For people with diabetes, disease management can become a part-time job that affects their actual jobs, their sleep, their relationships, and their recreational activities, according to a new survey by prescription manager UpWell Health.

The time spent on activities that come with diabetes management – blood glucose monitoring, diet planning, medical appointments – can add up to several hours a week. Among the 5,255 respondents to the online survey, 18% said that such tasks took up 5-10 hours each week, 7% said it was 10-15 hours, and 9% said they spent 15 or more hours a week on diabetes-related tasks, UpWell reported.

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For people with diabetes, disease management can become a part-time job that affects their actual jobs, their sleep, their relationships, and their recreational activities, according to a new survey by prescription manager UpWell Health.

The time spent on activities that come with diabetes management – blood glucose monitoring, diet planning, medical appointments – can add up to several hours a week. Among the 5,255 respondents to the online survey, 18% said that such tasks took up 5-10 hours each week, 7% said it was 10-15 hours, and 9% said they spent 15 or more hours a week on diabetes-related tasks, UpWell reported.

[email protected]

For people with diabetes, disease management can become a part-time job that affects their actual jobs, their sleep, their relationships, and their recreational activities, according to a new survey by prescription manager UpWell Health.

The time spent on activities that come with diabetes management – blood glucose monitoring, diet planning, medical appointments – can add up to several hours a week. Among the 5,255 respondents to the online survey, 18% said that such tasks took up 5-10 hours each week, 7% said it was 10-15 hours, and 9% said they spent 15 or more hours a week on diabetes-related tasks, UpWell reported.

[email protected]

In the United States, family physicians (general practitioners) used to manage their patients in the hospital, either as the primary care doctor or in consultation with specialists. Only since the 1990s has a new kind of physician gained widespread acceptance: the hospitalist (“specialist of inpatient care”).¹

In Italy the process has not been the same. In our health care system, primary care physicians have always transferred the responsibility of hospital care to an inpatient team. Actually, our hospital-based doctors dedicate their whole working time to inpatient care, and general practitioners are not expected to go to the hospital. The patients were (and are) admitted to one ward or another according to their main clinical problem.

Little by little, a huge number of organ specialty and subspecialty wards have filled Italian hospitals. In this context, the internal medicine specialty was unable to occupy its characteristic role, so that, a few years ago, the medical community wondered if the specialty should have continued to exist.

References

1. Baudendistel TE, Watcher RM. The evolution of the hospitalist movement in USA. Clin Med JRCPL. 2002;2:327-30.

2. Pantilat S. What is a Hospitalist? The Hospitalist 2006 February;2006(2).

3. Wachter RM, Goldman Lee. The emerging role of “Hospitalists” in the American Health Care System. N Engl J Med. 1996;335:514-7.

4. White HL, Glazier RH. Do hospitalist physicians improve the quality of inpatient care delivery? A systematic review of process, efficiency and outcome measures. BMC Medicine. 2011;9:58:1-22. http://www.biomedcentral.com/1741-7015/9/58.

5. Wachter RM, Goldman L. Zero to 50,000 – The 20th Anniversary of the Hospitalist. N Engl J Med. 2016;375:1009-11.
 

Valerio Verdiani, MD, director of internal medicine, Grosseto, Italy. Francesco Orlandini, MD, internal medicine, health administrator, ASL4 Liguria, Chiavari (GE), Italy. Micaela La Regina, MD, internal medicine, risk management and clinical governance, ASL5 Liguria, La Spezia, Italy. Giovanni Murialdo, MD, department of internal medicine and medical specialty, University of Genoa (Italy). Andrea Fontanella, MD, director of medicine department, president of the Federation of Associations of Hospital Doctors on Internal Medicine (FADOI), Naples, Italy. Mauro Silingardi, MD, director of internal medicine, director of training and refresher of FADOI, Bologna, Italy.

In the United States, family physicians (general practitioners) used to manage their patients in the hospital, either as the primary care doctor or in consultation with specialists. Only since the 1990s has a new kind of physician gained widespread acceptance: the hospitalist (“specialist of inpatient care”).¹

In Italy the process has not been the same. In our health care system, primary care physicians have always transferred the responsibility of hospital care to an inpatient team. Actually, our hospital-based doctors dedicate their whole working time to inpatient care, and general practitioners are not expected to go to the hospital. The patients were (and are) admitted to one ward or another according to their main clinical problem.

Little by little, a huge number of organ specialty and subspecialty wards have filled Italian hospitals. In this context, the internal medicine specialty was unable to occupy its characteristic role, so that, a few years ago, the medical community wondered if the specialty should have continued to exist.

References

1. Baudendistel TE, Watcher RM. The evolution of the hospitalist movement in USA. Clin Med JRCPL. 2002;2:327-30.

2. Pantilat S. What is a Hospitalist? The Hospitalist 2006 February;2006(2).

3. Wachter RM, Goldman Lee. The emerging role of “Hospitalists” in the American Health Care System. N Engl J Med. 1996;335:514-7.

4. White HL, Glazier RH. Do hospitalist physicians improve the quality of inpatient care delivery? A systematic review of process, efficiency and outcome measures. BMC Medicine. 2011;9:58:1-22. http://www.biomedcentral.com/1741-7015/9/58.

5. Wachter RM, Goldman L. Zero to 50,000 – The 20th Anniversary of the Hospitalist. N Engl J Med. 2016;375:1009-11.
 

Valerio Verdiani, MD, director of internal medicine, Grosseto, Italy. Francesco Orlandini, MD, internal medicine, health administrator, ASL4 Liguria, Chiavari (GE), Italy. Micaela La Regina, MD, internal medicine, risk management and clinical governance, ASL5 Liguria, La Spezia, Italy. Giovanni Murialdo, MD, department of internal medicine and medical specialty, University of Genoa (Italy). Andrea Fontanella, MD, director of medicine department, president of the Federation of Associations of Hospital Doctors on Internal Medicine (FADOI), Naples, Italy. Mauro Silingardi, MD, director of internal medicine, director of training and refresher of FADOI, Bologna, Italy.

In the United States, family physicians (general practitioners) used to manage their patients in the hospital, either as the primary care doctor or in consultation with specialists. Only since the 1990s has a new kind of physician gained widespread acceptance: the hospitalist (“specialist of inpatient care”).¹

In Italy the process has not been the same. In our health care system, primary care physicians have always transferred the responsibility of hospital care to an inpatient team. Actually, our hospital-based doctors dedicate their whole working time to inpatient care, and general practitioners are not expected to go to the hospital. The patients were (and are) admitted to one ward or another according to their main clinical problem.

Little by little, a huge number of organ specialty and subspecialty wards have filled Italian hospitals. In this context, the internal medicine specialty was unable to occupy its characteristic role, so that, a few years ago, the medical community wondered if the specialty should have continued to exist.

References

1. Baudendistel TE, Watcher RM. The evolution of the hospitalist movement in USA. Clin Med JRCPL. 2002;2:327-30.

2. Pantilat S. What is a Hospitalist? The Hospitalist 2006 February;2006(2).

3. Wachter RM, Goldman Lee. The emerging role of “Hospitalists” in the American Health Care System. N Engl J Med. 1996;335:514-7.

4. White HL, Glazier RH. Do hospitalist physicians improve the quality of inpatient care delivery? A systematic review of process, efficiency and outcome measures. BMC Medicine. 2011;9:58:1-22. http://www.biomedcentral.com/1741-7015/9/58.

5. Wachter RM, Goldman L. Zero to 50,000 – The 20th Anniversary of the Hospitalist. N Engl J Med. 2016;375:1009-11.
 

Valerio Verdiani, MD, director of internal medicine, Grosseto, Italy. Francesco Orlandini, MD, internal medicine, health administrator, ASL4 Liguria, Chiavari (GE), Italy. Micaela La Regina, MD, internal medicine, risk management and clinical governance, ASL5 Liguria, La Spezia, Italy. Giovanni Murialdo, MD, department of internal medicine and medical specialty, University of Genoa (Italy). Andrea Fontanella, MD, director of medicine department, president of the Federation of Associations of Hospital Doctors on Internal Medicine (FADOI), Naples, Italy. Mauro Silingardi, MD, director of internal medicine, director of training and refresher of FADOI, Bologna, Italy.

The American Society of Hematology (ASH) has released a new policy statement in favor of safeguarding access to opioids for hematology patients with chronic, severe pain as policymakers consider restrictions on opioid prescribing.

The statement is a recognition from ASH officials of the large number of opioid overdose deaths that involve prescription medication, and an acknowledgment that hematologists need to be advocates for their patients, said Joseph Alvarnas, MD, of City of Hope, Duarte, Calif.

Courtesy of City of Hope

In a rule finalized in April 2018, the CMS placed restrictions on the dosage of opioids available for chronic opioid users and limited the days’ supply for first-time opioid users. For chronic users, the CMS set a 90-morphine-milligram-equivalent (MME) per day limit that triggers pharmacist consultation with the prescriber. The agency instructed health plans to implement an “opioid care coordination edit” that would be triggered at 90 MME per day across all opioid prescriptions and would require pharmacists to contact prescribers to override for a higher dosage.

The entire exchange must be documented. The CMS instructed health plans in the Medicare Part D program to implement a “hard safety edit” that limits opioid prescription fills to no more than a 7-day supply for opioid-naive patients being treated for acute pain. The changes are set to take effect in January 2019.

But Diane E. Meier, MD, director of the Center to Advance Palliative Care in New York, said the most current data suggest the risk of addiction and substance use disorder among medically-ill patients taking opioids is less than 10%. “That means that 90% of patients with a serious medical illness can safely take opioids for the relief of pain that is causing functional disorder,” she said.

Policymakers should not conflate the use and prescription of opioids with cases of misuse and abuse, Dr. Alvarnas said. Some patients will require a higher dose of opioids depending on their age or number of pain episodes, or because of their body’s physiological response.

Patients may also have difficulty finding pharmacies that dispense opioid medications, or doctors who will prescribe them, because of fear of repercussions from the Drug Enforcement Administration or their state licensing boards, Dr. Meier said.

No ‘one-size-fits-all’

Because treatment is individualized, there is no “one-size-fits-all” approach to pain management for patients with hematological diseases.

“One of the concerns is that we care for populations of patients, such as those with sickle cell disease, those with blood cancers that can cause destructive bony lesions like somebody with multiple myeloma might experience, or even pain associated with the complication of a disease like hemophilia, where [patients experience] excruciating pain ... from bleeding into a joint,” Dr. Alvarnas said.

It’s not enough to offer anti-inflammatory medications to these patients – and in some cases doing so may create additional problems, experts said. Contraindications for anti-inflammatory agents tend to be more significant in hematology patients because of low platelet counts, liver disease, and kidney disease. This may prevent them from taking medications such as ibuprofen, acetaminophen, or naproxen sodium. Opioids are the “only option” for patients with these kinds of complications who have severe pain, Dr. Osunkwo said.
 

Pain management training

While hematologists are trained about the potential risks of common drugs such as steroids, “none of that education and training has occurred” for opioids, Dr. Meier said.

Finding balance

ASH leaders recognize the longstanding, complex nature of the opioid epidemic and want to be a part of the conversation to ensure their patients’ needs and considerations are met in future legislation, Dr. Alvarnas noted.

Dr. Meier, who is vice chair for public policy at Icahn School of Medicine at Mount Sinai, New York, said the issue of balance is paramount when considering good policymaking.

“No policy at either extreme is the right policy,” Dr. Meier said. “Good policymaking, good public health interventions attempt to achieve some balance ... in preventing harm and maximizing appropriate treatment of vulnerable, seriously ill patients. And the policies we have now don’t achieve that.”

The “Statement on Opioid Use in Patients with Hematologic Diseases and Disorders” is available on the ASH website.

Dr. Alvarnas is chair of the society’s Committee on Practice. Dr. Meier and Dr. Osunkwo reported having no relevant financial disclosures.

The American Society of Hematology (ASH) has released a new policy statement in favor of safeguarding access to opioids for hematology patients with chronic, severe pain as policymakers consider restrictions on opioid prescribing.

The statement is a recognition from ASH officials of the large number of opioid overdose deaths that involve prescription medication, and an acknowledgment that hematologists need to be advocates for their patients, said Joseph Alvarnas, MD, of City of Hope, Duarte, Calif.

Courtesy of City of Hope

In a rule finalized in April 2018, the CMS placed restrictions on the dosage of opioids available for chronic opioid users and limited the days’ supply for first-time opioid users. For chronic users, the CMS set a 90-morphine-milligram-equivalent (MME) per day limit that triggers pharmacist consultation with the prescriber. The agency instructed health plans to implement an “opioid care coordination edit” that would be triggered at 90 MME per day across all opioid prescriptions and would require pharmacists to contact prescribers to override for a higher dosage.

The entire exchange must be documented. The CMS instructed health plans in the Medicare Part D program to implement a “hard safety edit” that limits opioid prescription fills to no more than a 7-day supply for opioid-naive patients being treated for acute pain. The changes are set to take effect in January 2019.

But Diane E. Meier, MD, director of the Center to Advance Palliative Care in New York, said the most current data suggest the risk of addiction and substance use disorder among medically-ill patients taking opioids is less than 10%. “That means that 90% of patients with a serious medical illness can safely take opioids for the relief of pain that is causing functional disorder,” she said.

Policymakers should not conflate the use and prescription of opioids with cases of misuse and abuse, Dr. Alvarnas said. Some patients will require a higher dose of opioids depending on their age or number of pain episodes, or because of their body’s physiological response.

Patients may also have difficulty finding pharmacies that dispense opioid medications, or doctors who will prescribe them, because of fear of repercussions from the Drug Enforcement Administration or their state licensing boards, Dr. Meier said.

No ‘one-size-fits-all’

Because treatment is individualized, there is no “one-size-fits-all” approach to pain management for patients with hematological diseases.

“One of the concerns is that we care for populations of patients, such as those with sickle cell disease, those with blood cancers that can cause destructive bony lesions like somebody with multiple myeloma might experience, or even pain associated with the complication of a disease like hemophilia, where [patients experience] excruciating pain ... from bleeding into a joint,” Dr. Alvarnas said.

It’s not enough to offer anti-inflammatory medications to these patients – and in some cases doing so may create additional problems, experts said. Contraindications for anti-inflammatory agents tend to be more significant in hematology patients because of low platelet counts, liver disease, and kidney disease. This may prevent them from taking medications such as ibuprofen, acetaminophen, or naproxen sodium. Opioids are the “only option” for patients with these kinds of complications who have severe pain, Dr. Osunkwo said.
 

Pain management training

While hematologists are trained about the potential risks of common drugs such as steroids, “none of that education and training has occurred” for opioids, Dr. Meier said.

Finding balance

ASH leaders recognize the longstanding, complex nature of the opioid epidemic and want to be a part of the conversation to ensure their patients’ needs and considerations are met in future legislation, Dr. Alvarnas noted.

Dr. Meier, who is vice chair for public policy at Icahn School of Medicine at Mount Sinai, New York, said the issue of balance is paramount when considering good policymaking.

“No policy at either extreme is the right policy,” Dr. Meier said. “Good policymaking, good public health interventions attempt to achieve some balance ... in preventing harm and maximizing appropriate treatment of vulnerable, seriously ill patients. And the policies we have now don’t achieve that.”

The “Statement on Opioid Use in Patients with Hematologic Diseases and Disorders” is available on the ASH website.

Dr. Alvarnas is chair of the society’s Committee on Practice. Dr. Meier and Dr. Osunkwo reported having no relevant financial disclosures.

The American Society of Hematology (ASH) has released a new policy statement in favor of safeguarding access to opioids for hematology patients with chronic, severe pain as policymakers consider restrictions on opioid prescribing.

The statement is a recognition from ASH officials of the large number of opioid overdose deaths that involve prescription medication, and an acknowledgment that hematologists need to be advocates for their patients, said Joseph Alvarnas, MD, of City of Hope, Duarte, Calif.

Courtesy of City of Hope

In a rule finalized in April 2018, the CMS placed restrictions on the dosage of opioids available for chronic opioid users and limited the days’ supply for first-time opioid users. For chronic users, the CMS set a 90-morphine-milligram-equivalent (MME) per day limit that triggers pharmacist consultation with the prescriber. The agency instructed health plans to implement an “opioid care coordination edit” that would be triggered at 90 MME per day across all opioid prescriptions and would require pharmacists to contact prescribers to override for a higher dosage.

The entire exchange must be documented. The CMS instructed health plans in the Medicare Part D program to implement a “hard safety edit” that limits opioid prescription fills to no more than a 7-day supply for opioid-naive patients being treated for acute pain. The changes are set to take effect in January 2019.

But Diane E. Meier, MD, director of the Center to Advance Palliative Care in New York, said the most current data suggest the risk of addiction and substance use disorder among medically-ill patients taking opioids is less than 10%. “That means that 90% of patients with a serious medical illness can safely take opioids for the relief of pain that is causing functional disorder,” she said.

Policymakers should not conflate the use and prescription of opioids with cases of misuse and abuse, Dr. Alvarnas said. Some patients will require a higher dose of opioids depending on their age or number of pain episodes, or because of their body’s physiological response.

Patients may also have difficulty finding pharmacies that dispense opioid medications, or doctors who will prescribe them, because of fear of repercussions from the Drug Enforcement Administration or their state licensing boards, Dr. Meier said.

No ‘one-size-fits-all’

Because treatment is individualized, there is no “one-size-fits-all” approach to pain management for patients with hematological diseases.

“One of the concerns is that we care for populations of patients, such as those with sickle cell disease, those with blood cancers that can cause destructive bony lesions like somebody with multiple myeloma might experience, or even pain associated with the complication of a disease like hemophilia, where [patients experience] excruciating pain ... from bleeding into a joint,” Dr. Alvarnas said.

It’s not enough to offer anti-inflammatory medications to these patients – and in some cases doing so may create additional problems, experts said. Contraindications for anti-inflammatory agents tend to be more significant in hematology patients because of low platelet counts, liver disease, and kidney disease. This may prevent them from taking medications such as ibuprofen, acetaminophen, or naproxen sodium. Opioids are the “only option” for patients with these kinds of complications who have severe pain, Dr. Osunkwo said.
 

Pain management training

While hematologists are trained about the potential risks of common drugs such as steroids, “none of that education and training has occurred” for opioids, Dr. Meier said.

Finding balance

ASH leaders recognize the longstanding, complex nature of the opioid epidemic and want to be a part of the conversation to ensure their patients’ needs and considerations are met in future legislation, Dr. Alvarnas noted.

Dr. Meier, who is vice chair for public policy at Icahn School of Medicine at Mount Sinai, New York, said the issue of balance is paramount when considering good policymaking.

“No policy at either extreme is the right policy,” Dr. Meier said. “Good policymaking, good public health interventions attempt to achieve some balance ... in preventing harm and maximizing appropriate treatment of vulnerable, seriously ill patients. And the policies we have now don’t achieve that.”

The “Statement on Opioid Use in Patients with Hematologic Diseases and Disorders” is available on the ASH website.

Dr. Alvarnas is chair of the society’s Committee on Practice. Dr. Meier and Dr. Osunkwo reported having no relevant financial disclosures.

ORLANDO – Although cardiologists and neurologists aren’t typically the physicians who diagnose and treat major depressive disorder that’s newly identified in patients after MI or stroke, they’re the ones who’ll deal with the cardiovascular consequences if the mood disorder isn’t adequately treated.

That was a key message of a study presented by interventional cardiologist Sripal Bangalore, MD, at the annual meeting of the American College of Cardiology.

In his retrospective cohort study of 1,568 patients diagnosed with and treated for major depressive disorder (MDD) following an initial acute MI or stroke, antidepressant therapy deemed inadequate by either of two prespecified measures was associated during a mean follow-up of 2 years with a 20% higher risk of the primary endpoint – a composite of recurrent MI, stroke, angina, or heart failure – than the risk in patients who received what was judged to be adequate antidepressant pharmacotherapy. A precondition for study inclusion was that a patient could not have been taking any antidepressant during the year prior to the index MI or stroke.

The study utilized nationwide claims data from the Truven Health MarketScan Claims Database for 2010-2015. Depression therapy was considered adequate if during the first 90 days following diagnosis of MDD two conditions were met: a patient aged 65 or younger had to be on the equivalent of at least 20 mg of fluoxetine per day, or if older then on a fluoxetine-equivalent dose of at least 10 mg/day, and pharmacy records had to indicate the patient was covered by the antidepressant prescription for at least 72 of those 90 days.

The prevalence of inadequate antidepressant therapy for MDD by these criteria among these patients with known cardiovascular disease was eyebrow-raisingly high: fully 60%, noted Dr. Bangalore of New York University.

In a multivariate logistic regression analysis adjusted for baseline factors that could affect the propensity to receive adequate antidepressant care, Dr. Bangalore and his coinvestigators broke down the risks of insufficient antidepressant therapy associated with each of the individual components of the composite primary endpoint. The 1.2- and 1.95-fold increased risks of stroke and angina, respectively, were statistically significant. However, the 1.37-fold higher risk of MI and 1.14-fold greater risk of heart failure than in adequately treated patients with MDD, while trending in the same direction, didn’t achieve significance.

Dr. Bangalore reported serving as a consultant to Pfizer, which funded the study, as well as to Abbott, Gilead Sciences, and Merck.

[email protected]

ORLANDO – Although cardiologists and neurologists aren’t typically the physicians who diagnose and treat major depressive disorder that’s newly identified in patients after MI or stroke, they’re the ones who’ll deal with the cardiovascular consequences if the mood disorder isn’t adequately treated.

That was a key message of a study presented by interventional cardiologist Sripal Bangalore, MD, at the annual meeting of the American College of Cardiology.

In his retrospective cohort study of 1,568 patients diagnosed with and treated for major depressive disorder (MDD) following an initial acute MI or stroke, antidepressant therapy deemed inadequate by either of two prespecified measures was associated during a mean follow-up of 2 years with a 20% higher risk of the primary endpoint – a composite of recurrent MI, stroke, angina, or heart failure – than the risk in patients who received what was judged to be adequate antidepressant pharmacotherapy. A precondition for study inclusion was that a patient could not have been taking any antidepressant during the year prior to the index MI or stroke.

The study utilized nationwide claims data from the Truven Health MarketScan Claims Database for 2010-2015. Depression therapy was considered adequate if during the first 90 days following diagnosis of MDD two conditions were met: a patient aged 65 or younger had to be on the equivalent of at least 20 mg of fluoxetine per day, or if older then on a fluoxetine-equivalent dose of at least 10 mg/day, and pharmacy records had to indicate the patient was covered by the antidepressant prescription for at least 72 of those 90 days.

The prevalence of inadequate antidepressant therapy for MDD by these criteria among these patients with known cardiovascular disease was eyebrow-raisingly high: fully 60%, noted Dr. Bangalore of New York University.

In a multivariate logistic regression analysis adjusted for baseline factors that could affect the propensity to receive adequate antidepressant care, Dr. Bangalore and his coinvestigators broke down the risks of insufficient antidepressant therapy associated with each of the individual components of the composite primary endpoint. The 1.2- and 1.95-fold increased risks of stroke and angina, respectively, were statistically significant. However, the 1.37-fold higher risk of MI and 1.14-fold greater risk of heart failure than in adequately treated patients with MDD, while trending in the same direction, didn’t achieve significance.

Dr. Bangalore reported serving as a consultant to Pfizer, which funded the study, as well as to Abbott, Gilead Sciences, and Merck.

[email protected]

ORLANDO – Although cardiologists and neurologists aren’t typically the physicians who diagnose and treat major depressive disorder that’s newly identified in patients after MI or stroke, they’re the ones who’ll deal with the cardiovascular consequences if the mood disorder isn’t adequately treated.

That was a key message of a study presented by interventional cardiologist Sripal Bangalore, MD, at the annual meeting of the American College of Cardiology.

In his retrospective cohort study of 1,568 patients diagnosed with and treated for major depressive disorder (MDD) following an initial acute MI or stroke, antidepressant therapy deemed inadequate by either of two prespecified measures was associated during a mean follow-up of 2 years with a 20% higher risk of the primary endpoint – a composite of recurrent MI, stroke, angina, or heart failure – than the risk in patients who received what was judged to be adequate antidepressant pharmacotherapy. A precondition for study inclusion was that a patient could not have been taking any antidepressant during the year prior to the index MI or stroke.

The study utilized nationwide claims data from the Truven Health MarketScan Claims Database for 2010-2015. Depression therapy was considered adequate if during the first 90 days following diagnosis of MDD two conditions were met: a patient aged 65 or younger had to be on the equivalent of at least 20 mg of fluoxetine per day, or if older then on a fluoxetine-equivalent dose of at least 10 mg/day, and pharmacy records had to indicate the patient was covered by the antidepressant prescription for at least 72 of those 90 days.

The prevalence of inadequate antidepressant therapy for MDD by these criteria among these patients with known cardiovascular disease was eyebrow-raisingly high: fully 60%, noted Dr. Bangalore of New York University.

In a multivariate logistic regression analysis adjusted for baseline factors that could affect the propensity to receive adequate antidepressant care, Dr. Bangalore and his coinvestigators broke down the risks of insufficient antidepressant therapy associated with each of the individual components of the composite primary endpoint. The 1.2- and 1.95-fold increased risks of stroke and angina, respectively, were statistically significant. However, the 1.37-fold higher risk of MI and 1.14-fold greater risk of heart failure than in adequately treated patients with MDD, while trending in the same direction, didn’t achieve significance.

Dr. Bangalore reported serving as a consultant to Pfizer, which funded the study, as well as to Abbott, Gilead Sciences, and Merck.

[email protected]

WASHINGTON – Hospitalizations for shingles is twice as common among patients with inflammatory bowel disease than in the general U.S. population, based on analysis of data from the National Inpatient Sample.

Mitchel L. Zoler/MDedge News

This elevated risk for patients with inflammatory bowel disease (IBD) to develop a herpes zoster virus (HZV) reactivation severe enough to put them in the hospital makes it especially important for IBD patients to receive immunization against shingles, especially now that a more effective vaccine is available, Daniela G. Vinsard, MD, said at the annual Digestive Disease Week^®. Ideally, IBD patients should receive the full course of the adjuvanted, recombinant zoster vaccine Shingrix before starting an immunosuppressive regimen, said Dr. Vinsard, a physician at the University of Connecticut, Farmington.

This finding, which underscored the susceptibility of IBD patients to shingles because of their immunosuppressive treatments and the importance of vaccination, recently became even more relevant when the Food and Drug Administration approved tofacitinib (Xeljanz) to treat ulcerative colitis in late May, commented Gil Y. Melmed, MD, director of clinical inflammatory bowel disease at Cedars-Sinai Medical Center, Los Angeles. Tofacitinib, which may be an attractive option to some patients as an oral immunomodulator, carries a black box warning about the added risk for certain serious infections while taking the drug, including HZV. Recent recommendations from the American College of Gastroenterology said that IBD patients aged 51 years or older should “strongly consider” HZV vaccination, including immunosuppressed patients (Am J Gastroenterol. 2017 Feb; 112[2]:241-58). The introduction of a potentially popular drug for ulcerative colitis that’s known to pose a risk for shingles might lead to a stronger recommendation for vaccination in the near future, Dr. Melmed said in an interview.

The study Dr. Vinsard reported used data collected by the National Inpatient Sample from 2012 to September 2015, which represented, with weighting, more than 142 million hospitalized American patients. From this data set she and her associates identified 7,180 IBD patients hospitalized with a primary diagnosis of a vaccine-preventable disease, and about 589,000 weighted patients hospitalized for a vaccine-preventable disease but without IBD. The selection also focused on patients aged 18-65 years. Dr. Vinsard said that she excluded older patients to eliminate advanced age as a cause of immunosuppression.

[email protected]

WASHINGTON – Hospitalizations for shingles is twice as common among patients with inflammatory bowel disease than in the general U.S. population, based on analysis of data from the National Inpatient Sample.

Mitchel L. Zoler/MDedge News

This elevated risk for patients with inflammatory bowel disease (IBD) to develop a herpes zoster virus (HZV) reactivation severe enough to put them in the hospital makes it especially important for IBD patients to receive immunization against shingles, especially now that a more effective vaccine is available, Daniela G. Vinsard, MD, said at the annual Digestive Disease Week^®. Ideally, IBD patients should receive the full course of the adjuvanted, recombinant zoster vaccine Shingrix before starting an immunosuppressive regimen, said Dr. Vinsard, a physician at the University of Connecticut, Farmington.

This finding, which underscored the susceptibility of IBD patients to shingles because of their immunosuppressive treatments and the importance of vaccination, recently became even more relevant when the Food and Drug Administration approved tofacitinib (Xeljanz) to treat ulcerative colitis in late May, commented Gil Y. Melmed, MD, director of clinical inflammatory bowel disease at Cedars-Sinai Medical Center, Los Angeles. Tofacitinib, which may be an attractive option to some patients as an oral immunomodulator, carries a black box warning about the added risk for certain serious infections while taking the drug, including HZV. Recent recommendations from the American College of Gastroenterology said that IBD patients aged 51 years or older should “strongly consider” HZV vaccination, including immunosuppressed patients (Am J Gastroenterol. 2017 Feb; 112[2]:241-58). The introduction of a potentially popular drug for ulcerative colitis that’s known to pose a risk for shingles might lead to a stronger recommendation for vaccination in the near future, Dr. Melmed said in an interview.

The study Dr. Vinsard reported used data collected by the National Inpatient Sample from 2012 to September 2015, which represented, with weighting, more than 142 million hospitalized American patients. From this data set she and her associates identified 7,180 IBD patients hospitalized with a primary diagnosis of a vaccine-preventable disease, and about 589,000 weighted patients hospitalized for a vaccine-preventable disease but without IBD. The selection also focused on patients aged 18-65 years. Dr. Vinsard said that she excluded older patients to eliminate advanced age as a cause of immunosuppression.

[email protected]

WASHINGTON – Hospitalizations for shingles is twice as common among patients with inflammatory bowel disease than in the general U.S. population, based on analysis of data from the National Inpatient Sample.

Mitchel L. Zoler/MDedge News

This elevated risk for patients with inflammatory bowel disease (IBD) to develop a herpes zoster virus (HZV) reactivation severe enough to put them in the hospital makes it especially important for IBD patients to receive immunization against shingles, especially now that a more effective vaccine is available, Daniela G. Vinsard, MD, said at the annual Digestive Disease Week^®. Ideally, IBD patients should receive the full course of the adjuvanted, recombinant zoster vaccine Shingrix before starting an immunosuppressive regimen, said Dr. Vinsard, a physician at the University of Connecticut, Farmington.

This finding, which underscored the susceptibility of IBD patients to shingles because of their immunosuppressive treatments and the importance of vaccination, recently became even more relevant when the Food and Drug Administration approved tofacitinib (Xeljanz) to treat ulcerative colitis in late May, commented Gil Y. Melmed, MD, director of clinical inflammatory bowel disease at Cedars-Sinai Medical Center, Los Angeles. Tofacitinib, which may be an attractive option to some patients as an oral immunomodulator, carries a black box warning about the added risk for certain serious infections while taking the drug, including HZV. Recent recommendations from the American College of Gastroenterology said that IBD patients aged 51 years or older should “strongly consider” HZV vaccination, including immunosuppressed patients (Am J Gastroenterol. 2017 Feb; 112[2]:241-58). The introduction of a potentially popular drug for ulcerative colitis that’s known to pose a risk for shingles might lead to a stronger recommendation for vaccination in the near future, Dr. Melmed said in an interview.

The study Dr. Vinsard reported used data collected by the National Inpatient Sample from 2012 to September 2015, which represented, with weighting, more than 142 million hospitalized American patients. From this data set she and her associates identified 7,180 IBD patients hospitalized with a primary diagnosis of a vaccine-preventable disease, and about 589,000 weighted patients hospitalized for a vaccine-preventable disease but without IBD. The selection also focused on patients aged 18-65 years. Dr. Vinsard said that she excluded older patients to eliminate advanced age as a cause of immunosuppression.

[email protected]

Imiquimod is derived from the imidazoquinoline family and works by activating both innate and adaptive immune pathways. Imiquimod binds to toll-like receptor 7 located on monocytes, macrophages, and dendritic cells,¹ which allows nuclear factor κβ light chain enhancer of activated B cells to induce production of proinflammatory cytokines, including IFN-α and tumor necrosis factor α, as well as IL-1, IL-6, IL-8, IL-10, and IL-12.² These proinflammatory cytokines play a role in the innate immunity, triggering upregulation of the adaptive immune pathway and activating type 1 helper T cells, cytotoxic T cells, and natural killer cells. These cells have antiviral and antitumoral effects that lend to their significance in coordinating innate and adaptive immune mechanisms.³ More specifically, imiquimod enhances dendritic cell migration to regional lymph nodes and induces apoptosis via activation of proapoptotic B-cell lymphoma 2 proteins.^1,2 Imiquimod has been approved by the US Food and Drug Administration (FDA) to treat external genitalia and perianal condyloma acuminata, actinic keratoses (AKs), and superficial basal cell carcinoma (BCC). It often is used off label for antiviral or antitumoral therapy in Bowen disease, squamous cell carcinoma, lentigo maligna, vulvar intraepithelial neoplasia, molluscum contagiosum, common warts, and leishmaniasis.^1,2 Imiquimod is generally well tolerated; erythema and irritation at the application site are the most common side effects, with pigmentary change being less common.

Case Report

A 51-year-old man with a medical history of vitamin D deficiency, vitamin B₁₂ deficiency, tinea pedis, and BCC presented with periungual verruca vulgaris on the right fifth digit and left thumb (Figure 1). The patient was prescribed imiquimod cream 5% to be applied 3 times weekly for 3 months. At 5-month follow-up the patient reported new-onset vitiligolike patches of depigmentation on the hands and feet that abruptly began 3 months after initiating treatment with imiquimod. On examination he had several depigmented patches with well-defined irregular borders on the bilateral dorsal hands and right foot as well as the right elbow (Figure 2). There was no personal or family history of vitiligo, thyroid disease, or autoimmune disease. Thyroid function studies and autoimmune panel were unremarkable. The patient also denied applying imiquimod to areas other than the periungual region of the right fifth digit and left thumb. He declined a biopsy of the lesions and was given a prescription for tacrolimus ointment 0.1% for twice-daily application. At 3-month follow-up the depigmented patches had spread. The patient is currently on 5-fluorouracil cream 5%. Despite loss of pigmentation, the periungual verruca vulgaris has persisted as well as depigmentation.

Comment

Imiquimod therapy is commonly used to treat conditions for which an antiviral or antitumor immune response is necessary for treatment and full resolution of skin conditions. It can yield positive results in conditions that are difficult to treat, such as periungual verruca vulgaris.⁴ The most common adverse effects of imiquimod include localized inflammation and application-site reactions. Pigment changes, though less common, also have been reported. From 1997 to 2003, 1257 cases of imiquimod adverse effects were reported to the FDA. There were 68 reported cases of pigmentary change, of which 51 documented vitiligo, hypopigmentation, or depigmentation. The others reported hyperpigmentation following imiquimod use.⁴ The imiquimod package insert lists application-site hypopigmentation as a possible adverse effect.⁵ Imiquimod-induced hypopigmentation and depigmentation have been reported in the peer-reviewed literature.^4,6-14 Pigment loss has been reported in imiquimod treatment of condyloma acuminata, superficial BCC, nodular BCC, and extramammary Paget disease.^6-8 Duration of therapy to onset of pigment loss ranged from 7 to 28 weeks.⁹ Imiquimod dosing varied among reported cases, ranging from 3 times weekly to daily application. Interestingly, hypopigmentation or depigmentation are not commonly associated with imiquimod use for the treatment of AKs, which Burnett and Kouba⁹ proposed may be due to the twice weekly imiquimod dosing regimen recommended by the FDA for the treatment of AK (below the minimum threshold for pigment loss). Our patient applied imiquimod cream 5% to periungual verruca vulgaris 3 times weekly for 3 months and may have developed vitiligolike depigmentation because he met this theoretical dosage threshold. Further research is necessary to confirm a dosage-related threshold for the development of depigmentation. Imiquimod-induced pigment loss has mainly been limited to the site of application.

Depigmentation was limited to the application site the majority of the time; however, depigmentation at adjacent sites has been reported.¹⁰ This finding was consistent with the proposed notion that cytokines induced by imiquimod have localized paracrine activity.¹¹ Our patient was unique in that his depigmentation was present at the site of application, adjacent to the site of application, and at distant sites. He applied imiquimod only to the periungual area of the right fifth digit and left thumb but experienced depigmentation at several other sites. Although it is possible that our patient unintentionally spread imiquimod on the distant sites, it is less likely that the application would have been sufficient to cause depigmentation. Although systemic absorption of topical medications varies depending on multiple factors, the systemic absorption of imiquimod is minimal with mild systemic side effects reported, including headache, myalgia, and influenzalike symptoms.⁵ Thus, it is possible that our patient developed distant vitiligolike depigmentation as a systemic side effect of imiquimod therapy. Although our patient declined to have a biopsy performed, Gowda et al¹⁵ reported biopsy-proven vitiligo, demonstrating the absence of melanin and melanocytes following the use of imiquimod.

Several mechanisms have been proposed for imiquimod-induced depigmentation. For example, imiquimod may induce melanocyte apoptosis by increasing the levels of several proinflammatory and proapoptotic cytokines.¹⁶ Imiquimod-induced melanocyte apoptosis appears to involve elevated caspase-3, decreased B-cell lymphoma 2, altered mitogen-activated protein kinase expression, and ubiquitin-mediated proteolysis.^13,17 Additionally, increased levels of IL-6 appear to increase melanocyte-binding molecules and increase melanocyte-leukocyte interactions. Another proposed theory targets toll-like receptor 7 on melanocytes that are acted on directly by imiquimod.^11,17 In contrast, development of vitiligo following trauma (Koebner phenomenon) is not uncommon, and the immune effects induced by imiquimod may mimic those seen with trauma.¹⁴ Further research is needed to elucidate the mechanism by which imiquimod causes vitiligolike depigmentation.

Unfortunately, the depigmentation seen with imiquimod generally is permanent. Stefanaki et al¹⁰ showed repigmentation on cessation of imiquimod use. Our patient’s depigmentation remains unchanged despite treatment with tacrolimus ointment. Although it is possible for vitiligo to occur de novo without obvious inciting event or laboratory abnormality, the timeline and number of other cases in the literature make ours highly suspect for imiquimod-induced depigmentation.

Conclusion

Imiquimod is a commonly used immune-enhancing medication with an increasing list of off-label uses. Prior to prescribing imiquimod for a benign skin condition, clinicians should be cognizant of the potential for localized or possibly even distant depigmentation. We report a case of distant depigmentation following the use of imiquimod for periungual verruca vulgaris.

Imiquimod is derived from the imidazoquinoline family and works by activating both innate and adaptive immune pathways. Imiquimod binds to toll-like receptor 7 located on monocytes, macrophages, and dendritic cells,¹ which allows nuclear factor κβ light chain enhancer of activated B cells to induce production of proinflammatory cytokines, including IFN-α and tumor necrosis factor α, as well as IL-1, IL-6, IL-8, IL-10, and IL-12.² These proinflammatory cytokines play a role in the innate immunity, triggering upregulation of the adaptive immune pathway and activating type 1 helper T cells, cytotoxic T cells, and natural killer cells. These cells have antiviral and antitumoral effects that lend to their significance in coordinating innate and adaptive immune mechanisms.³ More specifically, imiquimod enhances dendritic cell migration to regional lymph nodes and induces apoptosis via activation of proapoptotic B-cell lymphoma 2 proteins.^1,2 Imiquimod has been approved by the US Food and Drug Administration (FDA) to treat external genitalia and perianal condyloma acuminata, actinic keratoses (AKs), and superficial basal cell carcinoma (BCC). It often is used off label for antiviral or antitumoral therapy in Bowen disease, squamous cell carcinoma, lentigo maligna, vulvar intraepithelial neoplasia, molluscum contagiosum, common warts, and leishmaniasis.^1,2 Imiquimod is generally well tolerated; erythema and irritation at the application site are the most common side effects, with pigmentary change being less common.

Case Report

A 51-year-old man with a medical history of vitamin D deficiency, vitamin B₁₂ deficiency, tinea pedis, and BCC presented with periungual verruca vulgaris on the right fifth digit and left thumb (Figure 1). The patient was prescribed imiquimod cream 5% to be applied 3 times weekly for 3 months. At 5-month follow-up the patient reported new-onset vitiligolike patches of depigmentation on the hands and feet that abruptly began 3 months after initiating treatment with imiquimod. On examination he had several depigmented patches with well-defined irregular borders on the bilateral dorsal hands and right foot as well as the right elbow (Figure 2). There was no personal or family history of vitiligo, thyroid disease, or autoimmune disease. Thyroid function studies and autoimmune panel were unremarkable. The patient also denied applying imiquimod to areas other than the periungual region of the right fifth digit and left thumb. He declined a biopsy of the lesions and was given a prescription for tacrolimus ointment 0.1% for twice-daily application. At 3-month follow-up the depigmented patches had spread. The patient is currently on 5-fluorouracil cream 5%. Despite loss of pigmentation, the periungual verruca vulgaris has persisted as well as depigmentation.

Comment

Imiquimod therapy is commonly used to treat conditions for which an antiviral or antitumor immune response is necessary for treatment and full resolution of skin conditions. It can yield positive results in conditions that are difficult to treat, such as periungual verruca vulgaris.⁴ The most common adverse effects of imiquimod include localized inflammation and application-site reactions. Pigment changes, though less common, also have been reported. From 1997 to 2003, 1257 cases of imiquimod adverse effects were reported to the FDA. There were 68 reported cases of pigmentary change, of which 51 documented vitiligo, hypopigmentation, or depigmentation. The others reported hyperpigmentation following imiquimod use.⁴ The imiquimod package insert lists application-site hypopigmentation as a possible adverse effect.⁵ Imiquimod-induced hypopigmentation and depigmentation have been reported in the peer-reviewed literature.^4,6-14 Pigment loss has been reported in imiquimod treatment of condyloma acuminata, superficial BCC, nodular BCC, and extramammary Paget disease.^6-8 Duration of therapy to onset of pigment loss ranged from 7 to 28 weeks.⁹ Imiquimod dosing varied among reported cases, ranging from 3 times weekly to daily application. Interestingly, hypopigmentation or depigmentation are not commonly associated with imiquimod use for the treatment of AKs, which Burnett and Kouba⁹ proposed may be due to the twice weekly imiquimod dosing regimen recommended by the FDA for the treatment of AK (below the minimum threshold for pigment loss). Our patient applied imiquimod cream 5% to periungual verruca vulgaris 3 times weekly for 3 months and may have developed vitiligolike depigmentation because he met this theoretical dosage threshold. Further research is necessary to confirm a dosage-related threshold for the development of depigmentation. Imiquimod-induced pigment loss has mainly been limited to the site of application.

Depigmentation was limited to the application site the majority of the time; however, depigmentation at adjacent sites has been reported.¹⁰ This finding was consistent with the proposed notion that cytokines induced by imiquimod have localized paracrine activity.¹¹ Our patient was unique in that his depigmentation was present at the site of application, adjacent to the site of application, and at distant sites. He applied imiquimod only to the periungual area of the right fifth digit and left thumb but experienced depigmentation at several other sites. Although it is possible that our patient unintentionally spread imiquimod on the distant sites, it is less likely that the application would have been sufficient to cause depigmentation. Although systemic absorption of topical medications varies depending on multiple factors, the systemic absorption of imiquimod is minimal with mild systemic side effects reported, including headache, myalgia, and influenzalike symptoms.⁵ Thus, it is possible that our patient developed distant vitiligolike depigmentation as a systemic side effect of imiquimod therapy. Although our patient declined to have a biopsy performed, Gowda et al¹⁵ reported biopsy-proven vitiligo, demonstrating the absence of melanin and melanocytes following the use of imiquimod.

Several mechanisms have been proposed for imiquimod-induced depigmentation. For example, imiquimod may induce melanocyte apoptosis by increasing the levels of several proinflammatory and proapoptotic cytokines.¹⁶ Imiquimod-induced melanocyte apoptosis appears to involve elevated caspase-3, decreased B-cell lymphoma 2, altered mitogen-activated protein kinase expression, and ubiquitin-mediated proteolysis.^13,17 Additionally, increased levels of IL-6 appear to increase melanocyte-binding molecules and increase melanocyte-leukocyte interactions. Another proposed theory targets toll-like receptor 7 on melanocytes that are acted on directly by imiquimod.^11,17 In contrast, development of vitiligo following trauma (Koebner phenomenon) is not uncommon, and the immune effects induced by imiquimod may mimic those seen with trauma.¹⁴ Further research is needed to elucidate the mechanism by which imiquimod causes vitiligolike depigmentation.

Unfortunately, the depigmentation seen with imiquimod generally is permanent. Stefanaki et al¹⁰ showed repigmentation on cessation of imiquimod use. Our patient’s depigmentation remains unchanged despite treatment with tacrolimus ointment. Although it is possible for vitiligo to occur de novo without obvious inciting event or laboratory abnormality, the timeline and number of other cases in the literature make ours highly suspect for imiquimod-induced depigmentation.

Conclusion

Imiquimod is a commonly used immune-enhancing medication with an increasing list of off-label uses. Prior to prescribing imiquimod for a benign skin condition, clinicians should be cognizant of the potential for localized or possibly even distant depigmentation. We report a case of distant depigmentation following the use of imiquimod for periungual verruca vulgaris.

Imiquimod is derived from the imidazoquinoline family and works by activating both innate and adaptive immune pathways. Imiquimod binds to toll-like receptor 7 located on monocytes, macrophages, and dendritic cells,¹ which allows nuclear factor κβ light chain enhancer of activated B cells to induce production of proinflammatory cytokines, including IFN-α and tumor necrosis factor α, as well as IL-1, IL-6, IL-8, IL-10, and IL-12.² These proinflammatory cytokines play a role in the innate immunity, triggering upregulation of the adaptive immune pathway and activating type 1 helper T cells, cytotoxic T cells, and natural killer cells. These cells have antiviral and antitumoral effects that lend to their significance in coordinating innate and adaptive immune mechanisms.³ More specifically, imiquimod enhances dendritic cell migration to regional lymph nodes and induces apoptosis via activation of proapoptotic B-cell lymphoma 2 proteins.^1,2 Imiquimod has been approved by the US Food and Drug Administration (FDA) to treat external genitalia and perianal condyloma acuminata, actinic keratoses (AKs), and superficial basal cell carcinoma (BCC). It often is used off label for antiviral or antitumoral therapy in Bowen disease, squamous cell carcinoma, lentigo maligna, vulvar intraepithelial neoplasia, molluscum contagiosum, common warts, and leishmaniasis.^1,2 Imiquimod is generally well tolerated; erythema and irritation at the application site are the most common side effects, with pigmentary change being less common.

Case Report

A 51-year-old man with a medical history of vitamin D deficiency, vitamin B₁₂ deficiency, tinea pedis, and BCC presented with periungual verruca vulgaris on the right fifth digit and left thumb (Figure 1). The patient was prescribed imiquimod cream 5% to be applied 3 times weekly for 3 months. At 5-month follow-up the patient reported new-onset vitiligolike patches of depigmentation on the hands and feet that abruptly began 3 months after initiating treatment with imiquimod. On examination he had several depigmented patches with well-defined irregular borders on the bilateral dorsal hands and right foot as well as the right elbow (Figure 2). There was no personal or family history of vitiligo, thyroid disease, or autoimmune disease. Thyroid function studies and autoimmune panel were unremarkable. The patient also denied applying imiquimod to areas other than the periungual region of the right fifth digit and left thumb. He declined a biopsy of the lesions and was given a prescription for tacrolimus ointment 0.1% for twice-daily application. At 3-month follow-up the depigmented patches had spread. The patient is currently on 5-fluorouracil cream 5%. Despite loss of pigmentation, the periungual verruca vulgaris has persisted as well as depigmentation.

Comment

Imiquimod therapy is commonly used to treat conditions for which an antiviral or antitumor immune response is necessary for treatment and full resolution of skin conditions. It can yield positive results in conditions that are difficult to treat, such as periungual verruca vulgaris.⁴ The most common adverse effects of imiquimod include localized inflammation and application-site reactions. Pigment changes, though less common, also have been reported. From 1997 to 2003, 1257 cases of imiquimod adverse effects were reported to the FDA. There were 68 reported cases of pigmentary change, of which 51 documented vitiligo, hypopigmentation, or depigmentation. The others reported hyperpigmentation following imiquimod use.⁴ The imiquimod package insert lists application-site hypopigmentation as a possible adverse effect.⁵ Imiquimod-induced hypopigmentation and depigmentation have been reported in the peer-reviewed literature.^4,6-14 Pigment loss has been reported in imiquimod treatment of condyloma acuminata, superficial BCC, nodular BCC, and extramammary Paget disease.^6-8 Duration of therapy to onset of pigment loss ranged from 7 to 28 weeks.⁹ Imiquimod dosing varied among reported cases, ranging from 3 times weekly to daily application. Interestingly, hypopigmentation or depigmentation are not commonly associated with imiquimod use for the treatment of AKs, which Burnett and Kouba⁹ proposed may be due to the twice weekly imiquimod dosing regimen recommended by the FDA for the treatment of AK (below the minimum threshold for pigment loss). Our patient applied imiquimod cream 5% to periungual verruca vulgaris 3 times weekly for 3 months and may have developed vitiligolike depigmentation because he met this theoretical dosage threshold. Further research is necessary to confirm a dosage-related threshold for the development of depigmentation. Imiquimod-induced pigment loss has mainly been limited to the site of application.

Depigmentation was limited to the application site the majority of the time; however, depigmentation at adjacent sites has been reported.¹⁰ This finding was consistent with the proposed notion that cytokines induced by imiquimod have localized paracrine activity.¹¹ Our patient was unique in that his depigmentation was present at the site of application, adjacent to the site of application, and at distant sites. He applied imiquimod only to the periungual area of the right fifth digit and left thumb but experienced depigmentation at several other sites. Although it is possible that our patient unintentionally spread imiquimod on the distant sites, it is less likely that the application would have been sufficient to cause depigmentation. Although systemic absorption of topical medications varies depending on multiple factors, the systemic absorption of imiquimod is minimal with mild systemic side effects reported, including headache, myalgia, and influenzalike symptoms.⁵ Thus, it is possible that our patient developed distant vitiligolike depigmentation as a systemic side effect of imiquimod therapy. Although our patient declined to have a biopsy performed, Gowda et al¹⁵ reported biopsy-proven vitiligo, demonstrating the absence of melanin and melanocytes following the use of imiquimod.

Several mechanisms have been proposed for imiquimod-induced depigmentation. For example, imiquimod may induce melanocyte apoptosis by increasing the levels of several proinflammatory and proapoptotic cytokines.¹⁶ Imiquimod-induced melanocyte apoptosis appears to involve elevated caspase-3, decreased B-cell lymphoma 2, altered mitogen-activated protein kinase expression, and ubiquitin-mediated proteolysis.^13,17 Additionally, increased levels of IL-6 appear to increase melanocyte-binding molecules and increase melanocyte-leukocyte interactions. Another proposed theory targets toll-like receptor 7 on melanocytes that are acted on directly by imiquimod.^11,17 In contrast, development of vitiligo following trauma (Koebner phenomenon) is not uncommon, and the immune effects induced by imiquimod may mimic those seen with trauma.¹⁴ Further research is needed to elucidate the mechanism by which imiquimod causes vitiligolike depigmentation.

Unfortunately, the depigmentation seen with imiquimod generally is permanent. Stefanaki et al¹⁰ showed repigmentation on cessation of imiquimod use. Our patient’s depigmentation remains unchanged despite treatment with tacrolimus ointment. Although it is possible for vitiligo to occur de novo without obvious inciting event or laboratory abnormality, the timeline and number of other cases in the literature make ours highly suspect for imiquimod-induced depigmentation.

Conclusion

Imiquimod is a commonly used immune-enhancing medication with an increasing list of off-label uses. Prior to prescribing imiquimod for a benign skin condition, clinicians should be cognizant of the potential for localized or possibly even distant depigmentation. We report a case of distant depigmentation following the use of imiquimod for periungual verruca vulgaris.

CHICAGO – The combination of the immune checkpoint inhibitor avelumab (Bavencio) and the ALK inhibitor lorlatinib in ALK-positive patients was associated with an acceptable safety profile and good activity – albeit not better than lorlatinib alone – in one arm of the phase 1/2b JAVELIN Lung 101 trial.

In contrast, although preclinical data suggested that the combination of an ALK inhibitor and immune checkpoint inhibitor might have synergistic activity in patients with advanced ALK-negative non–small-cell lung cancer (NSCLC), it didn’t pan out in the second arm of the trial, reported Alice T. Shaw, MD, PhD, of Massachusetts General Hospital Cancer Center in Boston.

Neil Osterweil/MDedge News

In the parallel group trial testing combinations of the programmed death ligand-1 (PD-L1) inhibitor avelumab with either of two tyrosine kinase inhibitors (TKIs) – crizotinib (Xalkori) or lorlatinib – the combination of avelumab and crizotinib had an objective response rate (ORR) of just 16.7% in ALK-negative patients, and 5 of 12 patients in this study arm had dose limiting toxicities (DLTs) due to serious adverse events.

“The most common DLTs were increased transaminases, consistent with the recent report of increased hepatotoxicity with the combination of nivolumab and crizotinib in Checkmate 370. While there were two confirmed partial responses, this efficacy would be expected for avelumab alone. No further development of this combination is planned,” Dr. Shaw said in an oral abstract session at the annual meeting of the American Society of Clinical Oncology.

In contrast, in ALK-positive patients, avelumab/lorlatinib was associated with an ORR of 46.4%, although it’s likely that the responses were attributable to lorlatinib alone, and not its anti-PD-L1 partner, she acknowledged.
 

Synergism sought

The investigators based the study on two hypotheses: The first was that ALK inhibitors, through their immunomodulatory properties, combined with checkpoint inhibitors, could have synergistic activity against non-ALK-driver NSCLC, hence the combination of avelumab and crizotinib in these patients.

Their second hypothesis was that a combination of an ALK inhibitor and checkpoint inhibitor could lead to enhanced efficacy in patients with previously treated ALK-positive NSCLC. To test this combination, they chose to pair avelumab with lorlatinib, a third-generation ALK-targeting TKI with the ability to penetrate the central nervous system. Dr. Shaw and her colleagues had previously shown in a phase 1 trial that this agent has potent activity against ALK-driven tumors with resistance mutations.

Two groups, two TKIs, one PD-L1 inhibitor

Group A in JAVELIN LUNG 101 included 12 patients with ALK-negative NSCLC, no known ROS1 gene rearrangement, c-MET gene amplification, or c-MET exon 14, skipping who had received at least one prior line of systemic therapy, and no prior checkpoint inhibitor. These patients were treated with avelumab 10 mg/kg over a 1-hour IV infusion every 2 weeks, plus 250 mg oral crizotinib twice daily.

Group B included 28 patients with advanced ALK-positive NSCLC, any number of prior regimens (or none), and no prior checkpoint inhibitor therapy. Patients with asymptomatic untreated brain metastases were eligible for treatment. These patients received avelumab at the same dose and schedule as in group A, plus oral lorlatinib 100 mg once daily.

In both arms, patients were assessed for maximum tolerated dose (MTD) and recommended phase 2 doses, DLTs, safety and tolerability, and antitumor activity.

There were no DLTs among 25 patients evaluable for this assessment in the avelumab/lorlatinib arm. In contrast, five patients had DLTs in the avelumab/crizotinib arm, included four transaminases increases and one case each of febrile neutropenia, hepatitis, QT interval prolongation, and rash.

Adverse events of any grade occurred in all patients in group A and in 27 of 28 patients (96.4%) in group B. Grade 3 or greater adverse events occurred in 58.3% and 53.6% of patients, respectively.

In group A, treatment-related serious adverse events were febrile neutropenia, hepatitis, and rash. In group B, these events included pneumonitis, elevated alanine aminotransferase, delirium, fatal dyspnea (one case), and pericardial effusion.

Antitumor activity

In group A (ALK-negative NSCLC), two patients had a partial response (PR), five had stable disease, and five had progressive disease, for an ORR of 16.7. The median time to response was 1.4 months, and the median duration of response was 4.1 months.

In group B (ALK-positive NSCLC). There was one complete response, 12 PRs, six cases of stable disease, and seven of progressive disease. Two patients in this arm were not evaluable for response at the time of the data cutoff in October 2017. The ORR in this arm was 46.4%, median time to response was 1.9 months, and the median duration of response was 7.4 months. Dr. Shaw cautioned, however, that the 95% confidence interval for duration of response in this group was wide (3.7 months to not estimable), because the data were not yet mature and the number of patients was small.

“Longer follow-up will be important to establish the true durability of these responses and to better assess the potential benefit of combined avelumab and lorlatinib in ALK-positive lung cancer,” Dr. Shaw said.

Neil Osterweil/MDedge News

But invited discussant Leora Horn, MD, MSc, of Vanderbilt University Medical Center in Nashville, Tenn., cast doubt on the ALK inhibitor/checkpoint inhibitor combination compared with targeted therapy alone.

“We were hoping to see that combination therapy with ALK tyrosine kinase inhibitors and immune checkpoint inhibitors are superior to therapy with an ALK tyrosine kinase inhibitor alone, that combination therapy is safe with a manageable toxicity profile, and lastly, that combination therapy with an ALK TKI and immune checkpoint inhibitor is superior to immune checkpoint inhibitor alone in ALK wild type patients,” she said.

She noted that previous phase 1 data with lorlatinib monotherapy in NSCLC showed an ORR of 46%, compared with 46.4% seen with the addition of avelumab to lorlatinib.

“So where do we go from here? We’ve seen that combination therapy with ALK tyrosine kinase inhibitors and immune checkpoint inhibitors are not the optimal therapeutic strategy in ALK-positive non–small-cell lung cancer. It is difficult to improve on a 70% response rate [with TKIs]. The progression-free survival, which is more important, was also not improved,” she said.

The mechanisms of additive toxicities between TKIs and checkpoints are not well understood, and she suggested that “further studies with biopsies exploring the tumor microenvironment in ALK or other driver-positive non–small-cell lung cancer prior to and after therapy with a TKI may help us better define the optimal combination strategy going forward.”

In a panel discussion following her talk, Dr. Shaw was asked what proportion of the responses her team saw could be attributed to lorlatinib rather than avelumab.

“As we showed, both the response rates and the duration of response were actually pretty similar to what was seen in our previous phase 1/2 study of lorlatinib alone. So one could say that perhaps all of the response that was seen with lorlatinib/avelumab was due to the lorlatinib,” she replied.

She added that several patients have ongoing responses, and that longer follow-up may reveal a benefit for the combination in terms of duration of response.

SOURCE: Shaw AT et al. ASCO 2018, Abstract 9008.

CHICAGO – The combination of the immune checkpoint inhibitor avelumab (Bavencio) and the ALK inhibitor lorlatinib in ALK-positive patients was associated with an acceptable safety profile and good activity – albeit not better than lorlatinib alone – in one arm of the phase 1/2b JAVELIN Lung 101 trial.

In contrast, although preclinical data suggested that the combination of an ALK inhibitor and immune checkpoint inhibitor might have synergistic activity in patients with advanced ALK-negative non–small-cell lung cancer (NSCLC), it didn’t pan out in the second arm of the trial, reported Alice T. Shaw, MD, PhD, of Massachusetts General Hospital Cancer Center in Boston.

Neil Osterweil/MDedge News

In the parallel group trial testing combinations of the programmed death ligand-1 (PD-L1) inhibitor avelumab with either of two tyrosine kinase inhibitors (TKIs) – crizotinib (Xalkori) or lorlatinib – the combination of avelumab and crizotinib had an objective response rate (ORR) of just 16.7% in ALK-negative patients, and 5 of 12 patients in this study arm had dose limiting toxicities (DLTs) due to serious adverse events.

“The most common DLTs were increased transaminases, consistent with the recent report of increased hepatotoxicity with the combination of nivolumab and crizotinib in Checkmate 370. While there were two confirmed partial responses, this efficacy would be expected for avelumab alone. No further development of this combination is planned,” Dr. Shaw said in an oral abstract session at the annual meeting of the American Society of Clinical Oncology.

In contrast, in ALK-positive patients, avelumab/lorlatinib was associated with an ORR of 46.4%, although it’s likely that the responses were attributable to lorlatinib alone, and not its anti-PD-L1 partner, she acknowledged.
 

Synergism sought

The investigators based the study on two hypotheses: The first was that ALK inhibitors, through their immunomodulatory properties, combined with checkpoint inhibitors, could have synergistic activity against non-ALK-driver NSCLC, hence the combination of avelumab and crizotinib in these patients.

Their second hypothesis was that a combination of an ALK inhibitor and checkpoint inhibitor could lead to enhanced efficacy in patients with previously treated ALK-positive NSCLC. To test this combination, they chose to pair avelumab with lorlatinib, a third-generation ALK-targeting TKI with the ability to penetrate the central nervous system. Dr. Shaw and her colleagues had previously shown in a phase 1 trial that this agent has potent activity against ALK-driven tumors with resistance mutations.

Two groups, two TKIs, one PD-L1 inhibitor

Group A in JAVELIN LUNG 101 included 12 patients with ALK-negative NSCLC, no known ROS1 gene rearrangement, c-MET gene amplification, or c-MET exon 14, skipping who had received at least one prior line of systemic therapy, and no prior checkpoint inhibitor. These patients were treated with avelumab 10 mg/kg over a 1-hour IV infusion every 2 weeks, plus 250 mg oral crizotinib twice daily.

Group B included 28 patients with advanced ALK-positive NSCLC, any number of prior regimens (or none), and no prior checkpoint inhibitor therapy. Patients with asymptomatic untreated brain metastases were eligible for treatment. These patients received avelumab at the same dose and schedule as in group A, plus oral lorlatinib 100 mg once daily.

In both arms, patients were assessed for maximum tolerated dose (MTD) and recommended phase 2 doses, DLTs, safety and tolerability, and antitumor activity.

There were no DLTs among 25 patients evaluable for this assessment in the avelumab/lorlatinib arm. In contrast, five patients had DLTs in the avelumab/crizotinib arm, included four transaminases increases and one case each of febrile neutropenia, hepatitis, QT interval prolongation, and rash.

Adverse events of any grade occurred in all patients in group A and in 27 of 28 patients (96.4%) in group B. Grade 3 or greater adverse events occurred in 58.3% and 53.6% of patients, respectively.

In group A, treatment-related serious adverse events were febrile neutropenia, hepatitis, and rash. In group B, these events included pneumonitis, elevated alanine aminotransferase, delirium, fatal dyspnea (one case), and pericardial effusion.

Antitumor activity

In group A (ALK-negative NSCLC), two patients had a partial response (PR), five had stable disease, and five had progressive disease, for an ORR of 16.7. The median time to response was 1.4 months, and the median duration of response was 4.1 months.

In group B (ALK-positive NSCLC). There was one complete response, 12 PRs, six cases of stable disease, and seven of progressive disease. Two patients in this arm were not evaluable for response at the time of the data cutoff in October 2017. The ORR in this arm was 46.4%, median time to response was 1.9 months, and the median duration of response was 7.4 months. Dr. Shaw cautioned, however, that the 95% confidence interval for duration of response in this group was wide (3.7 months to not estimable), because the data were not yet mature and the number of patients was small.

“Longer follow-up will be important to establish the true durability of these responses and to better assess the potential benefit of combined avelumab and lorlatinib in ALK-positive lung cancer,” Dr. Shaw said.

Neil Osterweil/MDedge News

But invited discussant Leora Horn, MD, MSc, of Vanderbilt University Medical Center in Nashville, Tenn., cast doubt on the ALK inhibitor/checkpoint inhibitor combination compared with targeted therapy alone.

“We were hoping to see that combination therapy with ALK tyrosine kinase inhibitors and immune checkpoint inhibitors are superior to therapy with an ALK tyrosine kinase inhibitor alone, that combination therapy is safe with a manageable toxicity profile, and lastly, that combination therapy with an ALK TKI and immune checkpoint inhibitor is superior to immune checkpoint inhibitor alone in ALK wild type patients,” she said.

She noted that previous phase 1 data with lorlatinib monotherapy in NSCLC showed an ORR of 46%, compared with 46.4% seen with the addition of avelumab to lorlatinib.

“So where do we go from here? We’ve seen that combination therapy with ALK tyrosine kinase inhibitors and immune checkpoint inhibitors are not the optimal therapeutic strategy in ALK-positive non–small-cell lung cancer. It is difficult to improve on a 70% response rate [with TKIs]. The progression-free survival, which is more important, was also not improved,” she said.

The mechanisms of additive toxicities between TKIs and checkpoints are not well understood, and she suggested that “further studies with biopsies exploring the tumor microenvironment in ALK or other driver-positive non–small-cell lung cancer prior to and after therapy with a TKI may help us better define the optimal combination strategy going forward.”

In a panel discussion following her talk, Dr. Shaw was asked what proportion of the responses her team saw could be attributed to lorlatinib rather than avelumab.

“As we showed, both the response rates and the duration of response were actually pretty similar to what was seen in our previous phase 1/2 study of lorlatinib alone. So one could say that perhaps all of the response that was seen with lorlatinib/avelumab was due to the lorlatinib,” she replied.

She added that several patients have ongoing responses, and that longer follow-up may reveal a benefit for the combination in terms of duration of response.

SOURCE: Shaw AT et al. ASCO 2018, Abstract 9008.

CHICAGO – The combination of the immune checkpoint inhibitor avelumab (Bavencio) and the ALK inhibitor lorlatinib in ALK-positive patients was associated with an acceptable safety profile and good activity – albeit not better than lorlatinib alone – in one arm of the phase 1/2b JAVELIN Lung 101 trial.

In contrast, although preclinical data suggested that the combination of an ALK inhibitor and immune checkpoint inhibitor might have synergistic activity in patients with advanced ALK-negative non–small-cell lung cancer (NSCLC), it didn’t pan out in the second arm of the trial, reported Alice T. Shaw, MD, PhD, of Massachusetts General Hospital Cancer Center in Boston.

Neil Osterweil/MDedge News

In the parallel group trial testing combinations of the programmed death ligand-1 (PD-L1) inhibitor avelumab with either of two tyrosine kinase inhibitors (TKIs) – crizotinib (Xalkori) or lorlatinib – the combination of avelumab and crizotinib had an objective response rate (ORR) of just 16.7% in ALK-negative patients, and 5 of 12 patients in this study arm had dose limiting toxicities (DLTs) due to serious adverse events.

“The most common DLTs were increased transaminases, consistent with the recent report of increased hepatotoxicity with the combination of nivolumab and crizotinib in Checkmate 370. While there were two confirmed partial responses, this efficacy would be expected for avelumab alone. No further development of this combination is planned,” Dr. Shaw said in an oral abstract session at the annual meeting of the American Society of Clinical Oncology.

In contrast, in ALK-positive patients, avelumab/lorlatinib was associated with an ORR of 46.4%, although it’s likely that the responses were attributable to lorlatinib alone, and not its anti-PD-L1 partner, she acknowledged.
 

Synergism sought

The investigators based the study on two hypotheses: The first was that ALK inhibitors, through their immunomodulatory properties, combined with checkpoint inhibitors, could have synergistic activity against non-ALK-driver NSCLC, hence the combination of avelumab and crizotinib in these patients.

Their second hypothesis was that a combination of an ALK inhibitor and checkpoint inhibitor could lead to enhanced efficacy in patients with previously treated ALK-positive NSCLC. To test this combination, they chose to pair avelumab with lorlatinib, a third-generation ALK-targeting TKI with the ability to penetrate the central nervous system. Dr. Shaw and her colleagues had previously shown in a phase 1 trial that this agent has potent activity against ALK-driven tumors with resistance mutations.

Two groups, two TKIs, one PD-L1 inhibitor

Group A in JAVELIN LUNG 101 included 12 patients with ALK-negative NSCLC, no known ROS1 gene rearrangement, c-MET gene amplification, or c-MET exon 14, skipping who had received at least one prior line of systemic therapy, and no prior checkpoint inhibitor. These patients were treated with avelumab 10 mg/kg over a 1-hour IV infusion every 2 weeks, plus 250 mg oral crizotinib twice daily.

Group B included 28 patients with advanced ALK-positive NSCLC, any number of prior regimens (or none), and no prior checkpoint inhibitor therapy. Patients with asymptomatic untreated brain metastases were eligible for treatment. These patients received avelumab at the same dose and schedule as in group A, plus oral lorlatinib 100 mg once daily.

In both arms, patients were assessed for maximum tolerated dose (MTD) and recommended phase 2 doses, DLTs, safety and tolerability, and antitumor activity.

There were no DLTs among 25 patients evaluable for this assessment in the avelumab/lorlatinib arm. In contrast, five patients had DLTs in the avelumab/crizotinib arm, included four transaminases increases and one case each of febrile neutropenia, hepatitis, QT interval prolongation, and rash.

Adverse events of any grade occurred in all patients in group A and in 27 of 28 patients (96.4%) in group B. Grade 3 or greater adverse events occurred in 58.3% and 53.6% of patients, respectively.

In group A, treatment-related serious adverse events were febrile neutropenia, hepatitis, and rash. In group B, these events included pneumonitis, elevated alanine aminotransferase, delirium, fatal dyspnea (one case), and pericardial effusion.

Antitumor activity

In group A (ALK-negative NSCLC), two patients had a partial response (PR), five had stable disease, and five had progressive disease, for an ORR of 16.7. The median time to response was 1.4 months, and the median duration of response was 4.1 months.

In group B (ALK-positive NSCLC). There was one complete response, 12 PRs, six cases of stable disease, and seven of progressive disease. Two patients in this arm were not evaluable for response at the time of the data cutoff in October 2017. The ORR in this arm was 46.4%, median time to response was 1.9 months, and the median duration of response was 7.4 months. Dr. Shaw cautioned, however, that the 95% confidence interval for duration of response in this group was wide (3.7 months to not estimable), because the data were not yet mature and the number of patients was small.

“Longer follow-up will be important to establish the true durability of these responses and to better assess the potential benefit of combined avelumab and lorlatinib in ALK-positive lung cancer,” Dr. Shaw said.

Neil Osterweil/MDedge News

But invited discussant Leora Horn, MD, MSc, of Vanderbilt University Medical Center in Nashville, Tenn., cast doubt on the ALK inhibitor/checkpoint inhibitor combination compared with targeted therapy alone.

“We were hoping to see that combination therapy with ALK tyrosine kinase inhibitors and immune checkpoint inhibitors are superior to therapy with an ALK tyrosine kinase inhibitor alone, that combination therapy is safe with a manageable toxicity profile, and lastly, that combination therapy with an ALK TKI and immune checkpoint inhibitor is superior to immune checkpoint inhibitor alone in ALK wild type patients,” she said.

She noted that previous phase 1 data with lorlatinib monotherapy in NSCLC showed an ORR of 46%, compared with 46.4% seen with the addition of avelumab to lorlatinib.

“So where do we go from here? We’ve seen that combination therapy with ALK tyrosine kinase inhibitors and immune checkpoint inhibitors are not the optimal therapeutic strategy in ALK-positive non–small-cell lung cancer. It is difficult to improve on a 70% response rate [with TKIs]. The progression-free survival, which is more important, was also not improved,” she said.

The mechanisms of additive toxicities between TKIs and checkpoints are not well understood, and she suggested that “further studies with biopsies exploring the tumor microenvironment in ALK or other driver-positive non–small-cell lung cancer prior to and after therapy with a TKI may help us better define the optimal combination strategy going forward.”

In a panel discussion following her talk, Dr. Shaw was asked what proportion of the responses her team saw could be attributed to lorlatinib rather than avelumab.

“As we showed, both the response rates and the duration of response were actually pretty similar to what was seen in our previous phase 1/2 study of lorlatinib alone. So one could say that perhaps all of the response that was seen with lorlatinib/avelumab was due to the lorlatinib,” she replied.

She added that several patients have ongoing responses, and that longer follow-up may reveal a benefit for the combination in terms of duration of response.

SOURCE: Shaw AT et al. ASCO 2018, Abstract 9008.

Erythema elevatum diutinum (EED) manifests on a clinicopathologic spectrum of chronic cutaneous small vessel vasculitis. The lesions typically present as persistent, symmetric, firm, red to purple papules or nodules on the extensor arms and dorsal hands.^1,2 Underlying infectious, malignant, or autoimmune processes are commonly associated with the disease, notably Streptococcus infection and IgA monoclonal gammopathy.^2,3 Hepatitis virus also is often implicated in association with EED. Cases of EED have been seen with concomitant human immunodeficiency virus (HIV) infection.^4-6 We report a case of EED presenting in various stages of evolution associated with underlying hepatitis B infection alone.

Case Report

A 57-year-old man originally presented to an outpatient dermatology practice with a nodular, painful, episodic rash on the trunk and upper and lower extremities. A biopsy revealed leukocytoclastic vasculitis (LCV) with prominent eosinophils. At the time, the skin findings were believed to be a manifestation of drug hypersensitivity, likely to opioid use. The patient was lost to follow-up.

Seven years later, the patient was admitted to the hospital with new-onset burning and stinging red nodules on the dorsum of the hands and persistence of the original episodic rash over the lower legs and bilateral flanks. In the interim, he was briefly treated with an oral prednisone taper and topical corticosteroids including triamcinolone cream 0.1% and clobetasol cream 0.05% without improvement.

On examination deep red to violaceous discrete nodules and plaques with overlying hyperkeratosis involving all distal and proximal interphalangeal joints of the hands and extensor elbows were seen (Figure 1A). On the bilateral posterior arms (Figure 1B), anterior legs, and periumbilical area were deeply erythematous papules and plaques with background hyperpigmentation. Across his lower back and bilateral flanks were erythematous papules with central hemorrhagic crusting (Figure 1C).

Pertinent laboratory findings included a positive hepatitis B surface antigen with hepatitis B DNA value 4,313,876 IU/mL and a hepatitis B virus quantitative polymerase chain reaction value of 6.64 U. The etiology was suspected to be intravenous drug abuse; however, the patient denied recreational drug use.

An additional infectious workup was negative for hepatitis C, streptococcus, syphilis, tuberculosis, and HIV. A complete blood cell count, complete metabolic panel, urinalysis, complement, cryoglobulins, and serum protein electrophoresis were within reference range. Autoimmune serologies were negative including antinuclear antibody, rheumatoid factor, anti-Sjögren syndrome–related antigen A and B, anticyclic citrullinated peptide, anti-Smith, and antineutrophilic cytoplasmic antibodies. Peripheral blood immunophenotyping, lactate dehydrogenase, quantitative immunoglobulins, and age-appropriate cancer screens did not demonstrate evidence for malignancy underlying the disease. Bilateral hand radiographs showed mild periostitis of the proximal phalanges without obvious erosions.

Three 4-mm punch biopsies were performed from the left fifth digit, left posterior arm, and left flank. Tissue of the left fifth digit showed an intradermal vascular proliferation with a concentric pattern resembling onion skin in a background of increased fibrosis. The blood vessels showed focal fibrinoid necrosis (Figure 2A). The biopsy of the left posterior arm showed an intradermal vascular proliferation with an associated mild acute and chronic perivascular inflammation (Figure 2B). The left flank biopsy showed LCV with focal epidermal necrosis (Figure 2C).

Comment

Overview of EED
Erythema elevatum diutinum represents a rare form of chronic cutaneous small vessel vasculitis. Originally described by Hutchinson⁷ and Bury⁸ as symmetric purpuric nodules of the skin, it was later named by Crocker and Williams⁹ in 1894. The disease classically presents as firm, fixed, red-brown to violaceous papules, plaques, and nodules affecting the extensor upper or lower extremities.¹ Lesions are most commonly found symmetrically overlying joints of the hands, feet, elbows, and knees, as well as the Achilles tendon and buttocks.³ Less common locations include the palms and soles, face,^10,11 trunk,¹² and periauricular region.¹ Although they are typically asymptomatic, sensations such as burning, stinging, and pruritus have been noted.¹ Our patient was unique because in addition to typical lesions of EED, he presented with crusted papules on the flanks and violaceous papules of the lower legs and periumbilicus.

Etiology
Originally associated with Streptococcus as isolated from EED lesions,^3,13 additional infectious etiologies include viral hepatitis,^4-6 human herpesvirus 6,¹⁴ and rarely HIV.^1,15 Hepatitis B and C are well known to be associated with EED, with only rare reports in patients with concomitant HIV infection. Erythema elevatum diutinum also has been described in relationship to myeloproliferative disorders and hematologic malignancies such as IgA myeloma,¹⁶ non-Hodgkin lymphoma,¹⁷ chronic lymphocytic leukemia,¹⁸ and hypergammaglobulinemia.¹⁹ In a study of 13 patients with EED, 4 had associated underlying IgA monoclonal gammopathy.² Autoimmune conditions such as rheumatoid arthritis,²⁰ ulcerative colitis,²¹ relapsing polychondritis,²² and systemic lupus erythematosus²³ also have been implicated.

Pathogenesis
Although the precise pathogenesis of EED remains unknown, it has been suggested that a complement cascade initiated by immune-complex deposition in postcapillary venules induces an LCV.^24,25 Chronic antigenic exposure or high antibody levels²⁶ in the face of infections, autoimmune disease, or malignancy may incite this immune-complex reaction. Skin lesions seen in association with hepatitis reflect circulating immune-complex deposition in vessel walls causing destruction. It has been postulated that the duration of immune complexemia may be sufficient to account for the differences in the type of vascular injury seen in acute versus chronic infection.²⁷

Histopathology
Erythema elevatum diutinum may present on a histopathologic spectrum of LCV, as manifested in our patient. Early lesions show predominantly polymorphonuclear cells with nuclear dust pattern in a wedge-shaped infiltrate with fibrin deposition in the superficial and mid dermis.^2,3 Later lesions show vasculitis in addition to dermal aggregates of lymphocytes, neutrophils, fibrosis, and areas of granulation tissue. The fibrosis may be dense and comprised of fibroblasts and myofibroblasts.²⁸ Newly formed vessels within the granulation tissue have been postulated to be more susceptible to immune-complex deposition, thus potentiating the process.^1,29

Management
Spontaneous resolution of EED may occur, albeit after a prolonged and recurrent course of up to 5 to 10 years.³⁰ Treatment of the underlying cause, when identified, remains paramount. First-line therapy includes dapsone, shown to be effective in reducing lesion size to complete resolution in 80% of the 47 cases reviewed by Momen et al.³¹ Dapsone monotherapy tends to be less effective in treating nodular lesions associated with HIV-positivity, likely due to the extensive fibrosis.^4,31 Combination therapy with dapsone and a sulfonamide,³² niacinamide and tetracycline,³³ colchicine,³⁴ or surgical excision³⁵ may be necessary in more resistant cases.

Conclusion

Our case exemplifies the clinical histologic spectrum that EED can present. The constellation of clinical findings was histologically confirmed to be manifestations of the disease in various stages of evolution. When typical lesions of EED present along with cutaneous findings in less common locations, performing multiple biopsies can be helpful. The clinician should retain a high index of suspicion for an underlying etiology and perform a complete workup for infection, malignancy, or autoimmune disease.

Erythema elevatum diutinum (EED) manifests on a clinicopathologic spectrum of chronic cutaneous small vessel vasculitis. The lesions typically present as persistent, symmetric, firm, red to purple papules or nodules on the extensor arms and dorsal hands.^1,2 Underlying infectious, malignant, or autoimmune processes are commonly associated with the disease, notably Streptococcus infection and IgA monoclonal gammopathy.^2,3 Hepatitis virus also is often implicated in association with EED. Cases of EED have been seen with concomitant human immunodeficiency virus (HIV) infection.^4-6 We report a case of EED presenting in various stages of evolution associated with underlying hepatitis B infection alone.

Case Report

A 57-year-old man originally presented to an outpatient dermatology practice with a nodular, painful, episodic rash on the trunk and upper and lower extremities. A biopsy revealed leukocytoclastic vasculitis (LCV) with prominent eosinophils. At the time, the skin findings were believed to be a manifestation of drug hypersensitivity, likely to opioid use. The patient was lost to follow-up.

Seven years later, the patient was admitted to the hospital with new-onset burning and stinging red nodules on the dorsum of the hands and persistence of the original episodic rash over the lower legs and bilateral flanks. In the interim, he was briefly treated with an oral prednisone taper and topical corticosteroids including triamcinolone cream 0.1% and clobetasol cream 0.05% without improvement.

On examination deep red to violaceous discrete nodules and plaques with overlying hyperkeratosis involving all distal and proximal interphalangeal joints of the hands and extensor elbows were seen (Figure 1A). On the bilateral posterior arms (Figure 1B), anterior legs, and periumbilical area were deeply erythematous papules and plaques with background hyperpigmentation. Across his lower back and bilateral flanks were erythematous papules with central hemorrhagic crusting (Figure 1C).

Pertinent laboratory findings included a positive hepatitis B surface antigen with hepatitis B DNA value 4,313,876 IU/mL and a hepatitis B virus quantitative polymerase chain reaction value of 6.64 U. The etiology was suspected to be intravenous drug abuse; however, the patient denied recreational drug use.

An additional infectious workup was negative for hepatitis C, streptococcus, syphilis, tuberculosis, and HIV. A complete blood cell count, complete metabolic panel, urinalysis, complement, cryoglobulins, and serum protein electrophoresis were within reference range. Autoimmune serologies were negative including antinuclear antibody, rheumatoid factor, anti-Sjögren syndrome–related antigen A and B, anticyclic citrullinated peptide, anti-Smith, and antineutrophilic cytoplasmic antibodies. Peripheral blood immunophenotyping, lactate dehydrogenase, quantitative immunoglobulins, and age-appropriate cancer screens did not demonstrate evidence for malignancy underlying the disease. Bilateral hand radiographs showed mild periostitis of the proximal phalanges without obvious erosions.

Three 4-mm punch biopsies were performed from the left fifth digit, left posterior arm, and left flank. Tissue of the left fifth digit showed an intradermal vascular proliferation with a concentric pattern resembling onion skin in a background of increased fibrosis. The blood vessels showed focal fibrinoid necrosis (Figure 2A). The biopsy of the left posterior arm showed an intradermal vascular proliferation with an associated mild acute and chronic perivascular inflammation (Figure 2B). The left flank biopsy showed LCV with focal epidermal necrosis (Figure 2C).

Comment

Overview of EED
Erythema elevatum diutinum represents a rare form of chronic cutaneous small vessel vasculitis. Originally described by Hutchinson⁷ and Bury⁸ as symmetric purpuric nodules of the skin, it was later named by Crocker and Williams⁹ in 1894. The disease classically presents as firm, fixed, red-brown to violaceous papules, plaques, and nodules affecting the extensor upper or lower extremities.¹ Lesions are most commonly found symmetrically overlying joints of the hands, feet, elbows, and knees, as well as the Achilles tendon and buttocks.³ Less common locations include the palms and soles, face,^10,11 trunk,¹² and periauricular region.¹ Although they are typically asymptomatic, sensations such as burning, stinging, and pruritus have been noted.¹ Our patient was unique because in addition to typical lesions of EED, he presented with crusted papules on the flanks and violaceous papules of the lower legs and periumbilicus.

Etiology
Originally associated with Streptococcus as isolated from EED lesions,^3,13 additional infectious etiologies include viral hepatitis,^4-6 human herpesvirus 6,¹⁴ and rarely HIV.^1,15 Hepatitis B and C are well known to be associated with EED, with only rare reports in patients with concomitant HIV infection. Erythema elevatum diutinum also has been described in relationship to myeloproliferative disorders and hematologic malignancies such as IgA myeloma,¹⁶ non-Hodgkin lymphoma,¹⁷ chronic lymphocytic leukemia,¹⁸ and hypergammaglobulinemia.¹⁹ In a study of 13 patients with EED, 4 had associated underlying IgA monoclonal gammopathy.² Autoimmune conditions such as rheumatoid arthritis,²⁰ ulcerative colitis,²¹ relapsing polychondritis,²² and systemic lupus erythematosus²³ also have been implicated.

Pathogenesis
Although the precise pathogenesis of EED remains unknown, it has been suggested that a complement cascade initiated by immune-complex deposition in postcapillary venules induces an LCV.^24,25 Chronic antigenic exposure or high antibody levels²⁶ in the face of infections, autoimmune disease, or malignancy may incite this immune-complex reaction. Skin lesions seen in association with hepatitis reflect circulating immune-complex deposition in vessel walls causing destruction. It has been postulated that the duration of immune complexemia may be sufficient to account for the differences in the type of vascular injury seen in acute versus chronic infection.²⁷

Histopathology
Erythema elevatum diutinum may present on a histopathologic spectrum of LCV, as manifested in our patient. Early lesions show predominantly polymorphonuclear cells with nuclear dust pattern in a wedge-shaped infiltrate with fibrin deposition in the superficial and mid dermis.^2,3 Later lesions show vasculitis in addition to dermal aggregates of lymphocytes, neutrophils, fibrosis, and areas of granulation tissue. The fibrosis may be dense and comprised of fibroblasts and myofibroblasts.²⁸ Newly formed vessels within the granulation tissue have been postulated to be more susceptible to immune-complex deposition, thus potentiating the process.^1,29

Management
Spontaneous resolution of EED may occur, albeit after a prolonged and recurrent course of up to 5 to 10 years.³⁰ Treatment of the underlying cause, when identified, remains paramount. First-line therapy includes dapsone, shown to be effective in reducing lesion size to complete resolution in 80% of the 47 cases reviewed by Momen et al.³¹ Dapsone monotherapy tends to be less effective in treating nodular lesions associated with HIV-positivity, likely due to the extensive fibrosis.^4,31 Combination therapy with dapsone and a sulfonamide,³² niacinamide and tetracycline,³³ colchicine,³⁴ or surgical excision³⁵ may be necessary in more resistant cases.

Conclusion

Our case exemplifies the clinical histologic spectrum that EED can present. The constellation of clinical findings was histologically confirmed to be manifestations of the disease in various stages of evolution. When typical lesions of EED present along with cutaneous findings in less common locations, performing multiple biopsies can be helpful. The clinician should retain a high index of suspicion for an underlying etiology and perform a complete workup for infection, malignancy, or autoimmune disease.

Erythema elevatum diutinum (EED) manifests on a clinicopathologic spectrum of chronic cutaneous small vessel vasculitis. The lesions typically present as persistent, symmetric, firm, red to purple papules or nodules on the extensor arms and dorsal hands.^1,2 Underlying infectious, malignant, or autoimmune processes are commonly associated with the disease, notably Streptococcus infection and IgA monoclonal gammopathy.^2,3 Hepatitis virus also is often implicated in association with EED. Cases of EED have been seen with concomitant human immunodeficiency virus (HIV) infection.^4-6 We report a case of EED presenting in various stages of evolution associated with underlying hepatitis B infection alone.

Case Report

A 57-year-old man originally presented to an outpatient dermatology practice with a nodular, painful, episodic rash on the trunk and upper and lower extremities. A biopsy revealed leukocytoclastic vasculitis (LCV) with prominent eosinophils. At the time, the skin findings were believed to be a manifestation of drug hypersensitivity, likely to opioid use. The patient was lost to follow-up.

Seven years later, the patient was admitted to the hospital with new-onset burning and stinging red nodules on the dorsum of the hands and persistence of the original episodic rash over the lower legs and bilateral flanks. In the interim, he was briefly treated with an oral prednisone taper and topical corticosteroids including triamcinolone cream 0.1% and clobetasol cream 0.05% without improvement.

On examination deep red to violaceous discrete nodules and plaques with overlying hyperkeratosis involving all distal and proximal interphalangeal joints of the hands and extensor elbows were seen (Figure 1A). On the bilateral posterior arms (Figure 1B), anterior legs, and periumbilical area were deeply erythematous papules and plaques with background hyperpigmentation. Across his lower back and bilateral flanks were erythematous papules with central hemorrhagic crusting (Figure 1C).

Pertinent laboratory findings included a positive hepatitis B surface antigen with hepatitis B DNA value 4,313,876 IU/mL and a hepatitis B virus quantitative polymerase chain reaction value of 6.64 U. The etiology was suspected to be intravenous drug abuse; however, the patient denied recreational drug use.

An additional infectious workup was negative for hepatitis C, streptococcus, syphilis, tuberculosis, and HIV. A complete blood cell count, complete metabolic panel, urinalysis, complement, cryoglobulins, and serum protein electrophoresis were within reference range. Autoimmune serologies were negative including antinuclear antibody, rheumatoid factor, anti-Sjögren syndrome–related antigen A and B, anticyclic citrullinated peptide, anti-Smith, and antineutrophilic cytoplasmic antibodies. Peripheral blood immunophenotyping, lactate dehydrogenase, quantitative immunoglobulins, and age-appropriate cancer screens did not demonstrate evidence for malignancy underlying the disease. Bilateral hand radiographs showed mild periostitis of the proximal phalanges without obvious erosions.

Three 4-mm punch biopsies were performed from the left fifth digit, left posterior arm, and left flank. Tissue of the left fifth digit showed an intradermal vascular proliferation with a concentric pattern resembling onion skin in a background of increased fibrosis. The blood vessels showed focal fibrinoid necrosis (Figure 2A). The biopsy of the left posterior arm showed an intradermal vascular proliferation with an associated mild acute and chronic perivascular inflammation (Figure 2B). The left flank biopsy showed LCV with focal epidermal necrosis (Figure 2C).

Comment

Overview of EED
Erythema elevatum diutinum represents a rare form of chronic cutaneous small vessel vasculitis. Originally described by Hutchinson⁷ and Bury⁸ as symmetric purpuric nodules of the skin, it was later named by Crocker and Williams⁹ in 1894. The disease classically presents as firm, fixed, red-brown to violaceous papules, plaques, and nodules affecting the extensor upper or lower extremities.¹ Lesions are most commonly found symmetrically overlying joints of the hands, feet, elbows, and knees, as well as the Achilles tendon and buttocks.³ Less common locations include the palms and soles, face,^10,11 trunk,¹² and periauricular region.¹ Although they are typically asymptomatic, sensations such as burning, stinging, and pruritus have been noted.¹ Our patient was unique because in addition to typical lesions of EED, he presented with crusted papules on the flanks and violaceous papules of the lower legs and periumbilicus.

Etiology
Originally associated with Streptococcus as isolated from EED lesions,^3,13 additional infectious etiologies include viral hepatitis,^4-6 human herpesvirus 6,¹⁴ and rarely HIV.^1,15 Hepatitis B and C are well known to be associated with EED, with only rare reports in patients with concomitant HIV infection. Erythema elevatum diutinum also has been described in relationship to myeloproliferative disorders and hematologic malignancies such as IgA myeloma,¹⁶ non-Hodgkin lymphoma,¹⁷ chronic lymphocytic leukemia,¹⁸ and hypergammaglobulinemia.¹⁹ In a study of 13 patients with EED, 4 had associated underlying IgA monoclonal gammopathy.² Autoimmune conditions such as rheumatoid arthritis,²⁰ ulcerative colitis,²¹ relapsing polychondritis,²² and systemic lupus erythematosus²³ also have been implicated.

Pathogenesis
Although the precise pathogenesis of EED remains unknown, it has been suggested that a complement cascade initiated by immune-complex deposition in postcapillary venules induces an LCV.^24,25 Chronic antigenic exposure or high antibody levels²⁶ in the face of infections, autoimmune disease, or malignancy may incite this immune-complex reaction. Skin lesions seen in association with hepatitis reflect circulating immune-complex deposition in vessel walls causing destruction. It has been postulated that the duration of immune complexemia may be sufficient to account for the differences in the type of vascular injury seen in acute versus chronic infection.²⁷

Histopathology
Erythema elevatum diutinum may present on a histopathologic spectrum of LCV, as manifested in our patient. Early lesions show predominantly polymorphonuclear cells with nuclear dust pattern in a wedge-shaped infiltrate with fibrin deposition in the superficial and mid dermis.^2,3 Later lesions show vasculitis in addition to dermal aggregates of lymphocytes, neutrophils, fibrosis, and areas of granulation tissue. The fibrosis may be dense and comprised of fibroblasts and myofibroblasts.²⁸ Newly formed vessels within the granulation tissue have been postulated to be more susceptible to immune-complex deposition, thus potentiating the process.^1,29

Management
Spontaneous resolution of EED may occur, albeit after a prolonged and recurrent course of up to 5 to 10 years.³⁰ Treatment of the underlying cause, when identified, remains paramount. First-line therapy includes dapsone, shown to be effective in reducing lesion size to complete resolution in 80% of the 47 cases reviewed by Momen et al.³¹ Dapsone monotherapy tends to be less effective in treating nodular lesions associated with HIV-positivity, likely due to the extensive fibrosis.^4,31 Combination therapy with dapsone and a sulfonamide,³² niacinamide and tetracycline,³³ colchicine,³⁴ or surgical excision³⁵ may be necessary in more resistant cases.

Conclusion

Our case exemplifies the clinical histologic spectrum that EED can present. The constellation of clinical findings was histologically confirmed to be manifestations of the disease in various stages of evolution. When typical lesions of EED present along with cutaneous findings in less common locations, performing multiple biopsies can be helpful. The clinician should retain a high index of suspicion for an underlying etiology and perform a complete workup for infection, malignancy, or autoimmune disease.

Methicillin, cloxacillin, flucloxacillin, and cefoxitin are stable, penicillinase-producing β-lactam antibiotics; Staphylococcus aureus strains resistant to these agents are designated as methicillin-resistant S aureus (MRSA). Based on genotypic and phenotypic differences there are 2 strains of MRSA: hospital acquired and community acquired.

The potential for nosocomial transmission and the limited number of antibiotics available to treat MRSA are problematic. Moreover, MRSA has emerged worldwide as a major nosocomial pathogen that contributes to morbidity and mortality. Methicillin-resistant S aureus infection in vesiculobullous disorders such as pemphigus vulgaris (PV) and toxic epidermal necrolysis (TEN) is known to contribute to mortality.¹

The reported prevalence of MRSA in India ranges from 12% to 38.44%.^2-4 We frequently encounter MRSA in dermatology inpatients, especially those with a vesiculobullous disorder. The primary objective of this study was to determine the prevalence of MRSA in dermatology inpatients with a vesiculobullous disorder; the secondary objective was to determine if MRSA contributes to mortality.

Materials and Methods

A 1-year prospective, cross-sectional, descriptive study was conducted in a tertiary-care center. The study population included all dermatology inpatients with a vesiculobullous disorder. Patients with a vesiculobullous disorder secondary to a primary viral or bacterial disorder were excluded. Permission to conduct the study was granted by the institution’s Human Ethics Committee.

All patients underwent a detailed history and clinical examination. Routine hematology testing, urinalysis, measurement of the blood glucose level, and other investigations relevant to the vesiculobullous disorder were performed. Special investigations were Gram staining, culture, and susceptibility testing of material from a nasal swab and a swab of a representative skin lesion.

Detection of MRSA
Skin lesions were thoroughly cleaned with sterile normal saline. Specimens of pus were drawn with a sterile swab for Gram staining, culture, and susceptibility testing and were analyzed in the institution’s microbiology department. A direct colony suspension (equivalent to McFarland Standard No. 0.5) was inoculated on a Mueller-Hinton agar plate, incorporating cefoxitin, linezolid, vancomycin, amikacin, and rifampicin supplemented with sodium chloride 2% and incubated at 37°C for 24 hours. Staphylococcus aureus colonies were identified by their smooth, convex, shiny, and opaque appearance with a golden yellow pigment, as well as by coagulase positivity, mannitol fermentation, and production of phosphatase.

Methicillin-resistant S aureus was defined as an isolate having a minimum inhibitory concentration of more than 2 μg/mL of cefoxitin; a methicillin-sensitive S aureus isolate was defined as having a minimum inhibitory concentration of less than or equal to 2 μg/mL of cefoxitin. Specimens showing moderate to heavy growth of MRSA were included in the study. For specimens showing mild growth, testing was repeated; if no growth was seen on repeat testing, results were interpreted as negative.

Data were collected and analyzed for frequency and percentage; P<.05 was considered significant.

Results

The number of patients analyzed in the study period was 43. Table 1 shows their salient demographic characteristics, clinical features, and findings of the investigation. The youngest patient was aged 13 years; the oldest was aged 80 years. The male to female ratio was 0.65 to 1. The most common primary lesion was a combined vesicle and bulla (34 patients [79.1%]); the most common secondary lesion was a combination of erosion with crusting (22 patients [51.2%]).

Table 2 lists the types of vesiculobullous disorders seen in this study. Pemphigus vulgaris was the most common (21 patients [48.8%])(Figure 1). Drug-induced vesiculobullous disorders (eg, TEN) were noted in 11 patients (25.6%)(Figure 2).

Table 2 also lists pathogens cultured in the study group. There were 24 bacterial isolates, of which S aureus accounted for 22 (91.7%). Methicillin-resistant S aureus was cultured in 14 patients (32.6%); culture was sterile in 19 patients (44.2%).

Among the 22 cultured staphylococcal species, MRSA accounted for 14 (63.6%) and constituted 58.3% (14/24) of all bacterial isolates. The nasal swab for MRSA was positive in 4 PV patients (9.3%), 2 TEN patients (4.6%), and 1 bullous pemphigoid patient (2.3%). Methicillin-resistant S aureus was most commonly cultured in PV patients (8/14 [57.1%]).

All MRSA strains (100%) were sensitive to vancomycin and linezolid; 34 (79.1%) were sensitive to amikacin. Additionally, 100% of MRSA strains were resistant to oxacillin, cloxacillin, and cefoxitin.

Three patients with PV (7.0%) and 1 patient with TEN (2.3%) died during the course of the study; only 1 death (2.3%) occurred in a patient who had a positive MRSA culture.

Comment

In this 1-year study, we tested and followed 43 patients with autoimmune and drug-induced vesiculobullous disorders. Vesiculobullous disorders in dermatology inpatients are a cause of great concern. When lesions rupture, they leave behind a large area of erosion that forms a nidus of bacterial colonization; often, these bacteria cause severe infection, including septicemia, and result in death.⁵ Moreover, autoimmune bullous disorders usually require a prolonged hospital stay and powerful immunosuppressive drugs, which contributes to bacterial infection, especially MRSA.⁶

The age of patients in this study ranged from 13 to 80 years; most patients were in the 6th decade, a pattern seen in studies worldwide.⁵ In a study by Kanwar and De,⁷ however, most cases were aged 20 to 40 years.⁷ In our study, there was a female preponderance (male to female ratio of 0.65 to 1).

Studies have shown that the duration of illness in vesiculobullous disorder is directly associated with MRSA infection. However, in our study with MRSA detected in 14 patients, most patients had a duration of illness less than 1 year (statistically insignificant [P>.05]), a finding similar to Shafi et al.⁸

The symptomatic nature of these diseases, their unsightly appearance, and mucous-membrane involvement of vesiculobullous disorders prompts these patients to present to the hospital early. However, a prolonged hospital stay by patients with an autoimmune vesiculobullous disorders sets the stage for MRSA colonization.

In this study, diabetes mellitus (DM) was seen in 15 patients (34.9%); 5 of them had MRSA infection (statistically insignificant [P>.05]). Diabetes mellitus contributing to sepsis and MRSA infection, which in turn contributes to morbidity and mortality, has been well-documented.^2,4,9

Methicillin-resistant S aureus in this study was isolated most often from blisters and erosions. Vesiculobullous disorders and drug reactions (eg, Stevens-Johnson syndrome, TEN) are characterized by blisters that rupture to form erosions and crusting, which form fissures in the epidermal barrier function that are nidi for colonization by microbes, especially S aureus and MRSA in particular; later, these bacteria can enter dermal vessels and then the bloodstream, leading to septicemia.¹⁰

The prevalence of MRSA in this study was 32.6% (14/43), which is high compared to other studies.^2-4 Pemphigus vulgaris was the most common disorder infected by MRSA in this study (57.1% [8/14] of MRSA isolates)(Table 1), a finding that reveals that the incidence of MRSA is high among staphylococcal isolates in vesiculobullous disorders. However, the high incidence of MRSA in this study could be a reflection of the number of patients with a severe and chronic vesiculobullous disorder, such as PV, and serious drug reactions such as TEN referred to our tertiary-care center, where we get a large number of patients affected by autoimmune and drug-induced vesiculobullous disorders. Similar findings have been reported by Stryjewski et al.¹¹

A high prevalence of MRSA in a dermatology unit has grave consequences, contributing to morbidity and mortality in particular among patients with a vesiculobullous disorder. Immunosuppressive therapy and comorbidities such as DM contribute to MRSA colonization in vesiculobullous disorders.¹² Overcrowding and poor sterilization techniques in public hospitals in India may contribute to the high prevalence of MRSA seen in hospital units.

Patients with a vesiculobullous disorder who are chronic nasal carriers of MRSA are at risk for cutaneous MRSA infection, which in turn can lead to MRSA septicemia and an elevated risk of death. In this study, however, a nasal swab was positive for MRSA in only 7 patients. One patient with MRSA colonization died, which was statistically insignificant (P=1).

In this study, all MRSA strains (100%) were resistant to first-line antibiotics, such as oxacillin, cloxacillin, and cefoxitin; all strains were susceptible to vancomycin and linezolid. This finding is similar to prior studies.^13,14 A distinctive finding in this study is that 34 (79.1%) of MRSA isolates were susceptible to amikacin. This finding has practical significance. Amikacin, an inexpensive antibiotic that is readily available in most units, can be used to treat MRSA infection in resource-poor settings where vancomycin and linezolid are unavailable.

Conclusion

Our study shows that MRSA is becoming the prominent pathogen in nosocomial infections, especially in bedridden patients, which has grave implications. The use of a prophylactic S aureus conjugate vaccine in patients with a chronic vesiculobullous disorder might be justified in the future.¹⁵ We found a high prevalence (32.6%) of MRSA in vesiculobullous disorders, no relationship between DM and MRSA colonization, PV was the most common disorder complicated by MRSA, no relationship between nasal colonization and MRSA infection, no relationship between death during the study period and MRSA infection, 100% of MRSA strains were susceptible to vancomycin and linezolid, and 79.1% of MRSA strains were susceptible to amikacin.

Methicillin, cloxacillin, flucloxacillin, and cefoxitin are stable, penicillinase-producing β-lactam antibiotics; Staphylococcus aureus strains resistant to these agents are designated as methicillin-resistant S aureus (MRSA). Based on genotypic and phenotypic differences there are 2 strains of MRSA: hospital acquired and community acquired.

The potential for nosocomial transmission and the limited number of antibiotics available to treat MRSA are problematic. Moreover, MRSA has emerged worldwide as a major nosocomial pathogen that contributes to morbidity and mortality. Methicillin-resistant S aureus infection in vesiculobullous disorders such as pemphigus vulgaris (PV) and toxic epidermal necrolysis (TEN) is known to contribute to mortality.¹

The reported prevalence of MRSA in India ranges from 12% to 38.44%.^2-4 We frequently encounter MRSA in dermatology inpatients, especially those with a vesiculobullous disorder. The primary objective of this study was to determine the prevalence of MRSA in dermatology inpatients with a vesiculobullous disorder; the secondary objective was to determine if MRSA contributes to mortality.

Materials and Methods

A 1-year prospective, cross-sectional, descriptive study was conducted in a tertiary-care center. The study population included all dermatology inpatients with a vesiculobullous disorder. Patients with a vesiculobullous disorder secondary to a primary viral or bacterial disorder were excluded. Permission to conduct the study was granted by the institution’s Human Ethics Committee.

All patients underwent a detailed history and clinical examination. Routine hematology testing, urinalysis, measurement of the blood glucose level, and other investigations relevant to the vesiculobullous disorder were performed. Special investigations were Gram staining, culture, and susceptibility testing of material from a nasal swab and a swab of a representative skin lesion.

Detection of MRSA
Skin lesions were thoroughly cleaned with sterile normal saline. Specimens of pus were drawn with a sterile swab for Gram staining, culture, and susceptibility testing and were analyzed in the institution’s microbiology department. A direct colony suspension (equivalent to McFarland Standard No. 0.5) was inoculated on a Mueller-Hinton agar plate, incorporating cefoxitin, linezolid, vancomycin, amikacin, and rifampicin supplemented with sodium chloride 2% and incubated at 37°C for 24 hours. Staphylococcus aureus colonies were identified by their smooth, convex, shiny, and opaque appearance with a golden yellow pigment, as well as by coagulase positivity, mannitol fermentation, and production of phosphatase.

Methicillin-resistant S aureus was defined as an isolate having a minimum inhibitory concentration of more than 2 μg/mL of cefoxitin; a methicillin-sensitive S aureus isolate was defined as having a minimum inhibitory concentration of less than or equal to 2 μg/mL of cefoxitin. Specimens showing moderate to heavy growth of MRSA were included in the study. For specimens showing mild growth, testing was repeated; if no growth was seen on repeat testing, results were interpreted as negative.

Data were collected and analyzed for frequency and percentage; P<.05 was considered significant.

Results

The number of patients analyzed in the study period was 43. Table 1 shows their salient demographic characteristics, clinical features, and findings of the investigation. The youngest patient was aged 13 years; the oldest was aged 80 years. The male to female ratio was 0.65 to 1. The most common primary lesion was a combined vesicle and bulla (34 patients [79.1%]); the most common secondary lesion was a combination of erosion with crusting (22 patients [51.2%]).

Table 2 lists the types of vesiculobullous disorders seen in this study. Pemphigus vulgaris was the most common (21 patients [48.8%])(Figure 1). Drug-induced vesiculobullous disorders (eg, TEN) were noted in 11 patients (25.6%)(Figure 2).

Table 2 also lists pathogens cultured in the study group. There were 24 bacterial isolates, of which S aureus accounted for 22 (91.7%). Methicillin-resistant S aureus was cultured in 14 patients (32.6%); culture was sterile in 19 patients (44.2%).

Among the 22 cultured staphylococcal species, MRSA accounted for 14 (63.6%) and constituted 58.3% (14/24) of all bacterial isolates. The nasal swab for MRSA was positive in 4 PV patients (9.3%), 2 TEN patients (4.6%), and 1 bullous pemphigoid patient (2.3%). Methicillin-resistant S aureus was most commonly cultured in PV patients (8/14 [57.1%]).

All MRSA strains (100%) were sensitive to vancomycin and linezolid; 34 (79.1%) were sensitive to amikacin. Additionally, 100% of MRSA strains were resistant to oxacillin, cloxacillin, and cefoxitin.

Three patients with PV (7.0%) and 1 patient with TEN (2.3%) died during the course of the study; only 1 death (2.3%) occurred in a patient who had a positive MRSA culture.

Comment

In this 1-year study, we tested and followed 43 patients with autoimmune and drug-induced vesiculobullous disorders. Vesiculobullous disorders in dermatology inpatients are a cause of great concern. When lesions rupture, they leave behind a large area of erosion that forms a nidus of bacterial colonization; often, these bacteria cause severe infection, including septicemia, and result in death.⁵ Moreover, autoimmune bullous disorders usually require a prolonged hospital stay and powerful immunosuppressive drugs, which contributes to bacterial infection, especially MRSA.⁶

The age of patients in this study ranged from 13 to 80 years; most patients were in the 6th decade, a pattern seen in studies worldwide.⁵ In a study by Kanwar and De,⁷ however, most cases were aged 20 to 40 years.⁷ In our study, there was a female preponderance (male to female ratio of 0.65 to 1).

Studies have shown that the duration of illness in vesiculobullous disorder is directly associated with MRSA infection. However, in our study with MRSA detected in 14 patients, most patients had a duration of illness less than 1 year (statistically insignificant [P>.05]), a finding similar to Shafi et al.⁸

The symptomatic nature of these diseases, their unsightly appearance, and mucous-membrane involvement of vesiculobullous disorders prompts these patients to present to the hospital early. However, a prolonged hospital stay by patients with an autoimmune vesiculobullous disorders sets the stage for MRSA colonization.

In this study, diabetes mellitus (DM) was seen in 15 patients (34.9%); 5 of them had MRSA infection (statistically insignificant [P>.05]). Diabetes mellitus contributing to sepsis and MRSA infection, which in turn contributes to morbidity and mortality, has been well-documented.^2,4,9

Methicillin-resistant S aureus in this study was isolated most often from blisters and erosions. Vesiculobullous disorders and drug reactions (eg, Stevens-Johnson syndrome, TEN) are characterized by blisters that rupture to form erosions and crusting, which form fissures in the epidermal barrier function that are nidi for colonization by microbes, especially S aureus and MRSA in particular; later, these bacteria can enter dermal vessels and then the bloodstream, leading to septicemia.¹⁰

The prevalence of MRSA in this study was 32.6% (14/43), which is high compared to other studies.^2-4 Pemphigus vulgaris was the most common disorder infected by MRSA in this study (57.1% [8/14] of MRSA isolates)(Table 1), a finding that reveals that the incidence of MRSA is high among staphylococcal isolates in vesiculobullous disorders. However, the high incidence of MRSA in this study could be a reflection of the number of patients with a severe and chronic vesiculobullous disorder, such as PV, and serious drug reactions such as TEN referred to our tertiary-care center, where we get a large number of patients affected by autoimmune and drug-induced vesiculobullous disorders. Similar findings have been reported by Stryjewski et al.¹¹

A high prevalence of MRSA in a dermatology unit has grave consequences, contributing to morbidity and mortality in particular among patients with a vesiculobullous disorder. Immunosuppressive therapy and comorbidities such as DM contribute to MRSA colonization in vesiculobullous disorders.¹² Overcrowding and poor sterilization techniques in public hospitals in India may contribute to the high prevalence of MRSA seen in hospital units.

Patients with a vesiculobullous disorder who are chronic nasal carriers of MRSA are at risk for cutaneous MRSA infection, which in turn can lead to MRSA septicemia and an elevated risk of death. In this study, however, a nasal swab was positive for MRSA in only 7 patients. One patient with MRSA colonization died, which was statistically insignificant (P=1).

In this study, all MRSA strains (100%) were resistant to first-line antibiotics, such as oxacillin, cloxacillin, and cefoxitin; all strains were susceptible to vancomycin and linezolid. This finding is similar to prior studies.^13,14 A distinctive finding in this study is that 34 (79.1%) of MRSA isolates were susceptible to amikacin. This finding has practical significance. Amikacin, an inexpensive antibiotic that is readily available in most units, can be used to treat MRSA infection in resource-poor settings where vancomycin and linezolid are unavailable.

Conclusion

Our study shows that MRSA is becoming the prominent pathogen in nosocomial infections, especially in bedridden patients, which has grave implications. The use of a prophylactic S aureus conjugate vaccine in patients with a chronic vesiculobullous disorder might be justified in the future.¹⁵ We found a high prevalence (32.6%) of MRSA in vesiculobullous disorders, no relationship between DM and MRSA colonization, PV was the most common disorder complicated by MRSA, no relationship between nasal colonization and MRSA infection, no relationship between death during the study period and MRSA infection, 100% of MRSA strains were susceptible to vancomycin and linezolid, and 79.1% of MRSA strains were susceptible to amikacin.

Methicillin, cloxacillin, flucloxacillin, and cefoxitin are stable, penicillinase-producing β-lactam antibiotics; Staphylococcus aureus strains resistant to these agents are designated as methicillin-resistant S aureus (MRSA). Based on genotypic and phenotypic differences there are 2 strains of MRSA: hospital acquired and community acquired.

The potential for nosocomial transmission and the limited number of antibiotics available to treat MRSA are problematic. Moreover, MRSA has emerged worldwide as a major nosocomial pathogen that contributes to morbidity and mortality. Methicillin-resistant S aureus infection in vesiculobullous disorders such as pemphigus vulgaris (PV) and toxic epidermal necrolysis (TEN) is known to contribute to mortality.¹

The reported prevalence of MRSA in India ranges from 12% to 38.44%.^2-4 We frequently encounter MRSA in dermatology inpatients, especially those with a vesiculobullous disorder. The primary objective of this study was to determine the prevalence of MRSA in dermatology inpatients with a vesiculobullous disorder; the secondary objective was to determine if MRSA contributes to mortality.

Materials and Methods

A 1-year prospective, cross-sectional, descriptive study was conducted in a tertiary-care center. The study population included all dermatology inpatients with a vesiculobullous disorder. Patients with a vesiculobullous disorder secondary to a primary viral or bacterial disorder were excluded. Permission to conduct the study was granted by the institution’s Human Ethics Committee.

All patients underwent a detailed history and clinical examination. Routine hematology testing, urinalysis, measurement of the blood glucose level, and other investigations relevant to the vesiculobullous disorder were performed. Special investigations were Gram staining, culture, and susceptibility testing of material from a nasal swab and a swab of a representative skin lesion.

Detection of MRSA
Skin lesions were thoroughly cleaned with sterile normal saline. Specimens of pus were drawn with a sterile swab for Gram staining, culture, and susceptibility testing and were analyzed in the institution’s microbiology department. A direct colony suspension (equivalent to McFarland Standard No. 0.5) was inoculated on a Mueller-Hinton agar plate, incorporating cefoxitin, linezolid, vancomycin, amikacin, and rifampicin supplemented with sodium chloride 2% and incubated at 37°C for 24 hours. Staphylococcus aureus colonies were identified by their smooth, convex, shiny, and opaque appearance with a golden yellow pigment, as well as by coagulase positivity, mannitol fermentation, and production of phosphatase.

Methicillin-resistant S aureus was defined as an isolate having a minimum inhibitory concentration of more than 2 μg/mL of cefoxitin; a methicillin-sensitive S aureus isolate was defined as having a minimum inhibitory concentration of less than or equal to 2 μg/mL of cefoxitin. Specimens showing moderate to heavy growth of MRSA were included in the study. For specimens showing mild growth, testing was repeated; if no growth was seen on repeat testing, results were interpreted as negative.

Data were collected and analyzed for frequency and percentage; P<.05 was considered significant.

Results

The number of patients analyzed in the study period was 43. Table 1 shows their salient demographic characteristics, clinical features, and findings of the investigation. The youngest patient was aged 13 years; the oldest was aged 80 years. The male to female ratio was 0.65 to 1. The most common primary lesion was a combined vesicle and bulla (34 patients [79.1%]); the most common secondary lesion was a combination of erosion with crusting (22 patients [51.2%]).

Table 2 lists the types of vesiculobullous disorders seen in this study. Pemphigus vulgaris was the most common (21 patients [48.8%])(Figure 1). Drug-induced vesiculobullous disorders (eg, TEN) were noted in 11 patients (25.6%)(Figure 2).

Table 2 also lists pathogens cultured in the study group. There were 24 bacterial isolates, of which S aureus accounted for 22 (91.7%). Methicillin-resistant S aureus was cultured in 14 patients (32.6%); culture was sterile in 19 patients (44.2%).

Among the 22 cultured staphylococcal species, MRSA accounted for 14 (63.6%) and constituted 58.3% (14/24) of all bacterial isolates. The nasal swab for MRSA was positive in 4 PV patients (9.3%), 2 TEN patients (4.6%), and 1 bullous pemphigoid patient (2.3%). Methicillin-resistant S aureus was most commonly cultured in PV patients (8/14 [57.1%]).

All MRSA strains (100%) were sensitive to vancomycin and linezolid; 34 (79.1%) were sensitive to amikacin. Additionally, 100% of MRSA strains were resistant to oxacillin, cloxacillin, and cefoxitin.

Three patients with PV (7.0%) and 1 patient with TEN (2.3%) died during the course of the study; only 1 death (2.3%) occurred in a patient who had a positive MRSA culture.

Comment

In this 1-year study, we tested and followed 43 patients with autoimmune and drug-induced vesiculobullous disorders. Vesiculobullous disorders in dermatology inpatients are a cause of great concern. When lesions rupture, they leave behind a large area of erosion that forms a nidus of bacterial colonization; often, these bacteria cause severe infection, including septicemia, and result in death.⁵ Moreover, autoimmune bullous disorders usually require a prolonged hospital stay and powerful immunosuppressive drugs, which contributes to bacterial infection, especially MRSA.⁶

The age of patients in this study ranged from 13 to 80 years; most patients were in the 6th decade, a pattern seen in studies worldwide.⁵ In a study by Kanwar and De,⁷ however, most cases were aged 20 to 40 years.⁷ In our study, there was a female preponderance (male to female ratio of 0.65 to 1).

Studies have shown that the duration of illness in vesiculobullous disorder is directly associated with MRSA infection. However, in our study with MRSA detected in 14 patients, most patients had a duration of illness less than 1 year (statistically insignificant [P>.05]), a finding similar to Shafi et al.⁸

The symptomatic nature of these diseases, their unsightly appearance, and mucous-membrane involvement of vesiculobullous disorders prompts these patients to present to the hospital early. However, a prolonged hospital stay by patients with an autoimmune vesiculobullous disorders sets the stage for MRSA colonization.

In this study, diabetes mellitus (DM) was seen in 15 patients (34.9%); 5 of them had MRSA infection (statistically insignificant [P>.05]). Diabetes mellitus contributing to sepsis and MRSA infection, which in turn contributes to morbidity and mortality, has been well-documented.^2,4,9

Methicillin-resistant S aureus in this study was isolated most often from blisters and erosions. Vesiculobullous disorders and drug reactions (eg, Stevens-Johnson syndrome, TEN) are characterized by blisters that rupture to form erosions and crusting, which form fissures in the epidermal barrier function that are nidi for colonization by microbes, especially S aureus and MRSA in particular; later, these bacteria can enter dermal vessels and then the bloodstream, leading to septicemia.¹⁰

The prevalence of MRSA in this study was 32.6% (14/43), which is high compared to other studies.^2-4 Pemphigus vulgaris was the most common disorder infected by MRSA in this study (57.1% [8/14] of MRSA isolates)(Table 1), a finding that reveals that the incidence of MRSA is high among staphylococcal isolates in vesiculobullous disorders. However, the high incidence of MRSA in this study could be a reflection of the number of patients with a severe and chronic vesiculobullous disorder, such as PV, and serious drug reactions such as TEN referred to our tertiary-care center, where we get a large number of patients affected by autoimmune and drug-induced vesiculobullous disorders. Similar findings have been reported by Stryjewski et al.¹¹

A high prevalence of MRSA in a dermatology unit has grave consequences, contributing to morbidity and mortality in particular among patients with a vesiculobullous disorder. Immunosuppressive therapy and comorbidities such as DM contribute to MRSA colonization in vesiculobullous disorders.¹² Overcrowding and poor sterilization techniques in public hospitals in India may contribute to the high prevalence of MRSA seen in hospital units.

Patients with a vesiculobullous disorder who are chronic nasal carriers of MRSA are at risk for cutaneous MRSA infection, which in turn can lead to MRSA septicemia and an elevated risk of death. In this study, however, a nasal swab was positive for MRSA in only 7 patients. One patient with MRSA colonization died, which was statistically insignificant (P=1).

In this study, all MRSA strains (100%) were resistant to first-line antibiotics, such as oxacillin, cloxacillin, and cefoxitin; all strains were susceptible to vancomycin and linezolid. This finding is similar to prior studies.^13,14 A distinctive finding in this study is that 34 (79.1%) of MRSA isolates were susceptible to amikacin. This finding has practical significance. Amikacin, an inexpensive antibiotic that is readily available in most units, can be used to treat MRSA infection in resource-poor settings where vancomycin and linezolid are unavailable.

Conclusion

Our study shows that MRSA is becoming the prominent pathogen in nosocomial infections, especially in bedridden patients, which has grave implications. The use of a prophylactic S aureus conjugate vaccine in patients with a chronic vesiculobullous disorder might be justified in the future.¹⁵ We found a high prevalence (32.6%) of MRSA in vesiculobullous disorders, no relationship between DM and MRSA colonization, PV was the most common disorder complicated by MRSA, no relationship between nasal colonization and MRSA infection, no relationship between death during the study period and MRSA infection, 100% of MRSA strains were susceptible to vancomycin and linezolid, and 79.1% of MRSA strains were susceptible to amikacin.

To the Editor:

An 84-year-old man was admitted to the hospital with 5 erythematous cutaneous nodules of several days’ duration on the legs ranging in size from 1.0 to 1.5 cm. Upon admission, the patient also had a chest radiograph suspicious for pneumonia. The patient had received sulfamethoxazole/trimethoprim for a urinary tract infection as an outpatient 5 days prior to presentation, but he stopped the medication due to the appearance of the cutaneous nodules. Of note, the patient also reported unintentional weight loss of 15 pounds over the last few months.

New nodules had developed at a rate of 1 to 2 lesions daily in the 3 days prior to presentation and continued to develop after admission to the hospital. The nodules appeared as tender, erythematous lesions that evolved to form pustules and developed overlying crusts in later stages (Figure 1). They were limited to the arms and legs, primarily involving the lower legs. There was no evidence of oral or ocular involvement. A hemoglobin count of 10.9 g/dL (reference range, 14.0–17.5 g/dL), white blood cell count of 8.8×10⁹/L (reference range, 4.5–11.0×10⁹/L), and erythrocyte sedimentation rate of 69 mm/h (reference range, 0–20 mm/h) were noted on admission.

The patient was started on ceftriaxone and azithromycin for suspected pneumonia. The differential diagnosis for the cutaneous nodules included lymphoma, acid-fast bacilli (AFB) infection, deep fungal infection, pyoderma gangrenosum, Sweet syndrome (SS), panniculitis, erythema elevatum diutinum, and polyarteritis nodosa. A punch biopsy of a nodule on the left foot was performed. Histopathology demonstrated a neutrophilic panniculitis (Figure 2) with an epidermal abscess. No vasculitis was identified, and periodic acid–Schiff and AFB staining of the skin biopsy were negative. These findings were consistent with SS. Computed tomography scans of the chest, abdomen, and pelvis, which were completed early in the course of hospitalization due to concern for underlying malignancy, revealed pericardial and pleural effusions as well as cystic lesions in the lungs, spleen, kidneys, and prostate, with the largest lesion on the spleen measuring 5.6×4.8 cm (Figure 3). Computed tomography scanning was negative for areas of consolidation in the lungs. A splenic biopsy was performed by an interventional radiologist during the patient's hospitalization that identified an aseptic, neutrophilic process. Fungal, bacterial, and AFB cultures of the splenic tissue and cystic contents were negative. Bilateral pleural effusions also were identified, and a thoracentesis was performed. The pleural fluid indicated rare mesothelial cells in the background of acute inflammation with no growth of the bacterial, fungal, or AFB cultures.

Our case could be consistent with either drug-induced or malignancy-associated SS. Sweet syndrome initially was described in 1964 in 8 female patients with leukocytosis and cutaneous plaques infiltrated by neutrophils.¹ The skin lesions typically are red and painful, ranging in size from 0.5 cm to 12.0 cm, and can last weeks to years if not treated.² Variations of skin lesions include bullous and pustular morphologies.³

Diagnostic criteria for SS have been established.⁴ Both of the major criteria must be met as well as 2 of 4 minor criteria. Major criteria include abrupt onset of tender erythematous plaques and nodules; secondly, a dense neutrophilic infiltrate without evidence of leukocytoclastic vasculitis must be seen on histopathology. Minor criteria include pyrexia, association with underlying condition (malignancy, pregnancy, drug exposure, inflammatory disorder), responsiveness to systemic steroids, and abnormal laboratory values (erythrocyte sedimentation rate, white blood cell count, C-reactive protein, neutrophilia).⁴

Sweet syndrome can be divided into 3 classifications: classical or idiopathic, drug-induced, or malignancy-associated.⁴ Classical SS most commonly is seen in middle-aged women after an upper respiratory or gastrointestinal infection. Drug-induced SS most often is associated with granulocyte-stimulating factor colony therapy⁴; however, it has been associated with use of trimethoprim/sulfamethoxazole.⁵ Malignancy-associated SS most commonly is seen in individuals with hematologic malignancy, specifically acute myeloid leukemia. Although its association with multiple myeloma is not as frequent, cases of malignancy-associated SS identifying this association have been reported.^6,7 Mucosal involvement in the form of aphthouslike lesions more frequently is seen in malignancy-associated SS.⁸ Differing from classical SS, which has a female predilection of around 4:1, the malignancy-associated disorder has a 1:1 female-to-male ratio.⁴

In the majority of cases of SS, the neutrophilic infiltrate is in the papillary and upper reticular dermis; however, if the neutrophilic infiltrate is predominately in the subcutaneous tissue (known as subcutaneous SS), there is a strong association with malignancy.⁹ The histopathology in our case demonstrated a neutrophilic infiltrate in the subcutaneous tissue.

Fever is the most common systemic manifestation of SS and is present in 54% to 65% of patients.^8,10 Besides the skin, the most common site affected is the eye, with 13% to 75% of patients reporting ocular involvement, usually conjunctivitis.^4,10 Although infrequent, extracutaneous SS has been identified in the bones, central nervous system, kidneys, heart, liver, spleen, lungs, ears, eyes, and intestines.⁴ A case of SS with splenic involvement in the form of sterile abscesses also was reported.¹¹ This case was related to parvovirus B19.

Sweet syndrome is a condition characterized by tender, erythematous cutaneous lesions with histopathology demonstrating neutrophilic infiltrate in the absence of vasculitis. We report a case of suspected extracutaneous SS in the form of splenic cysts in a patient whose SS was associated with malignancy and/or drug ingestion.

To the Editor:

An 84-year-old man was admitted to the hospital with 5 erythematous cutaneous nodules of several days’ duration on the legs ranging in size from 1.0 to 1.5 cm. Upon admission, the patient also had a chest radiograph suspicious for pneumonia. The patient had received sulfamethoxazole/trimethoprim for a urinary tract infection as an outpatient 5 days prior to presentation, but he stopped the medication due to the appearance of the cutaneous nodules. Of note, the patient also reported unintentional weight loss of 15 pounds over the last few months.

New nodules had developed at a rate of 1 to 2 lesions daily in the 3 days prior to presentation and continued to develop after admission to the hospital. The nodules appeared as tender, erythematous lesions that evolved to form pustules and developed overlying crusts in later stages (Figure 1). They were limited to the arms and legs, primarily involving the lower legs. There was no evidence of oral or ocular involvement. A hemoglobin count of 10.9 g/dL (reference range, 14.0–17.5 g/dL), white blood cell count of 8.8×10⁹/L (reference range, 4.5–11.0×10⁹/L), and erythrocyte sedimentation rate of 69 mm/h (reference range, 0–20 mm/h) were noted on admission.

The patient was started on ceftriaxone and azithromycin for suspected pneumonia. The differential diagnosis for the cutaneous nodules included lymphoma, acid-fast bacilli (AFB) infection, deep fungal infection, pyoderma gangrenosum, Sweet syndrome (SS), panniculitis, erythema elevatum diutinum, and polyarteritis nodosa. A punch biopsy of a nodule on the left foot was performed. Histopathology demonstrated a neutrophilic panniculitis (Figure 2) with an epidermal abscess. No vasculitis was identified, and periodic acid–Schiff and AFB staining of the skin biopsy were negative. These findings were consistent with SS. Computed tomography scans of the chest, abdomen, and pelvis, which were completed early in the course of hospitalization due to concern for underlying malignancy, revealed pericardial and pleural effusions as well as cystic lesions in the lungs, spleen, kidneys, and prostate, with the largest lesion on the spleen measuring 5.6×4.8 cm (Figure 3). Computed tomography scanning was negative for areas of consolidation in the lungs. A splenic biopsy was performed by an interventional radiologist during the patient's hospitalization that identified an aseptic, neutrophilic process. Fungal, bacterial, and AFB cultures of the splenic tissue and cystic contents were negative. Bilateral pleural effusions also were identified, and a thoracentesis was performed. The pleural fluid indicated rare mesothelial cells in the background of acute inflammation with no growth of the bacterial, fungal, or AFB cultures.

Our case could be consistent with either drug-induced or malignancy-associated SS. Sweet syndrome initially was described in 1964 in 8 female patients with leukocytosis and cutaneous plaques infiltrated by neutrophils.¹ The skin lesions typically are red and painful, ranging in size from 0.5 cm to 12.0 cm, and can last weeks to years if not treated.² Variations of skin lesions include bullous and pustular morphologies.³

Diagnostic criteria for SS have been established.⁴ Both of the major criteria must be met as well as 2 of 4 minor criteria. Major criteria include abrupt onset of tender erythematous plaques and nodules; secondly, a dense neutrophilic infiltrate without evidence of leukocytoclastic vasculitis must be seen on histopathology. Minor criteria include pyrexia, association with underlying condition (malignancy, pregnancy, drug exposure, inflammatory disorder), responsiveness to systemic steroids, and abnormal laboratory values (erythrocyte sedimentation rate, white blood cell count, C-reactive protein, neutrophilia).⁴

Sweet syndrome can be divided into 3 classifications: classical or idiopathic, drug-induced, or malignancy-associated.⁴ Classical SS most commonly is seen in middle-aged women after an upper respiratory or gastrointestinal infection. Drug-induced SS most often is associated with granulocyte-stimulating factor colony therapy⁴; however, it has been associated with use of trimethoprim/sulfamethoxazole.⁵ Malignancy-associated SS most commonly is seen in individuals with hematologic malignancy, specifically acute myeloid leukemia. Although its association with multiple myeloma is not as frequent, cases of malignancy-associated SS identifying this association have been reported.^6,7 Mucosal involvement in the form of aphthouslike lesions more frequently is seen in malignancy-associated SS.⁸ Differing from classical SS, which has a female predilection of around 4:1, the malignancy-associated disorder has a 1:1 female-to-male ratio.⁴

In the majority of cases of SS, the neutrophilic infiltrate is in the papillary and upper reticular dermis; however, if the neutrophilic infiltrate is predominately in the subcutaneous tissue (known as subcutaneous SS), there is a strong association with malignancy.⁹ The histopathology in our case demonstrated a neutrophilic infiltrate in the subcutaneous tissue.

Fever is the most common systemic manifestation of SS and is present in 54% to 65% of patients.^8,10 Besides the skin, the most common site affected is the eye, with 13% to 75% of patients reporting ocular involvement, usually conjunctivitis.^4,10 Although infrequent, extracutaneous SS has been identified in the bones, central nervous system, kidneys, heart, liver, spleen, lungs, ears, eyes, and intestines.⁴ A case of SS with splenic involvement in the form of sterile abscesses also was reported.¹¹ This case was related to parvovirus B19.

Sweet syndrome is a condition characterized by tender, erythematous cutaneous lesions with histopathology demonstrating neutrophilic infiltrate in the absence of vasculitis. We report a case of suspected extracutaneous SS in the form of splenic cysts in a patient whose SS was associated with malignancy and/or drug ingestion.

To the Editor:

An 84-year-old man was admitted to the hospital with 5 erythematous cutaneous nodules of several days’ duration on the legs ranging in size from 1.0 to 1.5 cm. Upon admission, the patient also had a chest radiograph suspicious for pneumonia. The patient had received sulfamethoxazole/trimethoprim for a urinary tract infection as an outpatient 5 days prior to presentation, but he stopped the medication due to the appearance of the cutaneous nodules. Of note, the patient also reported unintentional weight loss of 15 pounds over the last few months.

New nodules had developed at a rate of 1 to 2 lesions daily in the 3 days prior to presentation and continued to develop after admission to the hospital. The nodules appeared as tender, erythematous lesions that evolved to form pustules and developed overlying crusts in later stages (Figure 1). They were limited to the arms and legs, primarily involving the lower legs. There was no evidence of oral or ocular involvement. A hemoglobin count of 10.9 g/dL (reference range, 14.0–17.5 g/dL), white blood cell count of 8.8×10⁹/L (reference range, 4.5–11.0×10⁹/L), and erythrocyte sedimentation rate of 69 mm/h (reference range, 0–20 mm/h) were noted on admission.

The patient was started on ceftriaxone and azithromycin for suspected pneumonia. The differential diagnosis for the cutaneous nodules included lymphoma, acid-fast bacilli (AFB) infection, deep fungal infection, pyoderma gangrenosum, Sweet syndrome (SS), panniculitis, erythema elevatum diutinum, and polyarteritis nodosa. A punch biopsy of a nodule on the left foot was performed. Histopathology demonstrated a neutrophilic panniculitis (Figure 2) with an epidermal abscess. No vasculitis was identified, and periodic acid–Schiff and AFB staining of the skin biopsy were negative. These findings were consistent with SS. Computed tomography scans of the chest, abdomen, and pelvis, which were completed early in the course of hospitalization due to concern for underlying malignancy, revealed pericardial and pleural effusions as well as cystic lesions in the lungs, spleen, kidneys, and prostate, with the largest lesion on the spleen measuring 5.6×4.8 cm (Figure 3). Computed tomography scanning was negative for areas of consolidation in the lungs. A splenic biopsy was performed by an interventional radiologist during the patient's hospitalization that identified an aseptic, neutrophilic process. Fungal, bacterial, and AFB cultures of the splenic tissue and cystic contents were negative. Bilateral pleural effusions also were identified, and a thoracentesis was performed. The pleural fluid indicated rare mesothelial cells in the background of acute inflammation with no growth of the bacterial, fungal, or AFB cultures.

Our case could be consistent with either drug-induced or malignancy-associated SS. Sweet syndrome initially was described in 1964 in 8 female patients with leukocytosis and cutaneous plaques infiltrated by neutrophils.¹ The skin lesions typically are red and painful, ranging in size from 0.5 cm to 12.0 cm, and can last weeks to years if not treated.² Variations of skin lesions include bullous and pustular morphologies.³

Diagnostic criteria for SS have been established.⁴ Both of the major criteria must be met as well as 2 of 4 minor criteria. Major criteria include abrupt onset of tender erythematous plaques and nodules; secondly, a dense neutrophilic infiltrate without evidence of leukocytoclastic vasculitis must be seen on histopathology. Minor criteria include pyrexia, association with underlying condition (malignancy, pregnancy, drug exposure, inflammatory disorder), responsiveness to systemic steroids, and abnormal laboratory values (erythrocyte sedimentation rate, white blood cell count, C-reactive protein, neutrophilia).⁴

Sweet syndrome can be divided into 3 classifications: classical or idiopathic, drug-induced, or malignancy-associated.⁴ Classical SS most commonly is seen in middle-aged women after an upper respiratory or gastrointestinal infection. Drug-induced SS most often is associated with granulocyte-stimulating factor colony therapy⁴; however, it has been associated with use of trimethoprim/sulfamethoxazole.⁵ Malignancy-associated SS most commonly is seen in individuals with hematologic malignancy, specifically acute myeloid leukemia. Although its association with multiple myeloma is not as frequent, cases of malignancy-associated SS identifying this association have been reported.^6,7 Mucosal involvement in the form of aphthouslike lesions more frequently is seen in malignancy-associated SS.⁸ Differing from classical SS, which has a female predilection of around 4:1, the malignancy-associated disorder has a 1:1 female-to-male ratio.⁴

In the majority of cases of SS, the neutrophilic infiltrate is in the papillary and upper reticular dermis; however, if the neutrophilic infiltrate is predominately in the subcutaneous tissue (known as subcutaneous SS), there is a strong association with malignancy.⁹ The histopathology in our case demonstrated a neutrophilic infiltrate in the subcutaneous tissue.

Fever is the most common systemic manifestation of SS and is present in 54% to 65% of patients.^8,10 Besides the skin, the most common site affected is the eye, with 13% to 75% of patients reporting ocular involvement, usually conjunctivitis.^4,10 Although infrequent, extracutaneous SS has been identified in the bones, central nervous system, kidneys, heart, liver, spleen, lungs, ears, eyes, and intestines.⁴ A case of SS with splenic involvement in the form of sterile abscesses also was reported.¹¹ This case was related to parvovirus B19.

Sweet syndrome is a condition characterized by tender, erythematous cutaneous lesions with histopathology demonstrating neutrophilic infiltrate in the absence of vasculitis. We report a case of suspected extracutaneous SS in the form of splenic cysts in a patient whose SS was associated with malignancy and/or drug ingestion.