doublet” autoantibody recognizing 200- and 100-kDa proteins. All patients had weakness and a high CK level, and 63% had statin exposure before the weakness (this percentage increased to 83% in patients older than 50). All responded to immunosuppressive therapy, and many had a relapse when it was withdrawn.
Statins lower cholesterol by inhibiting 3-hydroxy-3-methylglutaryl-Co A reductase (HMGCR), and paradoxically, they also upregulate it. HMGCR has a molecular weight of 97 kDa. Mammen et al15 identified HMGCR as the 100-kDa target of the identified antibody and developed an enzyme-linked immunosorbent assay for it. Of 750 patients presenting to one center, only 45 (6%) had anti-HMGCR autoantibodies, but all 16 patients who had the abnormal doublet antibody tested positive for anti-HMGCR. Regenerating muscle cells express high levels of HMGCR, which may sustain the immune response after statins are discontinued.
Case 3 continued: Intravenous immunoglobulin brings improvement
In March 2010, when the 67-year-old patient presented to our myositis center, her CK level was 5,800 U/L, which increased as prednisone was tapered. She still felt weak. On examination, her muscle strength findings were deltoids 4+/5, neck flexors 4/5, and iliopsoas 3+/5. She was treated with methotrexate and azathioprine without benefit. She was next treated with intravenous immunoglobulin, and after 3 months, her strength normalized for the first time in years. Her CK level decreased but did not normalize. Testing showed that she was positive for anti-HMGCR autoantibody, as this test had become commercially available.
In 2015, Mammen and Tiniakou16 suggested using intravenous immunoglobulin as first-line therapy for statin-associated autoimmune necrotizing myopathy, based on experience at a single center with 3 patients who declined glucocorticoid treatment.
Necrotizing myopathy: Bottom line
Myositis overlap syndromes
Heterogeneity is the rule in myositis, and it can present with a wide variety of signs and symptoms as outlined in Table 2.
CASE 4: FEVER, NEW ‘RHEUMATOID ARTHRITIS,’ AND LUNG DISEASE
A 52-year-old woman with knee osteoarthritis saw her primary care physician in November 2013 for dyspnea and low-grade fever. The next month, she presented with polyarthritis, muscle weakness, and Raynaud phenomenon.
In January 2014, she developed acrocyanosis of her fingers. Examination revealed hyperkeratotic, cracked areas of her fingers. Her oxygen saturation by pulse oximetry was low. She was admitted to the hospital. Her doctor suspected new onset of rheumatoid arthritis, but blood tests revealed a negative antinuclear antibody, so an autoimmune condition was deemed unlikely. Her CK was mildly elevated at 350 U/L.
Because of her dyspnea, an open-lung biopsy was performed. High-resolution computed tomography (CT) revealed infiltrates and ground-glass opacities, leading to the diagnosis of nonspecific interstitial pneumonia. A rheumatologist was consulted and recommended pulse methylprednisolone, followed by prednisone 60 mg/day and mycophenolate mofetil. Testing for Jo-1 antibodies was positive.
Antisynthetase syndrome
The antisynthetase syndrome is a clinically heterogeneous condition that can occur with any or all of the following:
- Fever
- Myositis
- Arthritis (often misdiagnosed as rheumatoid arthritis)
- Raynaud phenomenon
- Mechanic’s hands (hyperkeratotic roughness with fissures on the lateral aspects of the fingers and finger pads)
- Interstitial lung disease.
The skin rashes and myositis may be subtle, making the presentation “lung-dominant,” and nonrheumatologists should be aware of this syndrome. Although in our patient the condition developed in a classic manner, with all of the aforementioned features of the antisynthetase syndrome, some patients will manifest one or a few of the features.
Clinically, patients with the Jo-1 antisynthetase syndrome often present differently than those with non-Jo-1 antisynthetase autoantibodies. When we compared 122 patients with Jo-1 vs 80 patients with a non-Jo-1 antisynthetase autoantibody, patients with Jo-1 antibodies were more likely to have initially received a diagnosis of myositis (83%), while myositis was the original diagnosis in only 17% of those possessing non-Jo-1 antisynthetase autoantibodies. In fact, many patients (approximately 50%) were diagnosed as having undifferentiated connective tissue disease or an overlap syndrome, and 13% had scleroderma as their first diagnosis.17
We also found that the survival rate was higher in patients with Jo-1 syndrome compared with patients with non-Jo-1 antisynthetase syndromes. We attributed the difference in survival rates to a delayed diagnosis in the non-Jo-1 group, perhaps due to their “nonclassic” presentations of the antisynthetase syndrome, delaying appropriate treatment. Patients received a diagnosis of Jo-1 antibody syndrome after a mean of 0.4 year (range 0.2–0.8), while those with a non-Jo-1 antisynthetase autoantibody had a delay in diagnosis of 1.0 year (range 0.4–5.1) (P < .01).17
In nearly half the cases in this cohort, pulmonary fibrosis was the cause of death, with primary pulmonary hypertension being the second leading cause (11%).
Antisynthetase syndrome: Bottom line
Antisynthetase syndrome is an often fatal disease that does not always present in a typical fashion with symptoms of myositis, as lung disease may be the predominant feature. A negative antinuclear antibody test result does not imply antibody negativity, as the autoantigen in these diseases is not located in the nucleus. Prompt diagnosis and appropriate immunosuppressive therapy are critical to improving outcomes.
CASE 5: FEVER, UNDIAGNOSED LUNG DISEASE, NO MYOSITIS
In January 2001, a 39-year-old woman was admitted to the hospital after 5 weeks of fever (temperatures 103°–104°F) and myalgias. An extensive workup was negative except for low-titer antinuclear antibody and for mild basilar fibrosis noted on chest radiography. She left the hospital against medical advice because of frustration with a lack of a specific diagnosis (“fever of unknown origin”).
Two months later, at a follow-up rheumatology consult, she reported more myalgias and arthralgias, as well as fever. Chest radiography now showed pleural effusions. Her fingers had color changes consistent with Raynaud phenomenon. At that time, I diagnosed an undifferentiated connective tissue disease and told her that I suspected an autoimmune condition that would need time to reveal itself. In the meantime, I treated her empirically with prednisone.
In April, she returned, much more short of breath and with more prominent diffuse pulmonary infiltrates. Physical examination revealed subtle Gottron changes. Testing revealed poor pulmonary function: forced vital capacity (FVC) 56%, forced expiratory volume in 1 second (FEV1) 52%, and diffusing capacity for carbon monoxide (Dlco) 40%. Blood testing was positive for anti-PL-12 antibody, one of the non-Jo-1 antisynthetase antibodies. At this time, we treated her with glucocorticoids and tacrolimus.
More than 15 years later, this patient is doing well. Her skin rash, joint symptoms, and fever have not returned, and interestingly, she never developed myositis. Her Raynaud symptoms are mild. Her most recent pulmonary function test results (January 2018) were FVC 75%, FEV1 87%, and Dlco 78%. Although these results are not normal, they are much improved and allow her to be completely functional without supplemental oxygen. Echocardiography showed normal pulmonary artery systolic pressure (25 mm Hg). She was still taking tacrolimus and prednisone. When we tried to stop tacrolimus after she had done well for many years, her condition flared.
Non-Jo-1 antisynthetase syndrome: Bottom line
Patients with a non-Jo-1 antisynthetase syndrome often present without myositis symptoms and may never manifest myositis symptoms. Likely because of this presentation, diagnosis of a specific connective tissue disorder is delayed, perhaps leading to increased mortality risk from pulmonary disease. Chronic immunosuppression is often required for these autoimmune conditions.
CASE 6: DERMATOMYOSITIS, RAPIDLY PROGRESSIVE INTERSTITIAL LUNG DISEASE
A 58-year-old woman presented in the summer of 2012 with a photosensitive rash. The following January, she returned with polyarthritis, mild muscle weakness, and a dermatomyositis-pattern rash. Her CK level was normal, and her antinuclear antibody and Sjögren syndrome antibody test results were negative. She improved on low-dose prednisone and methotrexate.
She was originally referred to me in May of that year for worsening rash and mild weakness. She denied pulmonary symptoms, but examination revealed faint basilar crackles. I increased her prednisone dosage to 20 mg/day and started mycophenolate mofetil mainly for the mild cutaneous and myositis features. I also recommended high-resolution CT of the lungs and pulmonary function tests, which she underwent in early June. High-resolution CT showed nonspecific mild infiltrates with minimal ground-glass opacities.
On July 1, she presented to her local emergency department with severe shortness of breath, requiring oxygen 12 L/min. She had a palmar rash. Repeat high-resolution CT showed dramatic worsening compared with the scan the previous month. Because of continued inadequate oxygenation, she was transferred to our center. A blood test later was positive for antimelanoma differentiation-associated gene 5 (MDA-5) autoantibody, previously known as anticlinically amyopathic dermatomyositis (anti-CADM)-140 antibody (based on immunoprecipitation results).
She died on the third day after transfer, just 2 months after I had originally seen her, at which time she had had no pulmonary symptoms.
Clinically amyopathic dermatomyositis
Anti-CADM-140, first reported from Asia,18–20 is an autoantibody-associated disease but not an antisynthetase. It is associated with dermatomyositis; patients often have a “vasculopathy” with cutaneous ulcerations and palmar papules.
MDA-5 is a cytoplasmic protein that “senses” viral RNA and induces production of type 1 interferon. It is involved in the innate immune defense against viruses.
Anti-MDA-5 positivity is associated with a poor pulmonary outcome.21 In our cohort from the University of Pittsburgh, many patients died within 3 years, compared with about a 40% survival rate in patients with dermatomyositis who tested negative for this antibody. That being said, many patients with anti-MDA-5 do not develop rapidly progressive interstitial lung disease.
Autoimmune interstitial lung disease: Bottom line
Autoimmune interstitial lung disease is easy to miss, especially in the case of a non-Jo-1 syndrome, for 3 important reasons:
- The autoimmune features may initially be subtle (eg, Raynaud phenomena, mild dermatomyositis rash, undifferentiated connective tissue disease)
- Autoantibody testing is not often ordered, is not standardized, or may be unavailable
- Providers are mistakenly reassured that a patient who tests negative for antinuclear antibody does not have an autoimmune condition.
To emphasize the last point, in a cohort of 202 patients who tested positive for an antisynthetase antibody, only half were antinuclear antibody-positive, but nearly three-quarters demonstrated anticytoplasmic staining on indirect immunofluorescence (due to the location of the autoantigen in the cytoplasm), making the latter a better screening test for an antisynthetase antibody. For scleroderma, 99% were antinculear antibody-positive, but for myositis, this test is much less sensitive.22
- Felice KJ, North WA. Inclusion body myositis in Connecticut: observations in 35 patients during an 8-year period. Medicine (Baltimore) 2001; 80(5):320–327. doi:10.1097/00005792-200109000-00006
- Lev EI, Tur-Kaspa I, Ashkenazy I, et al. Distribution of serum creatine kinase activity in young healthy persons. Clin Chim Acta 1999; 279(1-2):107–115. doi:10.1016/S0009-8981(98)00180-6
- Lilleng H, Abeler K, Johnsen SH, et al. Variation of serum creatine kinase (CK) levels and prevalence of persistent hyperCKemia in a Norwegian normal population. The Tromsø Study. Neuromuscul Disord 2011; 21(7):494–500. doi:10.1016/j.nmd.2011.04.007
- Johnston JD, Lloyd M, Mathews JA, Hawthorne SW. Racial variation in serum creatine kinase levels. J R Soc Med 1996; 89(8):462-464. pmid:8795501
- Prelle A, Tancredi L, Sciacco M, et al. Retrospective study of a large population of patients with asymptomatic or minimally symptomatic raised serum creatine kinase levels. J Neurol 2002; 249(3):305–311. pmid:11993531
- D’Adda E, Sciacco M, Fruguglietti ME, et al. Follow-up of a large population of asymptomatic/oligosymptomatic hyperckemic subjects. J Neurol 2006; 253(11):1399–1403. doi:10.1007/s00415-006-0223-y
- Madariaga MG. Polymyositis-like syndrome in hypothyroidism: review of cases reported over the past twenty-five years. Thyroid 2002; 12(4):331–336. doi:10.1089/10507250252949478
- de Sauvage Nolting PR, Buirma RJ, Hutten BA, Kastelein JJ; Dutch ExPRESS Investigator Group. Two-year efficacy and safety of simvastatin 80 mg in familial hypercholesterolemia (the Examination of Probands and Relatives in Statin Studies With Familial Hypercholesterolemia [ExPRESS FH]). Am J Cardiol 2002; 90(2):181–184. doi:10.1016/s0002-9149(02)02449-9
- Bruckert E, Hayem G, Dejager S, Yau C, Bégaud B. Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients--the PRIMO study. Cardiovasc Drugs Ther 2005; 19(6):403–414. doi:10.1007/s10557-005-5686-z
- Mosshammer D, Lorenz G, Meznaric S, Schwarz J, Muche R, Mörike K. Statin use and its association with musculoskeletal symptoms—a cross-sectional study in primary care settings. Fam Pract 2009; 26(2):88–95. doi:10.1093/fampra/cmp006
- Nichols GA, Koro CE. Does statin therapy initiation increase the risk for myopathy? An observational study of 32,225 diabetic and nondiabetic patients. Clin Ther 2007; 29(8):1761–1770. doi:10.1016/j.clinthera.2007.08.022
- Kassardjian CD, Lennon VA, Alfugham NB, Mahler M, Milone M. Clinical features and treatment outcomes of necrotizing autoimmune myopathy. JAMA Neurol 2015; 72(9):996–1003. doi:10.1001/jamaneurol.2015.1207
- Grable-Esposito P, Katzberg HD, Greenberg SA, Srinivasan J, Katz J, Amato AA. Immune-mediated necrotizing myopathy associated with statins. Muscle Nerve 2010; 41(2):185–190. doi:10.1002/mus.21486
- Christopher-Stine L, Casciola-Rosen LA, Hong G, Chung T, Corse AM, Mammen AL. A novel autoantibody recognizing 200-kd and 100-kd proteins is associated with an immune-mediated necrotizing myopathy. Arthritis Rheum 2010; 62(9):2757–2766. doi:10.1002/art.27572
- Mammen AL, Chung T, Christopher-Stine L, et al. Autoantibodies against 3-hydroxy-3-methylglutaryl-coenzyme A reductase in patients with statin-associated autoimmune myopathy. Arthritis Rheum 2011; 63(3):713–721. doi:10.1002/art.30156
- Mammen AL, Tiniakou E. Intravenous immune globulin for statin-triggered autoimmune myopathy. N Engl J Med 2015; 373(17):1680–1682. doi:10.1056/NEJMc1506163
- Aggarwal R, Cassidy E, Fertig N, et al. Patients with non-Jo-1 anti-tRNA-synthetase autoantibodies have worse survival than Jo-1 positive patients. Ann Rheum Dis 2014; 73(1):227–232. doi:10.1136/annrheumdis-2012-201800
- Sato S, Hirakata M, Kuwana M, et al. Autoantibodies to a 140-kd polypeptide, CADM-140, in Japanese patients with clinically amyopathic dermatomyositis. Arthritis Rheum 2005; 52(5):1571–1576. doi:10.1002/art.21023
- Sato S, Hoshino K, Satoh T, et al. RNA helicase encoded by melanoma differentiation-associated gene 5 is a major autoantigen in patients with clinically amyopathic dermatomyositis: association with rapidly progressive interstitial lung disease. Arthritis Rheum 2009; 60(7):2193–2200. doi:10.1002/art.24621
- Chen F, Wang D, Shu X, Nakashima R, Wang G. Anti-MDA5 antibody is associated with A/SIP and decreased T cells in peripheral blood and predicts poor prognosis of ILD in Chinese patients with dermatomyositis. Rheumatol Int 2012; 32(12):3909–3915. doi:10.1007/s00296-011-2323-y
- Moghadam-Kia S, Oddis CV, Sato S, Kuwana M, Aggarwal R. Anti-melanoma differentiation-associated gene 5 is associated with rapidly progressive lung disease and poor survival in US patients with amyopathic and myopathic dermatomyositis. Arthritis Care Res (Hoboken) 2016; 68(5):689–694. doi:10.1002/acr.22728
- Aggarwal R, Dhillon N, Fertig N, Koontz D, Qi Z, Oddis CV. A negative antinuclear antibody does not indicate autoantibody negativity in myositis: role of anticytoplasmic antibody as a screening test for antisynthetase syndrome. J Rheumatol 2017; 44(2):223–229. doi:10.3899/jrheum.160618
Myopathies can present with a wide variety of symptoms, so patients with muscle weakness are often seen initially by a general practitioner. Nonrheumatologists should be able to evaluate a patient presenting with muscle weakness or myalgia and be aware of red flags indicating potentially dangerous syndromes that require a prompt, thorough investigation.
This article reviews selected causes of muscle weakness, such as statin-induced and autoimmune disorders, and systemic features of inflammatory myopathies beyond myositis, such as dermatologic and pulmonary manifestations.
FOCUSING THE EVALUATION
The evaluation of a patient presenting with muscle weakness should include several assessments:
Temporal progression. Was the onset of symptoms rapid or insidious? Patterns of onset may give clues to etiology, including the possibility of an associated autoimmune condition.
Location of muscle weakness. Are symptoms global or localized? And if localized, are they proximal or distal? Proximal weakness can be manifested by difficulty rising from a chair (hip muscles) or combing one’s hair (shoulder muscles), whereas distal weakness can involve difficulty standing on toes (gastrocnemius and soleus muscles) or performing fine motor activities (intrinsic hand muscles).
Symmetry. A focal or asymmetric pattern often has a neurologic etiology, but this could also be consistent with inclusion body myositis.
Other symptoms. Arthritis, rash, and swallowing problems point to a possible underlying rheumatologic disease. Weight gain or loss may indicate a thyroid disorder.
Family history. Some patients report that others in their family have this pattern of weakness, indicating a likely genetic myopathy. If the patient reports a relative with multiple sclerosis, lupus erythematosus, rheumatoid arthritis, or another autoimmune disease, then an immune-mediated myopathy should be considered.
Medications should be reviewed, particularly statins.
CASE 1: SLOWLY PROGRESSIVE WEAKNESS
A 65-year-old man presented with the insidious onset of muscle weakness and episodes of falling. On review of his medical record, his serum creatine kinase (CK) levels were elevated at various periods at 2 to 4 times the upper limit of normal. Electromyography (EMG) previously showed a myopathic pattern, and a muscle biopsy was abnormal, consistent with endomysial inflammation (term is consistent with “polymyositis”). He was treated for polymyositis for several years with prednisone alone, with steroids plus methotrexate, and with combined immunosuppression including methotrexate and azathioprine, but with no improvement. Eventually, another muscle biopsy revealed inclusion bodies with rimmed vacuoles, consistent with inclusion body myositis.
Inclusion body myositis
Inclusion body myositis is the most common myopathy in middle-aged to elderly people, especially men. These patients are often told “You are just getting old,” but they have a defined condition. It should also be considered in patients failing to respond to treatment or with those with “refractory” polymyositis.
The onset of muscle weakness is insidious and painless, and the weakness progresses slowly. The pattern is distal and asymmetric (eg, foot drop), and muscle atrophy typically affects the forearm flexors, quadriceps, and intrinsic muscles of the hands.1
Magnetic resonance imaging may show marked muscle atrophy. Unfortunately, no treatment has shown efficacy, and most neuromuscular and rheumatology experts do not treat inclusion body myositis with immunosuppressive drugs.
CASE 2: MILD MYALGIA WITHOUT WEAKNESS
A black 52-year-old man was referred because of myalgia and a CK level of 862 U/L (reference range < 200). His physician wanted to start him on a statin but was hesitant to do so without first consulting a rheumatologist.
The patient had a long history of mild arthralgias and myalgias without muscle weakness. He had dyslipidemia and hypertension. He reported no family history of myopathy and no illicit drug use. He was formerly an athlete. Medications included a thiazide diuretic and a beta-blocker. On examination, his muscles were strong (rated 5 on a scale of 5) in the upper and lower extremities, without atrophy.
His records showed that his CK levels had risen and fallen repeatedly over the past few years, ranging from 600 to 1,100 U/L. On further questioning, he reported that when he had joined the army 30 years previously, a physician had recommended he undergo a liver biopsy in view of elevated liver function tests, but that he had refused because he felt fine.
Currently, his gamma-glutamyl transpeptidase levels were normal.
Idiopathic ‘hyperCKemia’
So-called idiopathic hyperCKemia is not a form of myositis but merely a laboratory result outside the “normal” range. Reference ranges are based predominantly on measurements in white people and on an assumption that the distribution is Gaussian (bell-shaped). A normal CK level is usually defined as less than 200 U/L. Using this standard, up to 20% of men and 5% of women have hyperCKemia.2
However, CK levels vary by sex and ethnicity, with mean levels highest in black men, followed by black women, white men, and white women. The mean level in black men is higher than the standard cutoff point for normal, and especially in this population, there is wide fluctuation around the mean, leading to hyperCKemia quite frequently in black men. Exercise and manual labor also drive up CK levels.3–5
Idiopathic hyperCKemia is benign. D’Adda et al6 followed 55 patients for a mean of 7.5 years. CK levels normalized in 12 patients or at least decreased in 24. Most remained symptom-free or had minimal symptoms.
Idiopathic hyperCKemia: Bottom line
Before prescribing a statin, determine the baseline CK level. If slightly elevated (ie, up to 3 to 5 times the upper limit of normal, or even higher) in the setting of normal muscle strength, there is no need for electromyography or muscle biopsy, and the patient can certainly receive a statin. Most of these patients do not need to see a rheumatologist but can simply have their CK and muscle strength monitored.
CLASSIFYING MYOSITIS
Myositis (idiopathic inflammatory myopathy) is a heterogeneous group of autoimmune syndromes of unknown cause characterized by chronic muscle weakness and inflammation of striated muscle. These syndromes likely arise as a result of genetic predisposition and an environmental or infectious “hit.”
Myositis is rare, with an incidence of 5 to 10 cases per million per year and an estimated prevalence of 50 to 90 cases per million. It has 2 incidence peaks: 1 in childhood (age 5–15) and another in adult midlife (age 30–50). Women are affected 2 to 3 times more often than men, with black women most commonly affected.
Myositis is traditionally classified as follows:
- Adult polymyositis
- Adult dermatomyositis
- Juvenile myositis (dermatomyositis much more frequent than polymyositis)
- Malignancy-associated myositis (usually dermatomyositis)
- Myositis overlapping with another autoimmune disease
- Inclusion body myositis.
However, polymyositis is less common than we originally thought, and the term necrotizing myopathy is now used in many patients, as noted in the case studies below. Further, myositis overlap syndromes are being increasingly diagnosed, likely related to the emergence of autoantibodies and clinical “syndromes” associated with these autoantibody subsets (discussed in cases below).
Dermatomyositis
Dermatomyositis is characterized by muscle weakness and a rash that can be obvious or subtle. Classic skin lesions are Gottron papules, which are raised, flat-topped red or purplish lesions over the knuckles, elbows, or knees.
Lesions may be confused with those of psoriasis. There can also be a V-neck rash over the anterior chest or upper back (“shawl sign”) or a rash over the lateral thigh (“holster sign”). A facial rash may occur, but unlike lupus, dermatomyositis does not spare the nasolabial area. However, the V-neck rash can be similar to that seen in lupus.
Dermatomyositis may cause muscle pain, perhaps related to muscle ischemia, whereas polymyositis and necrotizing myopathy are often painless. However, pain is also associated with fibromyalgia, which may be seen in many autoimmune conditions. It is important not to overtreat rheumatologic diseases with immunosuppression to try to control pain if the pain is actually caused by fibromyalgia.
Polymyositis mimics
Hypothyroid myopathy can present as classic polymyositis. The serum CK may be elevated, and there may be myalgias, muscle hypertrophy with stiffness, weakness, cramps, and even features of a proximal myopathy, and rhabdomyolysis. The electromyogram can be normal or myopathic. Results of muscle biopsy are often normal but may show focal necrosis and mild inflammatory infiltrates, thus mimicking that seen with inflammatory myopathy.7
Drug-induced or toxic myopathies can also mimic polymyositis. Statins are among the most commonly prescribed drugs in the United States, with more than 35 million people taking them. Statins are generally well tolerated but have a broad spectrum of toxicity, ranging from myalgias to life-threatening rhabdomyolysis. Myalgias lead to about 5% to 10% of patients refusing to take a statin or stopping it on their own.
Myalgias affect up to 20% of statin users in clinical practice.8,9 A small cross-sectional study10 of 1,000 patients in a primary care setting found that the risk of muscle complaints in statin users was 1.5 times higher than in nonstatin users, similar to findings in other studies.
My strategy for managing a patient with possible statin-induced myopathy is illustrated in Figure 1.
CASE 3: WEAKNESS, VERY HIGH CK ON A STATIN
In March 2010, a 67-year-old woman presented with muscle weakness. She had a history of hypertension, hyperlipidemia, and, more than 10 years previously, uterine cancer. In 2004, she was given atorvastatin for dyslipidemia. Four years later, she developed lower-extremity weakness, which her doctor attributed to normal aging. A year after that, she found it difficult to walk up steps and lift her arms overhead. In June 2009, she stopped taking the atorvastatin on her own, but the weakness did not improve.
In September 2009, she returned to her doctor, who found her CK level was 6,473 U/L but believed it to be an error, so the test was repeated, with a result of 9,375 U/L. She had no rash or joint involvement.
She was admitted to the hospital and underwent muscle biopsy, which showed myonecrosis with no inflammation or vasculitis. She was treated with prednisone 60 mg/day, and her elevated CK level and weakness improved.
Immune-mediated necrotizing myopathy associated with statins
The hallmark of necrotizing myopathy is myonecrosis without significant inflammation.12 This pattern contrasts with that of polymyositis, which is characterized by lymphocytic inflammation.
Although statins became available in the United States in 1987, immune-mediated necrotizing myopathy associated with statins was first described only in 2010. In that report, Grable-Esposito et al13 described 25 patients from 2 neuromuscular centers seen between 2000 and 2008 who had elevated CK and proximal weakness during or after statin use, both of which persisted despite stopping the statin. Patients improved with immunosuppressive agents but had a relapse when steroids were stopped or tapered, a pattern typical in autoimmune disease.
Autoantibody defines subgroup of necrotizing myopathy
Also in 2010, Christopher-Stine et al14 reported an antibody associated with necrotizing myopathy. Of 38 patients with the condition, 16 were found to have an abnormal “doublet” autoantibody recognizing 200- and 100-kDa proteins. All patients had weakness and a high CK level, and 63% had statin exposure before the weakness (this percentage increased to 83% in patients older than 50). All responded to immunosuppressive therapy, and many had a relapse when it was withdrawn.
Statins lower cholesterol by inhibiting 3-hydroxy-3-methylglutaryl-Co A reductase (HMGCR), and paradoxically, they also upregulate it. HMGCR has a molecular weight of 97 kDa. Mammen et al15 identified HMGCR as the 100-kDa target of the identified antibody and developed an enzyme-linked immunosorbent assay for it. Of 750 patients presenting to one center, only 45 (6%) had anti-HMGCR autoantibodies, but all 16 patients who had the abnormal doublet antibody tested positive for anti-HMGCR. Regenerating muscle cells express high levels of HMGCR, which may sustain the immune response after statins are discontinued.
Case 3 continued: Intravenous immunoglobulin brings improvement
In March 2010, when the 67-year-old patient presented to our myositis center, her CK level was 5,800 U/L, which increased as prednisone was tapered. She still felt weak. On examination, her muscle strength findings were deltoids 4+/5, neck flexors 4/5, and iliopsoas 3+/5. She was treated with methotrexate and azathioprine without benefit. She was next treated with intravenous immunoglobulin, and after 3 months, her strength normalized for the first time in years. Her CK level decreased but did not normalize. Testing showed that she was positive for anti-HMGCR autoantibody, as this test had become commercially available.
In 2015, Mammen and Tiniakou16 suggested using intravenous immunoglobulin as first-line therapy for statin-associated autoimmune necrotizing myopathy, based on experience at a single center with 3 patients who declined glucocorticoid treatment.
Necrotizing myopathy: Bottom line
Myositis overlap syndromes
Heterogeneity is the rule in myositis, and it can present with a wide variety of signs and symptoms as outlined in Table 2.
CASE 4: FEVER, NEW ‘RHEUMATOID ARTHRITIS,’ AND LUNG DISEASE
A 52-year-old woman with knee osteoarthritis saw her primary care physician in November 2013 for dyspnea and low-grade fever. The next month, she presented with polyarthritis, muscle weakness, and Raynaud phenomenon.
In January 2014, she developed acrocyanosis of her fingers. Examination revealed hyperkeratotic, cracked areas of her fingers. Her oxygen saturation by pulse oximetry was low. She was admitted to the hospital. Her doctor suspected new onset of rheumatoid arthritis, but blood tests revealed a negative antinuclear antibody, so an autoimmune condition was deemed unlikely. Her CK was mildly elevated at 350 U/L.
Because of her dyspnea, an open-lung biopsy was performed. High-resolution computed tomography (CT) revealed infiltrates and ground-glass opacities, leading to the diagnosis of nonspecific interstitial pneumonia. A rheumatologist was consulted and recommended pulse methylprednisolone, followed by prednisone 60 mg/day and mycophenolate mofetil. Testing for Jo-1 antibodies was positive.
Antisynthetase syndrome
The antisynthetase syndrome is a clinically heterogeneous condition that can occur with any or all of the following:
- Fever
- Myositis
- Arthritis (often misdiagnosed as rheumatoid arthritis)
- Raynaud phenomenon
- Mechanic’s hands (hyperkeratotic roughness with fissures on the lateral aspects of the fingers and finger pads)
- Interstitial lung disease.
The skin rashes and myositis may be subtle, making the presentation “lung-dominant,” and nonrheumatologists should be aware of this syndrome. Although in our patient the condition developed in a classic manner, with all of the aforementioned features of the antisynthetase syndrome, some patients will manifest one or a few of the features.
Clinically, patients with the Jo-1 antisynthetase syndrome often present differently than those with non-Jo-1 antisynthetase autoantibodies. When we compared 122 patients with Jo-1 vs 80 patients with a non-Jo-1 antisynthetase autoantibody, patients with Jo-1 antibodies were more likely to have initially received a diagnosis of myositis (83%), while myositis was the original diagnosis in only 17% of those possessing non-Jo-1 antisynthetase autoantibodies. In fact, many patients (approximately 50%) were diagnosed as having undifferentiated connective tissue disease or an overlap syndrome, and 13% had scleroderma as their first diagnosis.17
We also found that the survival rate was higher in patients with Jo-1 syndrome compared with patients with non-Jo-1 antisynthetase syndromes. We attributed the difference in survival rates to a delayed diagnosis in the non-Jo-1 group, perhaps due to their “nonclassic” presentations of the antisynthetase syndrome, delaying appropriate treatment. Patients received a diagnosis of Jo-1 antibody syndrome after a mean of 0.4 year (range 0.2–0.8), while those with a non-Jo-1 antisynthetase autoantibody had a delay in diagnosis of 1.0 year (range 0.4–5.1) (P < .01).17
In nearly half the cases in this cohort, pulmonary fibrosis was the cause of death, with primary pulmonary hypertension being the second leading cause (11%).
Antisynthetase syndrome: Bottom line
Antisynthetase syndrome is an often fatal disease that does not always present in a typical fashion with symptoms of myositis, as lung disease may be the predominant feature. A negative antinuclear antibody test result does not imply antibody negativity, as the autoantigen in these diseases is not located in the nucleus. Prompt diagnosis and appropriate immunosuppressive therapy are critical to improving outcomes.
CASE 5: FEVER, UNDIAGNOSED LUNG DISEASE, NO MYOSITIS
In January 2001, a 39-year-old woman was admitted to the hospital after 5 weeks of fever (temperatures 103°–104°F) and myalgias. An extensive workup was negative except for low-titer antinuclear antibody and for mild basilar fibrosis noted on chest radiography. She left the hospital against medical advice because of frustration with a lack of a specific diagnosis (“fever of unknown origin”).
Two months later, at a follow-up rheumatology consult, she reported more myalgias and arthralgias, as well as fever. Chest radiography now showed pleural effusions. Her fingers had color changes consistent with Raynaud phenomenon. At that time, I diagnosed an undifferentiated connective tissue disease and told her that I suspected an autoimmune condition that would need time to reveal itself. In the meantime, I treated her empirically with prednisone.
In April, she returned, much more short of breath and with more prominent diffuse pulmonary infiltrates. Physical examination revealed subtle Gottron changes. Testing revealed poor pulmonary function: forced vital capacity (FVC) 56%, forced expiratory volume in 1 second (FEV1) 52%, and diffusing capacity for carbon monoxide (Dlco) 40%. Blood testing was positive for anti-PL-12 antibody, one of the non-Jo-1 antisynthetase antibodies. At this time, we treated her with glucocorticoids and tacrolimus.
More than 15 years later, this patient is doing well. Her skin rash, joint symptoms, and fever have not returned, and interestingly, she never developed myositis. Her Raynaud symptoms are mild. Her most recent pulmonary function test results (January 2018) were FVC 75%, FEV1 87%, and Dlco 78%. Although these results are not normal, they are much improved and allow her to be completely functional without supplemental oxygen. Echocardiography showed normal pulmonary artery systolic pressure (25 mm Hg). She was still taking tacrolimus and prednisone. When we tried to stop tacrolimus after she had done well for many years, her condition flared.
Non-Jo-1 antisynthetase syndrome: Bottom line
Patients with a non-Jo-1 antisynthetase syndrome often present without myositis symptoms and may never manifest myositis symptoms. Likely because of this presentation, diagnosis of a specific connective tissue disorder is delayed, perhaps leading to increased mortality risk from pulmonary disease. Chronic immunosuppression is often required for these autoimmune conditions.
CASE 6: DERMATOMYOSITIS, RAPIDLY PROGRESSIVE INTERSTITIAL LUNG DISEASE
A 58-year-old woman presented in the summer of 2012 with a photosensitive rash. The following January, she returned with polyarthritis, mild muscle weakness, and a dermatomyositis-pattern rash. Her CK level was normal, and her antinuclear antibody and Sjögren syndrome antibody test results were negative. She improved on low-dose prednisone and methotrexate.
She was originally referred to me in May of that year for worsening rash and mild weakness. She denied pulmonary symptoms, but examination revealed faint basilar crackles. I increased her prednisone dosage to 20 mg/day and started mycophenolate mofetil mainly for the mild cutaneous and myositis features. I also recommended high-resolution CT of the lungs and pulmonary function tests, which she underwent in early June. High-resolution CT showed nonspecific mild infiltrates with minimal ground-glass opacities.
On July 1, she presented to her local emergency department with severe shortness of breath, requiring oxygen 12 L/min. She had a palmar rash. Repeat high-resolution CT showed dramatic worsening compared with the scan the previous month. Because of continued inadequate oxygenation, she was transferred to our center. A blood test later was positive for antimelanoma differentiation-associated gene 5 (MDA-5) autoantibody, previously known as anticlinically amyopathic dermatomyositis (anti-CADM)-140 antibody (based on immunoprecipitation results).
She died on the third day after transfer, just 2 months after I had originally seen her, at which time she had had no pulmonary symptoms.
Clinically amyopathic dermatomyositis
Anti-CADM-140, first reported from Asia,18–20 is an autoantibody-associated disease but not an antisynthetase. It is associated with dermatomyositis; patients often have a “vasculopathy” with cutaneous ulcerations and palmar papules.
MDA-5 is a cytoplasmic protein that “senses” viral RNA and induces production of type 1 interferon. It is involved in the innate immune defense against viruses.
Anti-MDA-5 positivity is associated with a poor pulmonary outcome.21 In our cohort from the University of Pittsburgh, many patients died within 3 years, compared with about a 40% survival rate in patients with dermatomyositis who tested negative for this antibody. That being said, many patients with anti-MDA-5 do not develop rapidly progressive interstitial lung disease.
Autoimmune interstitial lung disease: Bottom line
Autoimmune interstitial lung disease is easy to miss, especially in the case of a non-Jo-1 syndrome, for 3 important reasons:
- The autoimmune features may initially be subtle (eg, Raynaud phenomena, mild dermatomyositis rash, undifferentiated connective tissue disease)
- Autoantibody testing is not often ordered, is not standardized, or may be unavailable
- Providers are mistakenly reassured that a patient who tests negative for antinuclear antibody does not have an autoimmune condition.
To emphasize the last point, in a cohort of 202 patients who tested positive for an antisynthetase antibody, only half were antinuclear antibody-positive, but nearly three-quarters demonstrated anticytoplasmic staining on indirect immunofluorescence (due to the location of the autoantigen in the cytoplasm), making the latter a better screening test for an antisynthetase antibody. For scleroderma, 99% were antinculear antibody-positive, but for myositis, this test is much less sensitive.22
Myopathies can present with a wide variety of symptoms, so patients with muscle weakness are often seen initially by a general practitioner. Nonrheumatologists should be able to evaluate a patient presenting with muscle weakness or myalgia and be aware of red flags indicating potentially dangerous syndromes that require a prompt, thorough investigation.
This article reviews selected causes of muscle weakness, such as statin-induced and autoimmune disorders, and systemic features of inflammatory myopathies beyond myositis, such as dermatologic and pulmonary manifestations.
FOCUSING THE EVALUATION
The evaluation of a patient presenting with muscle weakness should include several assessments:
Temporal progression. Was the onset of symptoms rapid or insidious? Patterns of onset may give clues to etiology, including the possibility of an associated autoimmune condition.
Location of muscle weakness. Are symptoms global or localized? And if localized, are they proximal or distal? Proximal weakness can be manifested by difficulty rising from a chair (hip muscles) or combing one’s hair (shoulder muscles), whereas distal weakness can involve difficulty standing on toes (gastrocnemius and soleus muscles) or performing fine motor activities (intrinsic hand muscles).
Symmetry. A focal or asymmetric pattern often has a neurologic etiology, but this could also be consistent with inclusion body myositis.
Other symptoms. Arthritis, rash, and swallowing problems point to a possible underlying rheumatologic disease. Weight gain or loss may indicate a thyroid disorder.
Family history. Some patients report that others in their family have this pattern of weakness, indicating a likely genetic myopathy. If the patient reports a relative with multiple sclerosis, lupus erythematosus, rheumatoid arthritis, or another autoimmune disease, then an immune-mediated myopathy should be considered.
Medications should be reviewed, particularly statins.
CASE 1: SLOWLY PROGRESSIVE WEAKNESS
A 65-year-old man presented with the insidious onset of muscle weakness and episodes of falling. On review of his medical record, his serum creatine kinase (CK) levels were elevated at various periods at 2 to 4 times the upper limit of normal. Electromyography (EMG) previously showed a myopathic pattern, and a muscle biopsy was abnormal, consistent with endomysial inflammation (term is consistent with “polymyositis”). He was treated for polymyositis for several years with prednisone alone, with steroids plus methotrexate, and with combined immunosuppression including methotrexate and azathioprine, but with no improvement. Eventually, another muscle biopsy revealed inclusion bodies with rimmed vacuoles, consistent with inclusion body myositis.
Inclusion body myositis
Inclusion body myositis is the most common myopathy in middle-aged to elderly people, especially men. These patients are often told “You are just getting old,” but they have a defined condition. It should also be considered in patients failing to respond to treatment or with those with “refractory” polymyositis.
The onset of muscle weakness is insidious and painless, and the weakness progresses slowly. The pattern is distal and asymmetric (eg, foot drop), and muscle atrophy typically affects the forearm flexors, quadriceps, and intrinsic muscles of the hands.1
Magnetic resonance imaging may show marked muscle atrophy. Unfortunately, no treatment has shown efficacy, and most neuromuscular and rheumatology experts do not treat inclusion body myositis with immunosuppressive drugs.
CASE 2: MILD MYALGIA WITHOUT WEAKNESS
A black 52-year-old man was referred because of myalgia and a CK level of 862 U/L (reference range < 200). His physician wanted to start him on a statin but was hesitant to do so without first consulting a rheumatologist.
The patient had a long history of mild arthralgias and myalgias without muscle weakness. He had dyslipidemia and hypertension. He reported no family history of myopathy and no illicit drug use. He was formerly an athlete. Medications included a thiazide diuretic and a beta-blocker. On examination, his muscles were strong (rated 5 on a scale of 5) in the upper and lower extremities, without atrophy.
His records showed that his CK levels had risen and fallen repeatedly over the past few years, ranging from 600 to 1,100 U/L. On further questioning, he reported that when he had joined the army 30 years previously, a physician had recommended he undergo a liver biopsy in view of elevated liver function tests, but that he had refused because he felt fine.
Currently, his gamma-glutamyl transpeptidase levels were normal.
Idiopathic ‘hyperCKemia’
So-called idiopathic hyperCKemia is not a form of myositis but merely a laboratory result outside the “normal” range. Reference ranges are based predominantly on measurements in white people and on an assumption that the distribution is Gaussian (bell-shaped). A normal CK level is usually defined as less than 200 U/L. Using this standard, up to 20% of men and 5% of women have hyperCKemia.2
However, CK levels vary by sex and ethnicity, with mean levels highest in black men, followed by black women, white men, and white women. The mean level in black men is higher than the standard cutoff point for normal, and especially in this population, there is wide fluctuation around the mean, leading to hyperCKemia quite frequently in black men. Exercise and manual labor also drive up CK levels.3–5
Idiopathic hyperCKemia is benign. D’Adda et al6 followed 55 patients for a mean of 7.5 years. CK levels normalized in 12 patients or at least decreased in 24. Most remained symptom-free or had minimal symptoms.
Idiopathic hyperCKemia: Bottom line
Before prescribing a statin, determine the baseline CK level. If slightly elevated (ie, up to 3 to 5 times the upper limit of normal, or even higher) in the setting of normal muscle strength, there is no need for electromyography or muscle biopsy, and the patient can certainly receive a statin. Most of these patients do not need to see a rheumatologist but can simply have their CK and muscle strength monitored.
CLASSIFYING MYOSITIS
Myositis (idiopathic inflammatory myopathy) is a heterogeneous group of autoimmune syndromes of unknown cause characterized by chronic muscle weakness and inflammation of striated muscle. These syndromes likely arise as a result of genetic predisposition and an environmental or infectious “hit.”
Myositis is rare, with an incidence of 5 to 10 cases per million per year and an estimated prevalence of 50 to 90 cases per million. It has 2 incidence peaks: 1 in childhood (age 5–15) and another in adult midlife (age 30–50). Women are affected 2 to 3 times more often than men, with black women most commonly affected.
Myositis is traditionally classified as follows:
- Adult polymyositis
- Adult dermatomyositis
- Juvenile myositis (dermatomyositis much more frequent than polymyositis)
- Malignancy-associated myositis (usually dermatomyositis)
- Myositis overlapping with another autoimmune disease
- Inclusion body myositis.
However, polymyositis is less common than we originally thought, and the term necrotizing myopathy is now used in many patients, as noted in the case studies below. Further, myositis overlap syndromes are being increasingly diagnosed, likely related to the emergence of autoantibodies and clinical “syndromes” associated with these autoantibody subsets (discussed in cases below).
Dermatomyositis
Dermatomyositis is characterized by muscle weakness and a rash that can be obvious or subtle. Classic skin lesions are Gottron papules, which are raised, flat-topped red or purplish lesions over the knuckles, elbows, or knees.
Lesions may be confused with those of psoriasis. There can also be a V-neck rash over the anterior chest or upper back (“shawl sign”) or a rash over the lateral thigh (“holster sign”). A facial rash may occur, but unlike lupus, dermatomyositis does not spare the nasolabial area. However, the V-neck rash can be similar to that seen in lupus.
Dermatomyositis may cause muscle pain, perhaps related to muscle ischemia, whereas polymyositis and necrotizing myopathy are often painless. However, pain is also associated with fibromyalgia, which may be seen in many autoimmune conditions. It is important not to overtreat rheumatologic diseases with immunosuppression to try to control pain if the pain is actually caused by fibromyalgia.
Polymyositis mimics
Hypothyroid myopathy can present as classic polymyositis. The serum CK may be elevated, and there may be myalgias, muscle hypertrophy with stiffness, weakness, cramps, and even features of a proximal myopathy, and rhabdomyolysis. The electromyogram can be normal or myopathic. Results of muscle biopsy are often normal but may show focal necrosis and mild inflammatory infiltrates, thus mimicking that seen with inflammatory myopathy.7
Drug-induced or toxic myopathies can also mimic polymyositis. Statins are among the most commonly prescribed drugs in the United States, with more than 35 million people taking them. Statins are generally well tolerated but have a broad spectrum of toxicity, ranging from myalgias to life-threatening rhabdomyolysis. Myalgias lead to about 5% to 10% of patients refusing to take a statin or stopping it on their own.
Myalgias affect up to 20% of statin users in clinical practice.8,9 A small cross-sectional study10 of 1,000 patients in a primary care setting found that the risk of muscle complaints in statin users was 1.5 times higher than in nonstatin users, similar to findings in other studies.
My strategy for managing a patient with possible statin-induced myopathy is illustrated in Figure 1.
CASE 3: WEAKNESS, VERY HIGH CK ON A STATIN
In March 2010, a 67-year-old woman presented with muscle weakness. She had a history of hypertension, hyperlipidemia, and, more than 10 years previously, uterine cancer. In 2004, she was given atorvastatin for dyslipidemia. Four years later, she developed lower-extremity weakness, which her doctor attributed to normal aging. A year after that, she found it difficult to walk up steps and lift her arms overhead. In June 2009, she stopped taking the atorvastatin on her own, but the weakness did not improve.
In September 2009, she returned to her doctor, who found her CK level was 6,473 U/L but believed it to be an error, so the test was repeated, with a result of 9,375 U/L. She had no rash or joint involvement.
She was admitted to the hospital and underwent muscle biopsy, which showed myonecrosis with no inflammation or vasculitis. She was treated with prednisone 60 mg/day, and her elevated CK level and weakness improved.
Immune-mediated necrotizing myopathy associated with statins
The hallmark of necrotizing myopathy is myonecrosis without significant inflammation.12 This pattern contrasts with that of polymyositis, which is characterized by lymphocytic inflammation.
Although statins became available in the United States in 1987, immune-mediated necrotizing myopathy associated with statins was first described only in 2010. In that report, Grable-Esposito et al13 described 25 patients from 2 neuromuscular centers seen between 2000 and 2008 who had elevated CK and proximal weakness during or after statin use, both of which persisted despite stopping the statin. Patients improved with immunosuppressive agents but had a relapse when steroids were stopped or tapered, a pattern typical in autoimmune disease.
Autoantibody defines subgroup of necrotizing myopathy
Also in 2010, Christopher-Stine et al14 reported an antibody associated with necrotizing myopathy. Of 38 patients with the condition, 16 were found to have an abnormal “doublet” autoantibody recognizing 200- and 100-kDa proteins. All patients had weakness and a high CK level, and 63% had statin exposure before the weakness (this percentage increased to 83% in patients older than 50). All responded to immunosuppressive therapy, and many had a relapse when it was withdrawn.
Statins lower cholesterol by inhibiting 3-hydroxy-3-methylglutaryl-Co A reductase (HMGCR), and paradoxically, they also upregulate it. HMGCR has a molecular weight of 97 kDa. Mammen et al15 identified HMGCR as the 100-kDa target of the identified antibody and developed an enzyme-linked immunosorbent assay for it. Of 750 patients presenting to one center, only 45 (6%) had anti-HMGCR autoantibodies, but all 16 patients who had the abnormal doublet antibody tested positive for anti-HMGCR. Regenerating muscle cells express high levels of HMGCR, which may sustain the immune response after statins are discontinued.
Case 3 continued: Intravenous immunoglobulin brings improvement
In March 2010, when the 67-year-old patient presented to our myositis center, her CK level was 5,800 U/L, which increased as prednisone was tapered. She still felt weak. On examination, her muscle strength findings were deltoids 4+/5, neck flexors 4/5, and iliopsoas 3+/5. She was treated with methotrexate and azathioprine without benefit. She was next treated with intravenous immunoglobulin, and after 3 months, her strength normalized for the first time in years. Her CK level decreased but did not normalize. Testing showed that she was positive for anti-HMGCR autoantibody, as this test had become commercially available.
In 2015, Mammen and Tiniakou16 suggested using intravenous immunoglobulin as first-line therapy for statin-associated autoimmune necrotizing myopathy, based on experience at a single center with 3 patients who declined glucocorticoid treatment.
Necrotizing myopathy: Bottom line
Myositis overlap syndromes
Heterogeneity is the rule in myositis, and it can present with a wide variety of signs and symptoms as outlined in Table 2.
CASE 4: FEVER, NEW ‘RHEUMATOID ARTHRITIS,’ AND LUNG DISEASE
A 52-year-old woman with knee osteoarthritis saw her primary care physician in November 2013 for dyspnea and low-grade fever. The next month, she presented with polyarthritis, muscle weakness, and Raynaud phenomenon.
In January 2014, she developed acrocyanosis of her fingers. Examination revealed hyperkeratotic, cracked areas of her fingers. Her oxygen saturation by pulse oximetry was low. She was admitted to the hospital. Her doctor suspected new onset of rheumatoid arthritis, but blood tests revealed a negative antinuclear antibody, so an autoimmune condition was deemed unlikely. Her CK was mildly elevated at 350 U/L.
Because of her dyspnea, an open-lung biopsy was performed. High-resolution computed tomography (CT) revealed infiltrates and ground-glass opacities, leading to the diagnosis of nonspecific interstitial pneumonia. A rheumatologist was consulted and recommended pulse methylprednisolone, followed by prednisone 60 mg/day and mycophenolate mofetil. Testing for Jo-1 antibodies was positive.
Antisynthetase syndrome
The antisynthetase syndrome is a clinically heterogeneous condition that can occur with any or all of the following:
- Fever
- Myositis
- Arthritis (often misdiagnosed as rheumatoid arthritis)
- Raynaud phenomenon
- Mechanic’s hands (hyperkeratotic roughness with fissures on the lateral aspects of the fingers and finger pads)
- Interstitial lung disease.
The skin rashes and myositis may be subtle, making the presentation “lung-dominant,” and nonrheumatologists should be aware of this syndrome. Although in our patient the condition developed in a classic manner, with all of the aforementioned features of the antisynthetase syndrome, some patients will manifest one or a few of the features.
Clinically, patients with the Jo-1 antisynthetase syndrome often present differently than those with non-Jo-1 antisynthetase autoantibodies. When we compared 122 patients with Jo-1 vs 80 patients with a non-Jo-1 antisynthetase autoantibody, patients with Jo-1 antibodies were more likely to have initially received a diagnosis of myositis (83%), while myositis was the original diagnosis in only 17% of those possessing non-Jo-1 antisynthetase autoantibodies. In fact, many patients (approximately 50%) were diagnosed as having undifferentiated connective tissue disease or an overlap syndrome, and 13% had scleroderma as their first diagnosis.17
We also found that the survival rate was higher in patients with Jo-1 syndrome compared with patients with non-Jo-1 antisynthetase syndromes. We attributed the difference in survival rates to a delayed diagnosis in the non-Jo-1 group, perhaps due to their “nonclassic” presentations of the antisynthetase syndrome, delaying appropriate treatment. Patients received a diagnosis of Jo-1 antibody syndrome after a mean of 0.4 year (range 0.2–0.8), while those with a non-Jo-1 antisynthetase autoantibody had a delay in diagnosis of 1.0 year (range 0.4–5.1) (P < .01).17
In nearly half the cases in this cohort, pulmonary fibrosis was the cause of death, with primary pulmonary hypertension being the second leading cause (11%).
Antisynthetase syndrome: Bottom line
Antisynthetase syndrome is an often fatal disease that does not always present in a typical fashion with symptoms of myositis, as lung disease may be the predominant feature. A negative antinuclear antibody test result does not imply antibody negativity, as the autoantigen in these diseases is not located in the nucleus. Prompt diagnosis and appropriate immunosuppressive therapy are critical to improving outcomes.
CASE 5: FEVER, UNDIAGNOSED LUNG DISEASE, NO MYOSITIS
In January 2001, a 39-year-old woman was admitted to the hospital after 5 weeks of fever (temperatures 103°–104°F) and myalgias. An extensive workup was negative except for low-titer antinuclear antibody and for mild basilar fibrosis noted on chest radiography. She left the hospital against medical advice because of frustration with a lack of a specific diagnosis (“fever of unknown origin”).
Two months later, at a follow-up rheumatology consult, she reported more myalgias and arthralgias, as well as fever. Chest radiography now showed pleural effusions. Her fingers had color changes consistent with Raynaud phenomenon. At that time, I diagnosed an undifferentiated connective tissue disease and told her that I suspected an autoimmune condition that would need time to reveal itself. In the meantime, I treated her empirically with prednisone.
In April, she returned, much more short of breath and with more prominent diffuse pulmonary infiltrates. Physical examination revealed subtle Gottron changes. Testing revealed poor pulmonary function: forced vital capacity (FVC) 56%, forced expiratory volume in 1 second (FEV1) 52%, and diffusing capacity for carbon monoxide (Dlco) 40%. Blood testing was positive for anti-PL-12 antibody, one of the non-Jo-1 antisynthetase antibodies. At this time, we treated her with glucocorticoids and tacrolimus.
More than 15 years later, this patient is doing well. Her skin rash, joint symptoms, and fever have not returned, and interestingly, she never developed myositis. Her Raynaud symptoms are mild. Her most recent pulmonary function test results (January 2018) were FVC 75%, FEV1 87%, and Dlco 78%. Although these results are not normal, they are much improved and allow her to be completely functional without supplemental oxygen. Echocardiography showed normal pulmonary artery systolic pressure (25 mm Hg). She was still taking tacrolimus and prednisone. When we tried to stop tacrolimus after she had done well for many years, her condition flared.
Non-Jo-1 antisynthetase syndrome: Bottom line
Patients with a non-Jo-1 antisynthetase syndrome often present without myositis symptoms and may never manifest myositis symptoms. Likely because of this presentation, diagnosis of a specific connective tissue disorder is delayed, perhaps leading to increased mortality risk from pulmonary disease. Chronic immunosuppression is often required for these autoimmune conditions.
CASE 6: DERMATOMYOSITIS, RAPIDLY PROGRESSIVE INTERSTITIAL LUNG DISEASE
A 58-year-old woman presented in the summer of 2012 with a photosensitive rash. The following January, she returned with polyarthritis, mild muscle weakness, and a dermatomyositis-pattern rash. Her CK level was normal, and her antinuclear antibody and Sjögren syndrome antibody test results were negative. She improved on low-dose prednisone and methotrexate.
She was originally referred to me in May of that year for worsening rash and mild weakness. She denied pulmonary symptoms, but examination revealed faint basilar crackles. I increased her prednisone dosage to 20 mg/day and started mycophenolate mofetil mainly for the mild cutaneous and myositis features. I also recommended high-resolution CT of the lungs and pulmonary function tests, which she underwent in early June. High-resolution CT showed nonspecific mild infiltrates with minimal ground-glass opacities.
On July 1, she presented to her local emergency department with severe shortness of breath, requiring oxygen 12 L/min. She had a palmar rash. Repeat high-resolution CT showed dramatic worsening compared with the scan the previous month. Because of continued inadequate oxygenation, she was transferred to our center. A blood test later was positive for antimelanoma differentiation-associated gene 5 (MDA-5) autoantibody, previously known as anticlinically amyopathic dermatomyositis (anti-CADM)-140 antibody (based on immunoprecipitation results).
She died on the third day after transfer, just 2 months after I had originally seen her, at which time she had had no pulmonary symptoms.
Clinically amyopathic dermatomyositis
Anti-CADM-140, first reported from Asia,18–20 is an autoantibody-associated disease but not an antisynthetase. It is associated with dermatomyositis; patients often have a “vasculopathy” with cutaneous ulcerations and palmar papules.
MDA-5 is a cytoplasmic protein that “senses” viral RNA and induces production of type 1 interferon. It is involved in the innate immune defense against viruses.
Anti-MDA-5 positivity is associated with a poor pulmonary outcome.21 In our cohort from the University of Pittsburgh, many patients died within 3 years, compared with about a 40% survival rate in patients with dermatomyositis who tested negative for this antibody. That being said, many patients with anti-MDA-5 do not develop rapidly progressive interstitial lung disease.
Autoimmune interstitial lung disease: Bottom line
Autoimmune interstitial lung disease is easy to miss, especially in the case of a non-Jo-1 syndrome, for 3 important reasons:
- The autoimmune features may initially be subtle (eg, Raynaud phenomena, mild dermatomyositis rash, undifferentiated connective tissue disease)
- Autoantibody testing is not often ordered, is not standardized, or may be unavailable
- Providers are mistakenly reassured that a patient who tests negative for antinuclear antibody does not have an autoimmune condition.
To emphasize the last point, in a cohort of 202 patients who tested positive for an antisynthetase antibody, only half were antinuclear antibody-positive, but nearly three-quarters demonstrated anticytoplasmic staining on indirect immunofluorescence (due to the location of the autoantigen in the cytoplasm), making the latter a better screening test for an antisynthetase antibody. For scleroderma, 99% were antinculear antibody-positive, but for myositis, this test is much less sensitive.22
- Felice KJ, North WA. Inclusion body myositis in Connecticut: observations in 35 patients during an 8-year period. Medicine (Baltimore) 2001; 80(5):320–327. doi:10.1097/00005792-200109000-00006
- Lev EI, Tur-Kaspa I, Ashkenazy I, et al. Distribution of serum creatine kinase activity in young healthy persons. Clin Chim Acta 1999; 279(1-2):107–115. doi:10.1016/S0009-8981(98)00180-6
- Lilleng H, Abeler K, Johnsen SH, et al. Variation of serum creatine kinase (CK) levels and prevalence of persistent hyperCKemia in a Norwegian normal population. The Tromsø Study. Neuromuscul Disord 2011; 21(7):494–500. doi:10.1016/j.nmd.2011.04.007
- Johnston JD, Lloyd M, Mathews JA, Hawthorne SW. Racial variation in serum creatine kinase levels. J R Soc Med 1996; 89(8):462-464. pmid:8795501
- Prelle A, Tancredi L, Sciacco M, et al. Retrospective study of a large population of patients with asymptomatic or minimally symptomatic raised serum creatine kinase levels. J Neurol 2002; 249(3):305–311. pmid:11993531
- D’Adda E, Sciacco M, Fruguglietti ME, et al. Follow-up of a large population of asymptomatic/oligosymptomatic hyperckemic subjects. J Neurol 2006; 253(11):1399–1403. doi:10.1007/s00415-006-0223-y
- Madariaga MG. Polymyositis-like syndrome in hypothyroidism: review of cases reported over the past twenty-five years. Thyroid 2002; 12(4):331–336. doi:10.1089/10507250252949478
- de Sauvage Nolting PR, Buirma RJ, Hutten BA, Kastelein JJ; Dutch ExPRESS Investigator Group. Two-year efficacy and safety of simvastatin 80 mg in familial hypercholesterolemia (the Examination of Probands and Relatives in Statin Studies With Familial Hypercholesterolemia [ExPRESS FH]). Am J Cardiol 2002; 90(2):181–184. doi:10.1016/s0002-9149(02)02449-9
- Bruckert E, Hayem G, Dejager S, Yau C, Bégaud B. Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients--the PRIMO study. Cardiovasc Drugs Ther 2005; 19(6):403–414. doi:10.1007/s10557-005-5686-z
- Mosshammer D, Lorenz G, Meznaric S, Schwarz J, Muche R, Mörike K. Statin use and its association with musculoskeletal symptoms—a cross-sectional study in primary care settings. Fam Pract 2009; 26(2):88–95. doi:10.1093/fampra/cmp006
- Nichols GA, Koro CE. Does statin therapy initiation increase the risk for myopathy? An observational study of 32,225 diabetic and nondiabetic patients. Clin Ther 2007; 29(8):1761–1770. doi:10.1016/j.clinthera.2007.08.022
- Kassardjian CD, Lennon VA, Alfugham NB, Mahler M, Milone M. Clinical features and treatment outcomes of necrotizing autoimmune myopathy. JAMA Neurol 2015; 72(9):996–1003. doi:10.1001/jamaneurol.2015.1207
- Grable-Esposito P, Katzberg HD, Greenberg SA, Srinivasan J, Katz J, Amato AA. Immune-mediated necrotizing myopathy associated with statins. Muscle Nerve 2010; 41(2):185–190. doi:10.1002/mus.21486
- Christopher-Stine L, Casciola-Rosen LA, Hong G, Chung T, Corse AM, Mammen AL. A novel autoantibody recognizing 200-kd and 100-kd proteins is associated with an immune-mediated necrotizing myopathy. Arthritis Rheum 2010; 62(9):2757–2766. doi:10.1002/art.27572
- Mammen AL, Chung T, Christopher-Stine L, et al. Autoantibodies against 3-hydroxy-3-methylglutaryl-coenzyme A reductase in patients with statin-associated autoimmune myopathy. Arthritis Rheum 2011; 63(3):713–721. doi:10.1002/art.30156
- Mammen AL, Tiniakou E. Intravenous immune globulin for statin-triggered autoimmune myopathy. N Engl J Med 2015; 373(17):1680–1682. doi:10.1056/NEJMc1506163
- Aggarwal R, Cassidy E, Fertig N, et al. Patients with non-Jo-1 anti-tRNA-synthetase autoantibodies have worse survival than Jo-1 positive patients. Ann Rheum Dis 2014; 73(1):227–232. doi:10.1136/annrheumdis-2012-201800
- Sato S, Hirakata M, Kuwana M, et al. Autoantibodies to a 140-kd polypeptide, CADM-140, in Japanese patients with clinically amyopathic dermatomyositis. Arthritis Rheum 2005; 52(5):1571–1576. doi:10.1002/art.21023
- Sato S, Hoshino K, Satoh T, et al. RNA helicase encoded by melanoma differentiation-associated gene 5 is a major autoantigen in patients with clinically amyopathic dermatomyositis: association with rapidly progressive interstitial lung disease. Arthritis Rheum 2009; 60(7):2193–2200. doi:10.1002/art.24621
- Chen F, Wang D, Shu X, Nakashima R, Wang G. Anti-MDA5 antibody is associated with A/SIP and decreased T cells in peripheral blood and predicts poor prognosis of ILD in Chinese patients with dermatomyositis. Rheumatol Int 2012; 32(12):3909–3915. doi:10.1007/s00296-011-2323-y
- Moghadam-Kia S, Oddis CV, Sato S, Kuwana M, Aggarwal R. Anti-melanoma differentiation-associated gene 5 is associated with rapidly progressive lung disease and poor survival in US patients with amyopathic and myopathic dermatomyositis. Arthritis Care Res (Hoboken) 2016; 68(5):689–694. doi:10.1002/acr.22728
- Aggarwal R, Dhillon N, Fertig N, Koontz D, Qi Z, Oddis CV. A negative antinuclear antibody does not indicate autoantibody negativity in myositis: role of anticytoplasmic antibody as a screening test for antisynthetase syndrome. J Rheumatol 2017; 44(2):223–229. doi:10.3899/jrheum.160618
- Felice KJ, North WA. Inclusion body myositis in Connecticut: observations in 35 patients during an 8-year period. Medicine (Baltimore) 2001; 80(5):320–327. doi:10.1097/00005792-200109000-00006
- Lev EI, Tur-Kaspa I, Ashkenazy I, et al. Distribution of serum creatine kinase activity in young healthy persons. Clin Chim Acta 1999; 279(1-2):107–115. doi:10.1016/S0009-8981(98)00180-6
- Lilleng H, Abeler K, Johnsen SH, et al. Variation of serum creatine kinase (CK) levels and prevalence of persistent hyperCKemia in a Norwegian normal population. The Tromsø Study. Neuromuscul Disord 2011; 21(7):494–500. doi:10.1016/j.nmd.2011.04.007
- Johnston JD, Lloyd M, Mathews JA, Hawthorne SW. Racial variation in serum creatine kinase levels. J R Soc Med 1996; 89(8):462-464. pmid:8795501
- Prelle A, Tancredi L, Sciacco M, et al. Retrospective study of a large population of patients with asymptomatic or minimally symptomatic raised serum creatine kinase levels. J Neurol 2002; 249(3):305–311. pmid:11993531
- D’Adda E, Sciacco M, Fruguglietti ME, et al. Follow-up of a large population of asymptomatic/oligosymptomatic hyperckemic subjects. J Neurol 2006; 253(11):1399–1403. doi:10.1007/s00415-006-0223-y
- Madariaga MG. Polymyositis-like syndrome in hypothyroidism: review of cases reported over the past twenty-five years. Thyroid 2002; 12(4):331–336. doi:10.1089/10507250252949478
- de Sauvage Nolting PR, Buirma RJ, Hutten BA, Kastelein JJ; Dutch ExPRESS Investigator Group. Two-year efficacy and safety of simvastatin 80 mg in familial hypercholesterolemia (the Examination of Probands and Relatives in Statin Studies With Familial Hypercholesterolemia [ExPRESS FH]). Am J Cardiol 2002; 90(2):181–184. doi:10.1016/s0002-9149(02)02449-9
- Bruckert E, Hayem G, Dejager S, Yau C, Bégaud B. Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients--the PRIMO study. Cardiovasc Drugs Ther 2005; 19(6):403–414. doi:10.1007/s10557-005-5686-z
- Mosshammer D, Lorenz G, Meznaric S, Schwarz J, Muche R, Mörike K. Statin use and its association with musculoskeletal symptoms—a cross-sectional study in primary care settings. Fam Pract 2009; 26(2):88–95. doi:10.1093/fampra/cmp006
- Nichols GA, Koro CE. Does statin therapy initiation increase the risk for myopathy? An observational study of 32,225 diabetic and nondiabetic patients. Clin Ther 2007; 29(8):1761–1770. doi:10.1016/j.clinthera.2007.08.022
- Kassardjian CD, Lennon VA, Alfugham NB, Mahler M, Milone M. Clinical features and treatment outcomes of necrotizing autoimmune myopathy. JAMA Neurol 2015; 72(9):996–1003. doi:10.1001/jamaneurol.2015.1207
- Grable-Esposito P, Katzberg HD, Greenberg SA, Srinivasan J, Katz J, Amato AA. Immune-mediated necrotizing myopathy associated with statins. Muscle Nerve 2010; 41(2):185–190. doi:10.1002/mus.21486
- Christopher-Stine L, Casciola-Rosen LA, Hong G, Chung T, Corse AM, Mammen AL. A novel autoantibody recognizing 200-kd and 100-kd proteins is associated with an immune-mediated necrotizing myopathy. Arthritis Rheum 2010; 62(9):2757–2766. doi:10.1002/art.27572
- Mammen AL, Chung T, Christopher-Stine L, et al. Autoantibodies against 3-hydroxy-3-methylglutaryl-coenzyme A reductase in patients with statin-associated autoimmune myopathy. Arthritis Rheum 2011; 63(3):713–721. doi:10.1002/art.30156
- Mammen AL, Tiniakou E. Intravenous immune globulin for statin-triggered autoimmune myopathy. N Engl J Med 2015; 373(17):1680–1682. doi:10.1056/NEJMc1506163
- Aggarwal R, Cassidy E, Fertig N, et al. Patients with non-Jo-1 anti-tRNA-synthetase autoantibodies have worse survival than Jo-1 positive patients. Ann Rheum Dis 2014; 73(1):227–232. doi:10.1136/annrheumdis-2012-201800
- Sato S, Hirakata M, Kuwana M, et al. Autoantibodies to a 140-kd polypeptide, CADM-140, in Japanese patients with clinically amyopathic dermatomyositis. Arthritis Rheum 2005; 52(5):1571–1576. doi:10.1002/art.21023
- Sato S, Hoshino K, Satoh T, et al. RNA helicase encoded by melanoma differentiation-associated gene 5 is a major autoantigen in patients with clinically amyopathic dermatomyositis: association with rapidly progressive interstitial lung disease. Arthritis Rheum 2009; 60(7):2193–2200. doi:10.1002/art.24621
- Chen F, Wang D, Shu X, Nakashima R, Wang G. Anti-MDA5 antibody is associated with A/SIP and decreased T cells in peripheral blood and predicts poor prognosis of ILD in Chinese patients with dermatomyositis. Rheumatol Int 2012; 32(12):3909–3915. doi:10.1007/s00296-011-2323-y
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- Aggarwal R, Dhillon N, Fertig N, Koontz D, Qi Z, Oddis CV. A negative antinuclear antibody does not indicate autoantibody negativity in myositis: role of anticytoplasmic antibody as a screening test for antisynthetase syndrome. J Rheumatol 2017; 44(2):223–229. doi:10.3899/jrheum.160618
KEY POINTS
- Inclusion body myositis affects older men more than women and is characterized by slowly progressive, asymmetric, distal and proximal weakness and atrophy.
- Statin-associated muscle complaints are common, whereas necrotizing myopathy, characterized by a very high CK plus weakness, is rare but must be recognized.
- Elevated CK does not necessarily indicate myositis, especially in African Americans or after heavy exercise.
- Dermatomyositis is characterized by muscle weakness and raised red or purple Gottron papules over the knuckles, elbows, or knees.
- Autoimmune interstitial lung disease may be caused by a variety of antibodies, the most common being anti-Jo-1 (directed against histidyl tRNA synthetase).
- The rarer non-Jo-1 antisynthetase autoantibodies may be associated with rapidly progressive interstitial lung disease, which is a challenge to recognize because associated rheumatologic symptoms may be minimal.
