Pain

Juvenile idiopathic arthritis (JIA) is a clinically heterogeneous group of arthritides that are characterized by onset before 16 years of age and defined in part as lasting ≥6 weeks.¹ Significantly, the etiology of JIA is unknown, making it a diagnosis of exclusion.²

The most common autoimmune condition of childhood, JIA has a prevalence of 3.8 to 400 affected children for every 100,000 people.^3,4 As the leading cause of musculoskeletal disability in children,⁵ and comprising 7 categories of disease, JIA must be managed with appropriate initial and ongoing intervention.

The amalgam of care that a JIA patient requires—medical, social, physical, psychological—calls for a primary care physician’s expert ability to collaborate and coordinate with medical specialists and subspecialists, including rheumatology, ophthalmology, social work, physical and occupational therapy, and psychology. The goal? As this article describes, the goal is to provide prompt diagnosis, suitable and effective intervention, and continuity of care. (JIA is a lifelong disease, in many cases.)

How JIA is classifiedfor diagnosis and treatment

JIA comprises 7 categories, or classes.⁶ The scheme devised by the International League of Associations for Rheumatology (ILAR), now widely accepted, classifies JIA on the basis of clinical and biochemical markers that aid detection and treatment of the disorder, as well as research. (See “How efforts to classify JIA have caused confusion.”^7-10) The ILAR classes (TABLE¹¹) are:

• enthesitis-related arthritis (ERA)
• extended oligo-articular JIA (eoJIA), which involves ≤4 joints
• juvenile psoriatic arthritis (jPsA)
• rheumatoid factor (RF)-positive polyarticular JIA (RF+ pJIA)
• RF-negative polyarticular JIA (RF– pJIA)
• systemic-onset JIA (sJIA)
• undifferentiated JIA, which, generally, involves ≥4 joints.

Updated guidelines regarding the 7 ILAR classes of JIA emphasize heterogeneity among disease subtypes, with overlapping and exclusive features noted from class to class.¹¹

Extended oligo-articular JIA (27%-56%), pJIA (13%-35%), sJIA (4%-17%), and ERA,(3%-11%) are the most common JIA subtypes,¹² with age of onset and sex predilection differing according to JIA class.¹¹ The disease occurs more often in girls than in boys,¹¹ and the predisposition is higher among Whites and Asians. The incidence of JIA (all classes taken together, for every 100,000 people) is: in Japan, 10 to 15 cases¹³; in Turkey, 64 cases¹⁴; in Norway, 65 cases¹⁵; and in the United States and Canada, taken together, 10 to 15 cases.¹⁶

What causes JIA?

The etiology of JIA remains unclear. It is known that the disease involves inflammation of the synovium and destruction of hard and soft tissues in joints.¹⁷ It has been postulated, therefore, that a combination of genetic, environmental, and immunogenic mechanisms might be responsible for JIA.

Continue to: For example, there is an increased...

For example, there is an increased frequency of autoimmune diseases among JIA patients.¹⁸ There are also reports documenting an increased rate of infection, including with enteric pathogens, parvovirus B,¹⁹ rubella, mumps, hepatitis B, Epstein-Barr virus, mycoplasma, and chlamydia.¹⁹ Stress and trauma have also been implicated.¹²

The T-lymphocyte percentage is increased in the synovial fluid of JIA patients, although that percentage varies from subtype to subtype.²⁰ This elevation results in an increase in the number of macrophages, which are induced by secreted cytokines to produce interleukin (IL)-1, IL-6, and tumor necrosis factor alpha (TNF-a). This activity of cellular immunity leads to joint destruction.²¹

Clinical features

The most common signs and symptoms of JIA are arthralgias (39%), arthritis (25%), fever (18%), limping (9%), rash (8%), abdominal pain (1.3%), and uveitis (1.3%).¹⁵ Forty percent of JIA patients are reported to have temporomandibular joint involvement at some point in their life; mandibular asymmetry secondary to condylar resorption and remodeling¹⁷ is the most common presenting complaint—not arthralgia or pain, as would be expected.

Most JIA patients (52%) first present to the emergency department; another 42% present to the office of a general medical practitioner.¹⁵ On average, 3 visits to a physician, over the course of approximately 3 months, are made before a definitive diagnosis (usually by a pediatric rheumatologist) is made.¹⁵

Pertinent questions to ask a patient who has a confirmed diagnosis of JIA include the nature, severity, and duration of morning stiffness and pain, as well as any encumbering factors to regular functioning at home or school.²² Different scoring charts can be used to determine the extent of pain and disability, including the Juvenile Arthritis Disease Activity Score (JADAS)²³ and the clinical JADAS (cJADAS),²⁴ which measure minimal disease activity²⁵ and clinically inactive disease²⁶ cutoffs.

Continue to: Macrophage-activating syndrome increases risk of morbidity, mortality

An overactivation and expansion of T lymphocytes and macrophagic histiocytes with hemophagocytic activity, macrophage-activating syndrome (MAS) occurs in approximately 10% of JIA patients,²⁷ increasing their risk of morbidity and mortality. The syndrome, which typically presents as fever, seizures, hypotension, purpura, hepatitis, splenomegaly, and occasionally, multisystem organ failure, is seen in 30% to 40% of sJIA patients; approximately 11% of them experience sudden death as a consequence.²⁸

The clinical setting of MAS includes presenting symptoms of fever and a salmon-pink macular rash (FIGURE). For many sJIA patients with MAS, the diagnosis is made when laboratory results show hyperferritinemia, thrombocytopenia, anemia, leukopenia, coagulopathy, and elevated levels of C-reactive protein and D-dimer.²⁷

Different classes, different features

The following clinical profiles have been documented in different classes of JIA:

Systemic JIA presents with intermittent fever of at least 2 weeks’ duration, arthritis, and occasionally, a rash.

Extended oligo-articular JIA involves pain, in a mono-articular lower-extremity joint, that can develop suddenly or insidiously, and is characterized by early-morning stiffness and uveitis (especially in early-onset, antinuclear antibody-positive JIA patients).

Continue to: Poly-articular JIA

Poly-articular JIA patients present with mild fever, weight loss, and anemia.

Enthesis-related arthritis patients have findings of enthesopathy; asymmetric arthritis of the lower extremities, particularly the Achilles tendon²⁹; and recurrent acute, symptomatic iridocyclitis.³⁰

Juvenile psoriatic arthritis can involve any joint but is readily differentiated from pJIA by involvement of distal interphalangeal joints and psoriatic skin and nail changes.²⁹

Investigations

Imaging

Radiography is still the most widely used imaging tool for making the diagnosis of JIA. Plain films demonstrate structural joint damage and disturbances of growth and maturation in bones. Radiography has poor sensitivity for detecting acute synovitis and limited utility in visualizing erosion changes early in the course of disease, however, which has led to increased use of ultrasonography (US) and contrast-enhanced magnetic resonance imaging (MRI) to diagnose JIA.³⁰

Contrast-enhanced MRI is superior to US for detecting early inflammation and monitoring subsequent joint disease. Of course, MRI is more expensive than US, and less widely available. Other imaging options are computed tomography and positron emission tomography, but these scans are not as sensitive as contrast-enhanced MRI and have the disadvantage of radiation exposure (in the former) and cost (in the latter).

Continue to: Laboratory testing

Mandibular asymmetry secondary to condylar resorption and remodeling is the most common presenting complaint of juvenile idiopathic arthritis—not arthralgia or pain, as you might expect.

No diagnostic tests for JIA exist. Assays of acute-phase reactants, including C-reactive protein, the erythrocyte sedimentation rate, and serum amyloid-A proteins, can be utilized to demonstrate inflammation but not to confirm the diagnosis. For some classes of JIA, various tests, including rheumatoid factor, antinuclear antibody, human leukocyte antigen B-27, and cyclic citrullated peptide antibodies, can be used to confirm a specific class but, again, are not recommended for confirming JIA.⁶

The complete blood count, blood cultures, and tests of uric acid and lactate dehydrogenase can be ordered during treatment to monitor for complications, such as malignancy, infection, MAS, and sepsis.

Treatment is based on disease class

Nonsteroidal anti-inflammatory drugs (NSAIDs) and intra-articular steroids are used in all JIA classes, as an adjunct to class-specific treatment, or as induction agents.³¹ These therapies, although they alleviate acute signs and symptoms, such as pain, inflammation, swelling and joint contractures, are not useful for long-term treatment of JIA because they do not halt disease progression.

Systemic steroids can be utilized in exceptional cases, including chronic uveitis with arthritis or in patients with destructive arthritis and poor prognostic features, including cyclic citrullated peptide antibodies, positive RF, erosions, and joint-space narrowing.³²

Other drugs. Options include traditional disease-modifying anti-rheumatic drugs (csDMARDs), such as methotrexate and leflunomide; biologic agents, such as TNF-a inhibitors (eg, etanercept, adalimumab, and infliximab); and anti-IL monoclonal antibody drugs (eg, the IL-6 inhibitor tocilizumab and IL-1 inhibitors anakinra, and canakinumab).³¹ Indications by class include:

• csDMARDs as first-line therapy in persistent eoJIA and pJIA;
• TNF-Symbolα inhibitors for refractory eoJIA and for pJIA episodes³¹;
• tocilizumab, recommended for sJIA patients who have persistent systemic signs; and
• anakinra and canakinumab for refractory SJIA patients.³²

Continue to: Failure

When treatment of JIA fails with a given drug, options include increasing the dosage; switching to another agent in the same drug class; switching to a different class; and combining an NSAID with a csDMARD or a biologic agent.³² In class-specific JIA cases, a change in a drug regimen is warranted on the basis of the evidence-based historical clinical response rate.³²

What is the prognosis?

Treatment of JIA with novel agents, such as biologics, has opened up the possibility that JIA patients can live not just with suppressed symptoms but immunologically inactive disease. This is the result of better understanding of the pathogenesis of JIA and the mechanism of action of targeted drugs, and identification of biomarkers that are helpful in predicting prognosis, adverse effects, and response to treatment.

On average, it takes 3 visits to a physician, over the course of about 3 months, before definitive diagnosis of JIA is made.

JIA is often a lifelong disease; one-third of patients continue to exhibit symptoms into adulthood.⁴ If their disease is properly managed, however, these patients do not develop typical features of rheumatoid arthritis, including hand, limb, and spine deformities. Last, patients with JIA who have only intermittent disease tend to do better over the long term than those whose disease is continual.³²

The mortality rate of JIA has dropped: from 1% to 4% in the mid-1970s to 0.3% to 1% today⁴—an improvement in life expectancy that is echoed in enhanced quality of life for patients. According to the 4-level Steinbrocker functional classification scale³³ (used to rate the extent of physical disability), 15% of JIA patients were Class III (limited to few or no activities of the patient’s usual occupation) or Class IV (bedridden with little or no self-care) in the period from 1976 to 1994—a percentage that had declined to 5% by 2002.³⁴

The family physician plays pivotal role in JIA care

For the family physician, appropriate initial intervention in the management of JIA is imperative. This includes ordering imaging (whether plain films or MRI), laboratory tests as described earlier (although not to make the diagnosis), and the use of NSAIDs, intra-articular steroids, and other induction agents. Once the diagnosis is made, and a drug regimen is put in place, you will need to monitor for adverse effects. This monitoring will need to occur when a patient is escalated to csDMARDs, biological agents, or systemic steroids; is maintained on an NSAID; or is placed on a combination regimen.

Continue to: Before beginning therapy with a biologic agent...

Before beginning therapy with a biologic agent, it’s important to screen for hepatitis B, hepatitis C, human immunodeficiency virus infection, tuberculosis, and fungal infection (eg, Histoplasma capsulatum, Coccidioides immitis³²). Be sure to make a timely referral to the ophthalmology service for a bi-annual eye exam and, in the event that surgery is necessary, conduct a preoperative evaluation, with the knowledge of how long before surgery a biologic agent must be withheld (duration varies by drug).³²

CORRESPONDENCE
Tobe Momah, MD, Department of Family Medicine, Clinical Science Building, 4th Floor, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216; [email protected].

Juvenile idiopathic arthritis (JIA) is a clinically heterogeneous group of arthritides that are characterized by onset before 16 years of age and defined in part as lasting ≥6 weeks.¹ Significantly, the etiology of JIA is unknown, making it a diagnosis of exclusion.²

The most common autoimmune condition of childhood, JIA has a prevalence of 3.8 to 400 affected children for every 100,000 people.^3,4 As the leading cause of musculoskeletal disability in children,⁵ and comprising 7 categories of disease, JIA must be managed with appropriate initial and ongoing intervention.

The amalgam of care that a JIA patient requires—medical, social, physical, psychological—calls for a primary care physician’s expert ability to collaborate and coordinate with medical specialists and subspecialists, including rheumatology, ophthalmology, social work, physical and occupational therapy, and psychology. The goal? As this article describes, the goal is to provide prompt diagnosis, suitable and effective intervention, and continuity of care. (JIA is a lifelong disease, in many cases.)

How JIA is classifiedfor diagnosis and treatment

JIA comprises 7 categories, or classes.⁶ The scheme devised by the International League of Associations for Rheumatology (ILAR), now widely accepted, classifies JIA on the basis of clinical and biochemical markers that aid detection and treatment of the disorder, as well as research. (See “How efforts to classify JIA have caused confusion.”^7-10) The ILAR classes (TABLE¹¹) are:

• enthesitis-related arthritis (ERA)
• extended oligo-articular JIA (eoJIA), which involves ≤4 joints
• juvenile psoriatic arthritis (jPsA)
• rheumatoid factor (RF)-positive polyarticular JIA (RF+ pJIA)
• RF-negative polyarticular JIA (RF– pJIA)
• systemic-onset JIA (sJIA)
• undifferentiated JIA, which, generally, involves ≥4 joints.

Updated guidelines regarding the 7 ILAR classes of JIA emphasize heterogeneity among disease subtypes, with overlapping and exclusive features noted from class to class.¹¹

Extended oligo-articular JIA (27%-56%), pJIA (13%-35%), sJIA (4%-17%), and ERA,(3%-11%) are the most common JIA subtypes,¹² with age of onset and sex predilection differing according to JIA class.¹¹ The disease occurs more often in girls than in boys,¹¹ and the predisposition is higher among Whites and Asians. The incidence of JIA (all classes taken together, for every 100,000 people) is: in Japan, 10 to 15 cases¹³; in Turkey, 64 cases¹⁴; in Norway, 65 cases¹⁵; and in the United States and Canada, taken together, 10 to 15 cases.¹⁶

What causes JIA?

The etiology of JIA remains unclear. It is known that the disease involves inflammation of the synovium and destruction of hard and soft tissues in joints.¹⁷ It has been postulated, therefore, that a combination of genetic, environmental, and immunogenic mechanisms might be responsible for JIA.

Continue to: For example, there is an increased...

For example, there is an increased frequency of autoimmune diseases among JIA patients.¹⁸ There are also reports documenting an increased rate of infection, including with enteric pathogens, parvovirus B,¹⁹ rubella, mumps, hepatitis B, Epstein-Barr virus, mycoplasma, and chlamydia.¹⁹ Stress and trauma have also been implicated.¹²

The T-lymphocyte percentage is increased in the synovial fluid of JIA patients, although that percentage varies from subtype to subtype.²⁰ This elevation results in an increase in the number of macrophages, which are induced by secreted cytokines to produce interleukin (IL)-1, IL-6, and tumor necrosis factor alpha (TNF-a). This activity of cellular immunity leads to joint destruction.²¹

Clinical features

The most common signs and symptoms of JIA are arthralgias (39%), arthritis (25%), fever (18%), limping (9%), rash (8%), abdominal pain (1.3%), and uveitis (1.3%).¹⁵ Forty percent of JIA patients are reported to have temporomandibular joint involvement at some point in their life; mandibular asymmetry secondary to condylar resorption and remodeling¹⁷ is the most common presenting complaint—not arthralgia or pain, as would be expected.

Most JIA patients (52%) first present to the emergency department; another 42% present to the office of a general medical practitioner.¹⁵ On average, 3 visits to a physician, over the course of approximately 3 months, are made before a definitive diagnosis (usually by a pediatric rheumatologist) is made.¹⁵

Pertinent questions to ask a patient who has a confirmed diagnosis of JIA include the nature, severity, and duration of morning stiffness and pain, as well as any encumbering factors to regular functioning at home or school.²² Different scoring charts can be used to determine the extent of pain and disability, including the Juvenile Arthritis Disease Activity Score (JADAS)²³ and the clinical JADAS (cJADAS),²⁴ which measure minimal disease activity²⁵ and clinically inactive disease²⁶ cutoffs.

Continue to: Macrophage-activating syndrome increases risk of morbidity, mortality

An overactivation and expansion of T lymphocytes and macrophagic histiocytes with hemophagocytic activity, macrophage-activating syndrome (MAS) occurs in approximately 10% of JIA patients,²⁷ increasing their risk of morbidity and mortality. The syndrome, which typically presents as fever, seizures, hypotension, purpura, hepatitis, splenomegaly, and occasionally, multisystem organ failure, is seen in 30% to 40% of sJIA patients; approximately 11% of them experience sudden death as a consequence.²⁸

The clinical setting of MAS includes presenting symptoms of fever and a salmon-pink macular rash (FIGURE). For many sJIA patients with MAS, the diagnosis is made when laboratory results show hyperferritinemia, thrombocytopenia, anemia, leukopenia, coagulopathy, and elevated levels of C-reactive protein and D-dimer.²⁷

Different classes, different features

The following clinical profiles have been documented in different classes of JIA:

Systemic JIA presents with intermittent fever of at least 2 weeks’ duration, arthritis, and occasionally, a rash.

Extended oligo-articular JIA involves pain, in a mono-articular lower-extremity joint, that can develop suddenly or insidiously, and is characterized by early-morning stiffness and uveitis (especially in early-onset, antinuclear antibody-positive JIA patients).

Continue to: Poly-articular JIA

Poly-articular JIA patients present with mild fever, weight loss, and anemia.

Enthesis-related arthritis patients have findings of enthesopathy; asymmetric arthritis of the lower extremities, particularly the Achilles tendon²⁹; and recurrent acute, symptomatic iridocyclitis.³⁰

Juvenile psoriatic arthritis can involve any joint but is readily differentiated from pJIA by involvement of distal interphalangeal joints and psoriatic skin and nail changes.²⁹

Investigations

Imaging

Radiography is still the most widely used imaging tool for making the diagnosis of JIA. Plain films demonstrate structural joint damage and disturbances of growth and maturation in bones. Radiography has poor sensitivity for detecting acute synovitis and limited utility in visualizing erosion changes early in the course of disease, however, which has led to increased use of ultrasonography (US) and contrast-enhanced magnetic resonance imaging (MRI) to diagnose JIA.³⁰

Contrast-enhanced MRI is superior to US for detecting early inflammation and monitoring subsequent joint disease. Of course, MRI is more expensive than US, and less widely available. Other imaging options are computed tomography and positron emission tomography, but these scans are not as sensitive as contrast-enhanced MRI and have the disadvantage of radiation exposure (in the former) and cost (in the latter).

Continue to: Laboratory testing

Mandibular asymmetry secondary to condylar resorption and remodeling is the most common presenting complaint of juvenile idiopathic arthritis—not arthralgia or pain, as you might expect.

No diagnostic tests for JIA exist. Assays of acute-phase reactants, including C-reactive protein, the erythrocyte sedimentation rate, and serum amyloid-A proteins, can be utilized to demonstrate inflammation but not to confirm the diagnosis. For some classes of JIA, various tests, including rheumatoid factor, antinuclear antibody, human leukocyte antigen B-27, and cyclic citrullated peptide antibodies, can be used to confirm a specific class but, again, are not recommended for confirming JIA.⁶

The complete blood count, blood cultures, and tests of uric acid and lactate dehydrogenase can be ordered during treatment to monitor for complications, such as malignancy, infection, MAS, and sepsis.

Treatment is based on disease class

Nonsteroidal anti-inflammatory drugs (NSAIDs) and intra-articular steroids are used in all JIA classes, as an adjunct to class-specific treatment, or as induction agents.³¹ These therapies, although they alleviate acute signs and symptoms, such as pain, inflammation, swelling and joint contractures, are not useful for long-term treatment of JIA because they do not halt disease progression.

Systemic steroids can be utilized in exceptional cases, including chronic uveitis with arthritis or in patients with destructive arthritis and poor prognostic features, including cyclic citrullated peptide antibodies, positive RF, erosions, and joint-space narrowing.³²

Other drugs. Options include traditional disease-modifying anti-rheumatic drugs (csDMARDs), such as methotrexate and leflunomide; biologic agents, such as TNF-a inhibitors (eg, etanercept, adalimumab, and infliximab); and anti-IL monoclonal antibody drugs (eg, the IL-6 inhibitor tocilizumab and IL-1 inhibitors anakinra, and canakinumab).³¹ Indications by class include:

• csDMARDs as first-line therapy in persistent eoJIA and pJIA;
• TNF-Symbolα inhibitors for refractory eoJIA and for pJIA episodes³¹;
• tocilizumab, recommended for sJIA patients who have persistent systemic signs; and
• anakinra and canakinumab for refractory SJIA patients.³²

Continue to: Failure

When treatment of JIA fails with a given drug, options include increasing the dosage; switching to another agent in the same drug class; switching to a different class; and combining an NSAID with a csDMARD or a biologic agent.³² In class-specific JIA cases, a change in a drug regimen is warranted on the basis of the evidence-based historical clinical response rate.³²

What is the prognosis?

Treatment of JIA with novel agents, such as biologics, has opened up the possibility that JIA patients can live not just with suppressed symptoms but immunologically inactive disease. This is the result of better understanding of the pathogenesis of JIA and the mechanism of action of targeted drugs, and identification of biomarkers that are helpful in predicting prognosis, adverse effects, and response to treatment.

On average, it takes 3 visits to a physician, over the course of about 3 months, before definitive diagnosis of JIA is made.

JIA is often a lifelong disease; one-third of patients continue to exhibit symptoms into adulthood.⁴ If their disease is properly managed, however, these patients do not develop typical features of rheumatoid arthritis, including hand, limb, and spine deformities. Last, patients with JIA who have only intermittent disease tend to do better over the long term than those whose disease is continual.³²

The mortality rate of JIA has dropped: from 1% to 4% in the mid-1970s to 0.3% to 1% today⁴—an improvement in life expectancy that is echoed in enhanced quality of life for patients. According to the 4-level Steinbrocker functional classification scale³³ (used to rate the extent of physical disability), 15% of JIA patients were Class III (limited to few or no activities of the patient’s usual occupation) or Class IV (bedridden with little or no self-care) in the period from 1976 to 1994—a percentage that had declined to 5% by 2002.³⁴

The family physician plays pivotal role in JIA care

For the family physician, appropriate initial intervention in the management of JIA is imperative. This includes ordering imaging (whether plain films or MRI), laboratory tests as described earlier (although not to make the diagnosis), and the use of NSAIDs, intra-articular steroids, and other induction agents. Once the diagnosis is made, and a drug regimen is put in place, you will need to monitor for adverse effects. This monitoring will need to occur when a patient is escalated to csDMARDs, biological agents, or systemic steroids; is maintained on an NSAID; or is placed on a combination regimen.

Continue to: Before beginning therapy with a biologic agent...

Before beginning therapy with a biologic agent, it’s important to screen for hepatitis B, hepatitis C, human immunodeficiency virus infection, tuberculosis, and fungal infection (eg, Histoplasma capsulatum, Coccidioides immitis³²). Be sure to make a timely referral to the ophthalmology service for a bi-annual eye exam and, in the event that surgery is necessary, conduct a preoperative evaluation, with the knowledge of how long before surgery a biologic agent must be withheld (duration varies by drug).³²

CORRESPONDENCE
Tobe Momah, MD, Department of Family Medicine, Clinical Science Building, 4th Floor, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216; [email protected].

Juvenile idiopathic arthritis (JIA) is a clinically heterogeneous group of arthritides that are characterized by onset before 16 years of age and defined in part as lasting ≥6 weeks.¹ Significantly, the etiology of JIA is unknown, making it a diagnosis of exclusion.²

The most common autoimmune condition of childhood, JIA has a prevalence of 3.8 to 400 affected children for every 100,000 people.^3,4 As the leading cause of musculoskeletal disability in children,⁵ and comprising 7 categories of disease, JIA must be managed with appropriate initial and ongoing intervention.

The amalgam of care that a JIA patient requires—medical, social, physical, psychological—calls for a primary care physician’s expert ability to collaborate and coordinate with medical specialists and subspecialists, including rheumatology, ophthalmology, social work, physical and occupational therapy, and psychology. The goal? As this article describes, the goal is to provide prompt diagnosis, suitable and effective intervention, and continuity of care. (JIA is a lifelong disease, in many cases.)

How JIA is classifiedfor diagnosis and treatment

JIA comprises 7 categories, or classes.⁶ The scheme devised by the International League of Associations for Rheumatology (ILAR), now widely accepted, classifies JIA on the basis of clinical and biochemical markers that aid detection and treatment of the disorder, as well as research. (See “How efforts to classify JIA have caused confusion.”^7-10) The ILAR classes (TABLE¹¹) are:

• enthesitis-related arthritis (ERA)
• extended oligo-articular JIA (eoJIA), which involves ≤4 joints
• juvenile psoriatic arthritis (jPsA)
• rheumatoid factor (RF)-positive polyarticular JIA (RF+ pJIA)
• RF-negative polyarticular JIA (RF– pJIA)
• systemic-onset JIA (sJIA)
• undifferentiated JIA, which, generally, involves ≥4 joints.

Updated guidelines regarding the 7 ILAR classes of JIA emphasize heterogeneity among disease subtypes, with overlapping and exclusive features noted from class to class.¹¹

Extended oligo-articular JIA (27%-56%), pJIA (13%-35%), sJIA (4%-17%), and ERA,(3%-11%) are the most common JIA subtypes,¹² with age of onset and sex predilection differing according to JIA class.¹¹ The disease occurs more often in girls than in boys,¹¹ and the predisposition is higher among Whites and Asians. The incidence of JIA (all classes taken together, for every 100,000 people) is: in Japan, 10 to 15 cases¹³; in Turkey, 64 cases¹⁴; in Norway, 65 cases¹⁵; and in the United States and Canada, taken together, 10 to 15 cases.¹⁶

What causes JIA?

The etiology of JIA remains unclear. It is known that the disease involves inflammation of the synovium and destruction of hard and soft tissues in joints.¹⁷ It has been postulated, therefore, that a combination of genetic, environmental, and immunogenic mechanisms might be responsible for JIA.

Continue to: For example, there is an increased...

For example, there is an increased frequency of autoimmune diseases among JIA patients.¹⁸ There are also reports documenting an increased rate of infection, including with enteric pathogens, parvovirus B,¹⁹ rubella, mumps, hepatitis B, Epstein-Barr virus, mycoplasma, and chlamydia.¹⁹ Stress and trauma have also been implicated.¹²

The T-lymphocyte percentage is increased in the synovial fluid of JIA patients, although that percentage varies from subtype to subtype.²⁰ This elevation results in an increase in the number of macrophages, which are induced by secreted cytokines to produce interleukin (IL)-1, IL-6, and tumor necrosis factor alpha (TNF-a). This activity of cellular immunity leads to joint destruction.²¹

Clinical features

The most common signs and symptoms of JIA are arthralgias (39%), arthritis (25%), fever (18%), limping (9%), rash (8%), abdominal pain (1.3%), and uveitis (1.3%).¹⁵ Forty percent of JIA patients are reported to have temporomandibular joint involvement at some point in their life; mandibular asymmetry secondary to condylar resorption and remodeling¹⁷ is the most common presenting complaint—not arthralgia or pain, as would be expected.

Most JIA patients (52%) first present to the emergency department; another 42% present to the office of a general medical practitioner.¹⁵ On average, 3 visits to a physician, over the course of approximately 3 months, are made before a definitive diagnosis (usually by a pediatric rheumatologist) is made.¹⁵

Pertinent questions to ask a patient who has a confirmed diagnosis of JIA include the nature, severity, and duration of morning stiffness and pain, as well as any encumbering factors to regular functioning at home or school.²² Different scoring charts can be used to determine the extent of pain and disability, including the Juvenile Arthritis Disease Activity Score (JADAS)²³ and the clinical JADAS (cJADAS),²⁴ which measure minimal disease activity²⁵ and clinically inactive disease²⁶ cutoffs.

Continue to: Macrophage-activating syndrome increases risk of morbidity, mortality

An overactivation and expansion of T lymphocytes and macrophagic histiocytes with hemophagocytic activity, macrophage-activating syndrome (MAS) occurs in approximately 10% of JIA patients,²⁷ increasing their risk of morbidity and mortality. The syndrome, which typically presents as fever, seizures, hypotension, purpura, hepatitis, splenomegaly, and occasionally, multisystem organ failure, is seen in 30% to 40% of sJIA patients; approximately 11% of them experience sudden death as a consequence.²⁸

The clinical setting of MAS includes presenting symptoms of fever and a salmon-pink macular rash (FIGURE). For many sJIA patients with MAS, the diagnosis is made when laboratory results show hyperferritinemia, thrombocytopenia, anemia, leukopenia, coagulopathy, and elevated levels of C-reactive protein and D-dimer.²⁷

Different classes, different features

The following clinical profiles have been documented in different classes of JIA:

Systemic JIA presents with intermittent fever of at least 2 weeks’ duration, arthritis, and occasionally, a rash.

Extended oligo-articular JIA involves pain, in a mono-articular lower-extremity joint, that can develop suddenly or insidiously, and is characterized by early-morning stiffness and uveitis (especially in early-onset, antinuclear antibody-positive JIA patients).

Continue to: Poly-articular JIA

Poly-articular JIA patients present with mild fever, weight loss, and anemia.

Enthesis-related arthritis patients have findings of enthesopathy; asymmetric arthritis of the lower extremities, particularly the Achilles tendon²⁹; and recurrent acute, symptomatic iridocyclitis.³⁰

Juvenile psoriatic arthritis can involve any joint but is readily differentiated from pJIA by involvement of distal interphalangeal joints and psoriatic skin and nail changes.²⁹

Investigations

Imaging

Radiography is still the most widely used imaging tool for making the diagnosis of JIA. Plain films demonstrate structural joint damage and disturbances of growth and maturation in bones. Radiography has poor sensitivity for detecting acute synovitis and limited utility in visualizing erosion changes early in the course of disease, however, which has led to increased use of ultrasonography (US) and contrast-enhanced magnetic resonance imaging (MRI) to diagnose JIA.³⁰

Contrast-enhanced MRI is superior to US for detecting early inflammation and monitoring subsequent joint disease. Of course, MRI is more expensive than US, and less widely available. Other imaging options are computed tomography and positron emission tomography, but these scans are not as sensitive as contrast-enhanced MRI and have the disadvantage of radiation exposure (in the former) and cost (in the latter).

Continue to: Laboratory testing

Mandibular asymmetry secondary to condylar resorption and remodeling is the most common presenting complaint of juvenile idiopathic arthritis—not arthralgia or pain, as you might expect.

No diagnostic tests for JIA exist. Assays of acute-phase reactants, including C-reactive protein, the erythrocyte sedimentation rate, and serum amyloid-A proteins, can be utilized to demonstrate inflammation but not to confirm the diagnosis. For some classes of JIA, various tests, including rheumatoid factor, antinuclear antibody, human leukocyte antigen B-27, and cyclic citrullated peptide antibodies, can be used to confirm a specific class but, again, are not recommended for confirming JIA.⁶

The complete blood count, blood cultures, and tests of uric acid and lactate dehydrogenase can be ordered during treatment to monitor for complications, such as malignancy, infection, MAS, and sepsis.

Treatment is based on disease class

Nonsteroidal anti-inflammatory drugs (NSAIDs) and intra-articular steroids are used in all JIA classes, as an adjunct to class-specific treatment, or as induction agents.³¹ These therapies, although they alleviate acute signs and symptoms, such as pain, inflammation, swelling and joint contractures, are not useful for long-term treatment of JIA because they do not halt disease progression.

Systemic steroids can be utilized in exceptional cases, including chronic uveitis with arthritis or in patients with destructive arthritis and poor prognostic features, including cyclic citrullated peptide antibodies, positive RF, erosions, and joint-space narrowing.³²

Other drugs. Options include traditional disease-modifying anti-rheumatic drugs (csDMARDs), such as methotrexate and leflunomide; biologic agents, such as TNF-a inhibitors (eg, etanercept, adalimumab, and infliximab); and anti-IL monoclonal antibody drugs (eg, the IL-6 inhibitor tocilizumab and IL-1 inhibitors anakinra, and canakinumab).³¹ Indications by class include:

• csDMARDs as first-line therapy in persistent eoJIA and pJIA;
• TNF-Symbolα inhibitors for refractory eoJIA and for pJIA episodes³¹;
• tocilizumab, recommended for sJIA patients who have persistent systemic signs; and
• anakinra and canakinumab for refractory SJIA patients.³²

Continue to: Failure

When treatment of JIA fails with a given drug, options include increasing the dosage; switching to another agent in the same drug class; switching to a different class; and combining an NSAID with a csDMARD or a biologic agent.³² In class-specific JIA cases, a change in a drug regimen is warranted on the basis of the evidence-based historical clinical response rate.³²

What is the prognosis?

Treatment of JIA with novel agents, such as biologics, has opened up the possibility that JIA patients can live not just with suppressed symptoms but immunologically inactive disease. This is the result of better understanding of the pathogenesis of JIA and the mechanism of action of targeted drugs, and identification of biomarkers that are helpful in predicting prognosis, adverse effects, and response to treatment.

On average, it takes 3 visits to a physician, over the course of about 3 months, before definitive diagnosis of JIA is made.

JIA is often a lifelong disease; one-third of patients continue to exhibit symptoms into adulthood.⁴ If their disease is properly managed, however, these patients do not develop typical features of rheumatoid arthritis, including hand, limb, and spine deformities. Last, patients with JIA who have only intermittent disease tend to do better over the long term than those whose disease is continual.³²

The mortality rate of JIA has dropped: from 1% to 4% in the mid-1970s to 0.3% to 1% today⁴—an improvement in life expectancy that is echoed in enhanced quality of life for patients. According to the 4-level Steinbrocker functional classification scale³³ (used to rate the extent of physical disability), 15% of JIA patients were Class III (limited to few or no activities of the patient’s usual occupation) or Class IV (bedridden with little or no self-care) in the period from 1976 to 1994—a percentage that had declined to 5% by 2002.³⁴

The family physician plays pivotal role in JIA care

For the family physician, appropriate initial intervention in the management of JIA is imperative. This includes ordering imaging (whether plain films or MRI), laboratory tests as described earlier (although not to make the diagnosis), and the use of NSAIDs, intra-articular steroids, and other induction agents. Once the diagnosis is made, and a drug regimen is put in place, you will need to monitor for adverse effects. This monitoring will need to occur when a patient is escalated to csDMARDs, biological agents, or systemic steroids; is maintained on an NSAID; or is placed on a combination regimen.

Continue to: Before beginning therapy with a biologic agent...

Before beginning therapy with a biologic agent, it’s important to screen for hepatitis B, hepatitis C, human immunodeficiency virus infection, tuberculosis, and fungal infection (eg, Histoplasma capsulatum, Coccidioides immitis³²). Be sure to make a timely referral to the ophthalmology service for a bi-annual eye exam and, in the event that surgery is necessary, conduct a preoperative evaluation, with the knowledge of how long before surgery a biologic agent must be withheld (duration varies by drug).³²

CORRESPONDENCE
Tobe Momah, MD, Department of Family Medicine, Clinical Science Building, 4th Floor, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216; [email protected].

EVIDENCE SUMMARY

PRP vs placebo. Three RCTs compared PRP with saline placebo injections and 2 found that PRP improved the Western Ontario and McMaster Universities Arthritis Index (WOMAC, a standardized scale assessing knee pain, function, and stiffness) by 40% to 70%; the third found 24% to 32% improvements in the EuroQol visual analog scale (EQ-VAS) scores at 6 months^1-3 (TABLE^1-12).

The first 2 studies enrolled patients (mean age early 60s, approximately 50% women) with clinically and radiographically evaluated knee OA of mostly moderate severity (baseline WOMAC scores about 50).^1,2 Investigators in the first RCT injected PRP once in one subgroup and twice in another subgroup, compared with a single injection of saline in a third subgroup.¹ They gave 3 weekly injections of PRP or saline in the second RCT.²

The third study enrolled mainly patients with early osteoarthritis (mean age early 50s, slightly more women). Investigators injected PRP 3 times in one subgroup and once (plus 2 saline injections) in another, compared with 3 saline injections, and evaluated patients at baseline and 6 months.³

PRP vs HA. Nine RCTs compared PRP with HA injections. Six studies (673 patients) found no significant difference; 3 studies (376 patients) found that PRP improved standardized knee assessment scores by 35% to 40% at 24-48 weeks.^7,8,10 All studies enrolled patients (mean age early 60s, approximately 50% women) with clinically and radiographically evaluated knee OA of mostly moderate severity. In 7 RCTs, ^4-6,9-12 investigators injected PRP or HA weekly for 3 weeks, in one RCT⁸ they gave 4 weekly injections, and in one⁷they gave 2 PRP injections separated by 4 weeks.

Three RCTs used the International Knee Documentation Committee (IKDC) score, considered the most reliable standardized scoring system, which quantifies subjective symptoms (pain, stiffness, swelling, giving way), activity (climbing stairs, rising from a chair, squatting, jumping), and function pre- and postintervention.^5,9,12 All 3 studies using the IKDC found no difference between PRP and HA injections. Most RCTs used the WOMAC standardized scale, scoring 5 items for pain, 2 for stiffness, and 17 for function.^1,2,4,6-8.10

Risk for bias

A systematic review¹³ that evaluated methodologic quality of the 3 studies comparing PRP with placebo rated 2^1,3 at high risk of bias and one² at moderate risk. Another meta-analysis¹⁴ performed a quality assessment including 4 of the 9 RCTs^,8-10,12 comparing PRP with HA and concluded that 3 had a high risk of bias; the fourth RCT had a moderate risk. No independent quality assessments of the other RCTs were available.^4-7,11

RECOMMENDATIONS

The American Academy of Orthopaedic Surgeons doesn’t recommend for or against PRP injections because of insufficient evidence and strongly recommends against HA injections based on multiple RCTs of moderate quality that found no difference between HA and placebo.¹⁵

EVIDENCE SUMMARY

PRP vs placebo. Three RCTs compared PRP with saline placebo injections and 2 found that PRP improved the Western Ontario and McMaster Universities Arthritis Index (WOMAC, a standardized scale assessing knee pain, function, and stiffness) by 40% to 70%; the third found 24% to 32% improvements in the EuroQol visual analog scale (EQ-VAS) scores at 6 months^1-3 (TABLE^1-12).

The first 2 studies enrolled patients (mean age early 60s, approximately 50% women) with clinically and radiographically evaluated knee OA of mostly moderate severity (baseline WOMAC scores about 50).^1,2 Investigators in the first RCT injected PRP once in one subgroup and twice in another subgroup, compared with a single injection of saline in a third subgroup.¹ They gave 3 weekly injections of PRP or saline in the second RCT.²

The third study enrolled mainly patients with early osteoarthritis (mean age early 50s, slightly more women). Investigators injected PRP 3 times in one subgroup and once (plus 2 saline injections) in another, compared with 3 saline injections, and evaluated patients at baseline and 6 months.³

PRP vs HA. Nine RCTs compared PRP with HA injections. Six studies (673 patients) found no significant difference; 3 studies (376 patients) found that PRP improved standardized knee assessment scores by 35% to 40% at 24-48 weeks.^7,8,10 All studies enrolled patients (mean age early 60s, approximately 50% women) with clinically and radiographically evaluated knee OA of mostly moderate severity. In 7 RCTs, ^4-6,9-12 investigators injected PRP or HA weekly for 3 weeks, in one RCT⁸ they gave 4 weekly injections, and in one⁷they gave 2 PRP injections separated by 4 weeks.

Three RCTs used the International Knee Documentation Committee (IKDC) score, considered the most reliable standardized scoring system, which quantifies subjective symptoms (pain, stiffness, swelling, giving way), activity (climbing stairs, rising from a chair, squatting, jumping), and function pre- and postintervention.^5,9,12 All 3 studies using the IKDC found no difference between PRP and HA injections. Most RCTs used the WOMAC standardized scale, scoring 5 items for pain, 2 for stiffness, and 17 for function.^1,2,4,6-8.10

Risk for bias

A systematic review¹³ that evaluated methodologic quality of the 3 studies comparing PRP with placebo rated 2^1,3 at high risk of bias and one² at moderate risk. Another meta-analysis¹⁴ performed a quality assessment including 4 of the 9 RCTs^,8-10,12 comparing PRP with HA and concluded that 3 had a high risk of bias; the fourth RCT had a moderate risk. No independent quality assessments of the other RCTs were available.^4-7,11

RECOMMENDATIONS

The American Academy of Orthopaedic Surgeons doesn’t recommend for or against PRP injections because of insufficient evidence and strongly recommends against HA injections based on multiple RCTs of moderate quality that found no difference between HA and placebo.¹⁵

EVIDENCE SUMMARY

PRP vs placebo. Three RCTs compared PRP with saline placebo injections and 2 found that PRP improved the Western Ontario and McMaster Universities Arthritis Index (WOMAC, a standardized scale assessing knee pain, function, and stiffness) by 40% to 70%; the third found 24% to 32% improvements in the EuroQol visual analog scale (EQ-VAS) scores at 6 months^1-3 (TABLE^1-12).

The first 2 studies enrolled patients (mean age early 60s, approximately 50% women) with clinically and radiographically evaluated knee OA of mostly moderate severity (baseline WOMAC scores about 50).^1,2 Investigators in the first RCT injected PRP once in one subgroup and twice in another subgroup, compared with a single injection of saline in a third subgroup.¹ They gave 3 weekly injections of PRP or saline in the second RCT.²

The third study enrolled mainly patients with early osteoarthritis (mean age early 50s, slightly more women). Investigators injected PRP 3 times in one subgroup and once (plus 2 saline injections) in another, compared with 3 saline injections, and evaluated patients at baseline and 6 months.³

PRP vs HA. Nine RCTs compared PRP with HA injections. Six studies (673 patients) found no significant difference; 3 studies (376 patients) found that PRP improved standardized knee assessment scores by 35% to 40% at 24-48 weeks.^7,8,10 All studies enrolled patients (mean age early 60s, approximately 50% women) with clinically and radiographically evaluated knee OA of mostly moderate severity. In 7 RCTs, ^4-6,9-12 investigators injected PRP or HA weekly for 3 weeks, in one RCT⁸ they gave 4 weekly injections, and in one⁷they gave 2 PRP injections separated by 4 weeks.

Three RCTs used the International Knee Documentation Committee (IKDC) score, considered the most reliable standardized scoring system, which quantifies subjective symptoms (pain, stiffness, swelling, giving way), activity (climbing stairs, rising from a chair, squatting, jumping), and function pre- and postintervention.^5,9,12 All 3 studies using the IKDC found no difference between PRP and HA injections. Most RCTs used the WOMAC standardized scale, scoring 5 items for pain, 2 for stiffness, and 17 for function.^1,2,4,6-8.10

Risk for bias

A systematic review¹³ that evaluated methodologic quality of the 3 studies comparing PRP with placebo rated 2^1,3 at high risk of bias and one² at moderate risk. Another meta-analysis¹⁴ performed a quality assessment including 4 of the 9 RCTs^,8-10,12 comparing PRP with HA and concluded that 3 had a high risk of bias; the fourth RCT had a moderate risk. No independent quality assessments of the other RCTs were available.^4-7,11

RECOMMENDATIONS

The American Academy of Orthopaedic Surgeons doesn’t recommend for or against PRP injections because of insufficient evidence and strongly recommends against HA injections based on multiple RCTs of moderate quality that found no difference between HA and placebo.¹⁵

Menstrual bleeding is considered normal when it occurs regularly (every 21-35 days), lasts 4 to 8 days, and is not associated with heavy bleeding.¹ During the first few years after menarche, it is normal for girls to experience irregular menstrual cycles but, by the third year, 60% to 80% of girls have an adult pattern of menstrual bleeding.²

Menstrual flow without normal volume, duration, regularity, or frequency is considered abnormal uterine bleeding (AUB). The condition is considered acute if there is need for immediate intervention. In the absence of the need for immediate intervention, recurrent AUB is classified as chronic.³ Chronic AUB is the focus of this article.

Invaluable tool: The FIGO classification

In 2011, the International Federation of Gynecology and Obstetrics (FIGO) proposed what is known as the PALM–COEIN AUB classification system (TABLE 1).³ This mnemonic system divides AUB into 2 broad types:

• structural causes, recalled by “PALM” (Polyps, Adenomyosis, Leiomyoma, and Malignancy/hyperplasia)
• nonstructural causes, recalled by “COEIN” (Coagulopathy, Ovulatory dysfunction, Endometrial, Iatrogenic, and Not yet classified).

The PALM–COEIN system also uses descriptive terminology (heavy bleeding, intermenstrual bleeding) to characterize the bleeding pattern.³ The American College of Obstetricians and Gynecologists has adopted this classification system and recommends that such historically used terminology as “dysfunctional uterine bleeding,” “menorrhagia,” and “metrorrhagia” be abandoned.¹

The initial workup of all causes of chronic uterine bleeding begins with a history; physical examination, including pelvic exam; and laboratory testing, including a urine pregnancy test, complete blood count, and a test of thyroid-stimulating hormone (TABLE 2). The need for additional laboratory testing, imaging, or endometrial biopsy depends on the suspected cause of AUB, detailed stepwise in FIGURE 1 (women <18 years) and FIGURE 2 (≥18 years).

We first briefly review the 9 categories of AUB in the PALM–COEIN system; discuss the most common causes in more detail; and review common treatment options (TABLE 3).

CASE 1

Marsha R, a 41-year-old-woman, complains of heavy menstrual bleeding for the past year that has become worse over the past 2 months. Her menstrual cycles have occurred every 28 days and last 10 days; she uses 10 to 12 pads a day.

Continue to: Recently, Ms. R reports...

Recently, Ms. R reports, she has been bleeding continuously for 14 days, with episodes of lighter bleeding followed by heavier bleeding. She also complains of fatigue.

Bimanual examination is notable for an enlarged uterus.

How would you proceed with the workup of this patient, to determine the cause of her bleeding and tailor management accordingly?

Structural AUB: The “PALM” mnemonic

A structural cause of AUB must be considered when you encounter an abnormality on physical exam (TABLE 1).³ In obese women or other patients in whom the physical exam is difficult, historical clues—including postcoital bleeding, intermenstrual bleeding, or pelvic pain or pressure—also suggest a structural abnormality.⁴

Transvaginal ultrasonography (TVUS) is the initial method of evaluation when a structural abnormality is suspected.^1,4 However, although TVUS is excellent at visualizing the myometrium, lesions within the uterine cavity can be missed. If intracavitary pathology, such as submucosal fibroids or endometrial polyps, is suspected, additional imaging with saline infusion sonohysterography (SIS) should be performed. If a cavitary abnormality is confirmed, hysteroscopy is indicated.¹ Magnetic resonance imaging (MRI) is reserved for cases in which a uterine cavity abnormality is found on TVUS but cannot be further characterized by SIS or hysteroscopy.¹

Continue to: Endometrial biopsy...

Endometrial biopsy (EMB) is indicated as part of the initial evaluation of AUB in all women >45 years and in younger women who have risk factors for endometrial cancer, including polycystic ovary syndrome (PCOS), obesity, and hereditary nonpolyposis colorectal cancer. Such biopsy is necessary in these women whether or not another condition is the cause of the AUB and regardless of findings on TVUS.^1-4 Endometrial biopsy should also be performed in women with AUB that persists despite medical management. If office EMB is nondiagnostic, hysteroscopy or SIS can be used to obtain tissue samples for further evaluation.⁵

Emotional barriers might exist in an adolescent being evaluated for abnormal uterine bleeding that make it difficult for her to talk about menses and sexual activity.

Polyps. An endometrial polyp is a benign growth of endometrial tissue that is covered with epithelial cells. Polyps are often diagnosed by EMB or TVUS when these techniques are performed as part of the workup for AUB.⁶ Endometrial polyps are found more commonly in postmenopausal women, but should be considered as a cause of AUB in premenopausal women, too, especially those with intermenstrual bleeding or postcoital bleeding (or both) that is unresponsive to medical management.⁷ Risk factors for polyps include older age, obesity, and treatment with tamoxifen.⁷ The usual treatment for symptomatic endometrial polyps is removal by operative hysteroscopy.⁷

Adenomyosis. Ectopic endometrial tissue in the myometrium that leads to hypertrophy of the myometrium and uterine enlargement is known as adenomyosis. The disorder is most often diagnosed in women 40 to 50 years of age, who commonly complain of heavy uterine bleeding (40%-60% of cases) and dysmenorrhea (65%).⁸ Although definitive diagnosis is made histologically at hysterectomy, TVUS and MRI can be useful tools to help narrow the differential diagnosis in women with unexplained AUB.

According to a systematic review,⁹ the sensitivity and specificity of imaging in the diagnosis of adenomyosis is 72% and 81%, respectively, for TVUS and 77% and 89%, respectively, for MRI. Needle biopsy, performed hysteroscopically or laparoscopically, is less useful because the technique has low sensitivity (reported variously as 8%-56%) in diagnosing adenomyosis.⁸

Treatment options for adenomyosis are medical management with agents that reduce bleeding (eg, a combination oral contraceptive [OC], nonsteroidal anti-inflammatory drugs [NSAIDs], the antifibrinolytic tranexamic acid, and, when there is no distortion of the uterine cavity, a levonorgestrel intrauterine device [LNG-IUD]); uterine artery embolization; and hysterectomy.⁸

Continue to: Leiomyoma

Leiomyoma. Uterine fibroids, or leiomyomas, are benign, fibromuscular solid tumors, thought to be hormone-dependent because many regress after menopause. In women of reproductive age, uterine fibroids are the most common cause of structural AUB, with a cumulative incidence of 70% to 80% among women in this age group.^3,10 Fibroids are more common in African-American women, women who experienced early menarche, and women who are obese, have PCOS, or had a late first pregnancy.^3-10

Many fibroids are asymptomatic, and are found incidentally on sonographic examination performed for other reasons; in one-third of affected patients, the fibroids result in heavy menstrual bleeding.¹⁰ Intermenstrual bleeding and postcoital bleeding can occur, but are not common symptoms with fibroids. Consider other causes of AUB, such as endometrial polyps, when these symptoms are present.

Treatment of fibroids is medical or surgical. Medical management is a reasonable first-line option, especially in women who have not completed childbearing and who have small (<3 cm in diameter) fibroids. Options include a combination OC, NSAIDs, tranexamic acid, and, when the uterine cavity is not distorted, an LNG-IUD.^4,10,11

For women with larger fibroids, those for whom the aforementioned medical treatments are unsuccessful, and those who are seeking more definitive treatment, uterine artery embolization, myomectomy, or hysterectomy can be considered.

› Uterine artery embolization is performed by an interventional radiologist under local anesthesia and, if necessary, moderate sedation.¹² After the procedure, fibroids decrease in size due to avascular necrosis, but the remainder of the myometrium is relatively unaffected because collateral blood supply develops.^13,14 Patients might experience abdominal cramping for 2 or 3 days following the procedure, which can be managed with an oral NSAID.¹² Approximately 90% of women treated with embolization note improvement in AUB by 3 months after the procedure.¹⁵ Uterine artery embolization is not recommended in women who have not completed childbearing.^12,16,17

Continue to: Myomectomy

› Myomectomy (removal of the leiomyoma) is the surgical treatment of choice for women who want to maintain fertility. Depending on the size and location of the fibroid(s), myomectomy can be performed as an open surgical procedure, laparoscopically, or hysteroscopically. At the discretion of the surgeon, leuprolide acetate, a gonadotropin-releasing hormone agonist, can be prescribed for 3 months before myomectomy to reduce intraoperative blood loss by decreasing the vascularity of the fibroids.^4,18 Reduction in bleeding is reported in 70% to 90% of patients who undergo myomectomy.¹⁹

› Hysterectomy, the definitive treatment for uterine fibroids, should be reserved for women who have completed childbearing and who have failed (or have a contraindication to) other treatment options.

Malignancy/hyperplasia. EMB should be performed when endometrial malignancy/hyperplasia is suspected. As noted, endometrial cancer should be considered as a diagnostic possibility in women >45 years, in younger women with risk factors, and in women who have failed to respond to medical treatment for other suspected causes of AUB.⁵

When hyperplasia without atypia is diagnosed, the LNG-IUD or oral progesterone is an acceptable treatment option; note that fewer women who have an LNG-IUD eventually require hysterectomy, compared to women who take oral hormone therapy for AUB.²⁰ When hyperplasia with atypia is diagnosed, hysterectomy is the treatment of choice. If a woman wishes to maintain fertility, however, oral progesterone therapy can be offered.²¹

When the diagnosis is cancer, the patient should be referred to a gynecologic oncologist for staging and treatment. Treatment varies depending on stage, but generally requires hysterectomy including bilateral salpingo-oophorectomy, with possible chemotherapy or radiation, or both.²²

Continue to: CASE 1

CASE 1

Ms. R undergoes a sonogram that reveals a 4-cm fibroid in the uterine fundus that has not distorted the uterine cavity. Although she has completed childbearing, Ms. R is not interested in a surgical procedure at this time. You recommend insertion of an LNG-IUD; she accepts your advice.

CASE 2

Claire G, 27 years old, with a body mass index of 41,* complains of irregular menses for several months. Her menstrual cycle is irregular, as is the duration of menses and amount of bleeding. She has some mild fatigue without dizziness.

Endometrial biopsy should be part of the initial evaluation of abnormal uterine bleeding in all women >45 years and in younger women who have risk factors for endometrial cancer.

The physical exam is notable for mild hirsutism, without abnormalities on pelvic examination. Lab testing reveals iron-deficiency anemia; a pregnancy test is negative.

The questions that were raised by Ms. R’s case challenge you here, too: What is the appropriate workup of Ms. G’s bleeding? Once the cause is confirmed, how should you treat her?

Nonstructural AUB: The “COEIN” mnemonic

In the absence of abnormalities on a pelvic exam, and after excluding endometrial malignancy/hyperplasia in patients with the aforementioned risk factors, a nonstructural cause of AUB should be considered (TABLE 1).³ In women 20 to 40 years of age, the primary common cause of nonstructural uterine bleeding is ovulatory dysfunction, most often caused by PCOS or anovulatory bleeding.

Continue to: For nonstructual causes of AUB...

For nonstructural causes of AUB, the recommended laboratory workup varies with the suspected diagnosis. In addition, recently pregnant women should have a quantitative assay of β human chorionic gonadotropin to evaluate for trophoblastic disease.^5,23

Imaging is not usually recommended when the cause of AUB is suspected to be nonstructural. However, when PCOS is suspected, TVUS can be used to confirm the presence of polycystic ovaries.²³

As noted, EMB should be performed when AUB is present in women >45 years, in patients of any age group who fail to respond to medical therapy, and in those at increased risk for endometrial cancer.

Coagulopathy. When heavy bleeding has been present since the onset of menarche, inherited bleeding disorders must be considered, the most common of which is von Willebrand disease, a disorder of platelet adhesion.²⁴ It is estimated that just under 50% of adolescents with abnormal uterine bleeding have a coagulopathy, most often a platelet function disorder.²⁵ Additional clues to the presence of a coagulation disorder include a family history of bleeding disorder, a personal history of bleeding problems associated with surgery, and a history of iron-deficiency anemia.²⁶ Abnormal uterine bleeding might resolve with treatment of the underlying coagulopathy; if it does not, consider consultation with a hematologist before prescribing an NSAID or an OC.

Heavy bleeding in patients taking an anticoagulant falls into the category of coagulopathy-related AUB. No further workup is generally needed for these women.³

Continue to: Ovulatory dysfunction

Ovulatory dysfunction. Abnormal uterine bleeding caused by ovulatory dysfunction is generally due to PCOS or anovulatory bleeding. Other causes, beyond the scope of this discussion, include hypothyroidism, hyperandrogenism, female athlete triad, stress, and hyperprolactinemia.

› Polycystic ovary syndrome. A diagnosis of PCOS is made using any of several recognized criteria. The commonly used Rotterdam 2003 criteria²⁷ require that at least 2 of the following be present to make a diagnosis of PCOS:

• oligo-ovulation or anovulation
• hyperandrogenism

• polycystic ovaries seen on ultrasonography.

In addition, women with PCOS are frequently obese, show signs of insulin resistance (diabetes, prediabetes, acanthosis nigricans), or hyperandrogenism (hirsutism, acne). Even if these latter findings are not present at diagnosis, women with PCOS are at risk for a metabolic disorder. Once a diagnosis of PCOS has been established, therefore, screening tests for diabetes and cardiac risk factors (eg, dyslipidemia) should be performed.^28.29

Hysterectomy is the definitive treatment for uterine fibroids, but is reserved for women who have completed childbearing and failed (or have a contraindication to) other options.

To evaluate for hyperandrogenism, free testosterone should be measured using a high-sensitivity immunoassay in all women in whom PCOS is suspected. Because of a higher prevalence of nonclassical (ie, late-onset) congenital adrenal hyperplasia (CAH) in women of Ashkenazi Jewish (estimated prevalence, 3.7%), Hispanic (1.9%), Slavic (1.6%), and Italian (0.3%) descent, screening for CAH as a possible cause of hyperandrogenism is also recommended, by a test of a morning 17-hydroxyprogesterone level.^23,29,30 (Note: The general Caucasian population has an estimated prevalence of nonclassical CAH of 0.1%.³⁰)

Treatment of PCOS should be individualized, based on a patient’s symptoms and comorbidities. For overweight and obese women, weight loss, exercise, and metformin (1500-2000 mg/d) are the mainstays of therapy, and might reduce AUB.^29,31 If these measures do not reduce AUB, other options include an OC, an LNG-IUD, and NSAIDs.

Continue to: Information on treating other PCOS-related symptoms...

Information on treating other PCOS-related symptoms (acne, hirsutism) is available from many sources²⁹; these treatments do not typically help the patient’s AUB, however, and are therefore not addressed in this article.

› Anovulatory bleeding. In adolescence, the most common cause of AUB is anovulation resulting from immaturity of the hypothalamic–pituitary–ovarian axis. During anovulatory cycles, the imbalance of estrogen and progesterone creates a fragile endometrium, leading to unpredictable bleeding and irregular cycles. Other less common causes of AUB, such as ovarian or adrenal tumor, should be considered in adolescents who have hirsutism but do not meet the criteria for PCOS.⁵

Endometrial dysfunction as the cause of abnormal uterine bleeding stems from aberrations in biochemical pathways— making it difficult to confirm by lab analysis or histology.

When seeing an adolescent for evaluation of AUB, be aware that emotional barriers might be present that make it difficult for her to talk about menses and sexual activity. Be patient and normalize the patient’s symptoms when appropriate. Pelvic exam can be deferred, especially in adolescents who have not yet had vaginal intercourse. When AUB occurs in an adolescent and the cause is thought to be immaturity of the hypothalamic–pituitary–ovarian axis, there is no need for laboratory testing or imaging studies, other than excluding hypothyroidism and pregnancy as the cause.

Oral contraceptives, NSAIDs, tranexamic acid, and the LNG-IUD are all options for treating patients who have anovulatory bleeding^4,5 (TABLE 3). An OC has a major advantage for adolescents because it alleviates other complaints related to adolescent hormonal changes, such as acne, and provides contraception when taken on a regular basis.

Alternatively, the LNG-IUD has the benefit of ease of use once inserted, while still providing the added benefit of contraception. In women who have not yet had vaginal intercourse, an intrauterine device might not be the first choice of treatment, however, and should be prescribed only after discussion with the patient. For both OCs and the LNG-IUD, myths surrounding the use of these medications must be addressed with the patient and, if she is a minor, her parents or guardian.³²

Continue to: NSAIDS can be effective because...

NSAIDs can be effective because they reduce bleeding by causing vasoconstriction, but they provide the greatest benefit when started before menses, which can be difficult for a patient who has irregular cycles.

Endometrial causes of AUB should be suspected when a patient has heavy menstrual bleeding with regular menstrual cycles and no other causes can be identified. Endometrial dysfunction as the cause of AUB stems from aberrations in the biochemical pathways of endometrial hemostasis and repair, and therefore is difficult to confirm by laboratory analysis or histologic evaluation.³ Medical management focuses on alleviating heavy menstrual bleeding (TABLE 3).

Iatrogenic. The most common type of iatrogenic AUB is unscheduled bleeding, also known as breakthrough bleeding, that occurs during hormonal treatment with an OC or during the first few months after insertion of an LNG-IUD or contraceptive implant.³ In most cases, no specific treatment is required; bleeding resolves upon continued use of the contraceptive.

Not yet classified. This category is difficult to define; it was created for causes of AUB that have not yet been identified and remain unclear. For example, a condition known as chronic endometritis is under study as a possible cause of AUB, but has not been assigned to a PALM–COEIN category.³ As more data become available and understanding of pathophysiologic mechanisms lead to better definitions of disease, this and other poorly understood conditions will be moved to an appropriate category in the FIGO classification system.

CASE 2

Ms. G is given a diagnosis of PCOS, based on her history. You recommend weight loss and exercise; screen her for diabetes and dyslipidemia; and prescribe metformin.

ACKNOWLEDGMENT
Barry D. Weiss, MD, University of Arizona College of Medicine, Department of Family and Community Medicine, Tucson, assisted with the editing of this manuscript.

CORRESPONDENCE
Melody A. Jordahl-Iafrato, MD, Community Hospital East Family Medicine Residency, 10122 East 10th Street, Suite 100, Indianapolis, IN 46229; [email protected].

Menstrual bleeding is considered normal when it occurs regularly (every 21-35 days), lasts 4 to 8 days, and is not associated with heavy bleeding.¹ During the first few years after menarche, it is normal for girls to experience irregular menstrual cycles but, by the third year, 60% to 80% of girls have an adult pattern of menstrual bleeding.²

Menstrual flow without normal volume, duration, regularity, or frequency is considered abnormal uterine bleeding (AUB). The condition is considered acute if there is need for immediate intervention. In the absence of the need for immediate intervention, recurrent AUB is classified as chronic.³ Chronic AUB is the focus of this article.

Invaluable tool: The FIGO classification

In 2011, the International Federation of Gynecology and Obstetrics (FIGO) proposed what is known as the PALM–COEIN AUB classification system (TABLE 1).³ This mnemonic system divides AUB into 2 broad types:

• structural causes, recalled by “PALM” (Polyps, Adenomyosis, Leiomyoma, and Malignancy/hyperplasia)
• nonstructural causes, recalled by “COEIN” (Coagulopathy, Ovulatory dysfunction, Endometrial, Iatrogenic, and Not yet classified).

The PALM–COEIN system also uses descriptive terminology (heavy bleeding, intermenstrual bleeding) to characterize the bleeding pattern.³ The American College of Obstetricians and Gynecologists has adopted this classification system and recommends that such historically used terminology as “dysfunctional uterine bleeding,” “menorrhagia,” and “metrorrhagia” be abandoned.¹

The initial workup of all causes of chronic uterine bleeding begins with a history; physical examination, including pelvic exam; and laboratory testing, including a urine pregnancy test, complete blood count, and a test of thyroid-stimulating hormone (TABLE 2). The need for additional laboratory testing, imaging, or endometrial biopsy depends on the suspected cause of AUB, detailed stepwise in FIGURE 1 (women <18 years) and FIGURE 2 (≥18 years).

We first briefly review the 9 categories of AUB in the PALM–COEIN system; discuss the most common causes in more detail; and review common treatment options (TABLE 3).

CASE 1

Marsha R, a 41-year-old-woman, complains of heavy menstrual bleeding for the past year that has become worse over the past 2 months. Her menstrual cycles have occurred every 28 days and last 10 days; she uses 10 to 12 pads a day.

Continue to: Recently, Ms. R reports...

Recently, Ms. R reports, she has been bleeding continuously for 14 days, with episodes of lighter bleeding followed by heavier bleeding. She also complains of fatigue.

Bimanual examination is notable for an enlarged uterus.

How would you proceed with the workup of this patient, to determine the cause of her bleeding and tailor management accordingly?

Structural AUB: The “PALM” mnemonic

A structural cause of AUB must be considered when you encounter an abnormality on physical exam (TABLE 1).³ In obese women or other patients in whom the physical exam is difficult, historical clues—including postcoital bleeding, intermenstrual bleeding, or pelvic pain or pressure—also suggest a structural abnormality.⁴

Transvaginal ultrasonography (TVUS) is the initial method of evaluation when a structural abnormality is suspected.^1,4 However, although TVUS is excellent at visualizing the myometrium, lesions within the uterine cavity can be missed. If intracavitary pathology, such as submucosal fibroids or endometrial polyps, is suspected, additional imaging with saline infusion sonohysterography (SIS) should be performed. If a cavitary abnormality is confirmed, hysteroscopy is indicated.¹ Magnetic resonance imaging (MRI) is reserved for cases in which a uterine cavity abnormality is found on TVUS but cannot be further characterized by SIS or hysteroscopy.¹

Continue to: Endometrial biopsy...

Endometrial biopsy (EMB) is indicated as part of the initial evaluation of AUB in all women >45 years and in younger women who have risk factors for endometrial cancer, including polycystic ovary syndrome (PCOS), obesity, and hereditary nonpolyposis colorectal cancer. Such biopsy is necessary in these women whether or not another condition is the cause of the AUB and regardless of findings on TVUS.^1-4 Endometrial biopsy should also be performed in women with AUB that persists despite medical management. If office EMB is nondiagnostic, hysteroscopy or SIS can be used to obtain tissue samples for further evaluation.⁵

Emotional barriers might exist in an adolescent being evaluated for abnormal uterine bleeding that make it difficult for her to talk about menses and sexual activity.

Polyps. An endometrial polyp is a benign growth of endometrial tissue that is covered with epithelial cells. Polyps are often diagnosed by EMB or TVUS when these techniques are performed as part of the workup for AUB.⁶ Endometrial polyps are found more commonly in postmenopausal women, but should be considered as a cause of AUB in premenopausal women, too, especially those with intermenstrual bleeding or postcoital bleeding (or both) that is unresponsive to medical management.⁷ Risk factors for polyps include older age, obesity, and treatment with tamoxifen.⁷ The usual treatment for symptomatic endometrial polyps is removal by operative hysteroscopy.⁷

Adenomyosis. Ectopic endometrial tissue in the myometrium that leads to hypertrophy of the myometrium and uterine enlargement is known as adenomyosis. The disorder is most often diagnosed in women 40 to 50 years of age, who commonly complain of heavy uterine bleeding (40%-60% of cases) and dysmenorrhea (65%).⁸ Although definitive diagnosis is made histologically at hysterectomy, TVUS and MRI can be useful tools to help narrow the differential diagnosis in women with unexplained AUB.

According to a systematic review,⁹ the sensitivity and specificity of imaging in the diagnosis of adenomyosis is 72% and 81%, respectively, for TVUS and 77% and 89%, respectively, for MRI. Needle biopsy, performed hysteroscopically or laparoscopically, is less useful because the technique has low sensitivity (reported variously as 8%-56%) in diagnosing adenomyosis.⁸

Treatment options for adenomyosis are medical management with agents that reduce bleeding (eg, a combination oral contraceptive [OC], nonsteroidal anti-inflammatory drugs [NSAIDs], the antifibrinolytic tranexamic acid, and, when there is no distortion of the uterine cavity, a levonorgestrel intrauterine device [LNG-IUD]); uterine artery embolization; and hysterectomy.⁸

Continue to: Leiomyoma

Leiomyoma. Uterine fibroids, or leiomyomas, are benign, fibromuscular solid tumors, thought to be hormone-dependent because many regress after menopause. In women of reproductive age, uterine fibroids are the most common cause of structural AUB, with a cumulative incidence of 70% to 80% among women in this age group.^3,10 Fibroids are more common in African-American women, women who experienced early menarche, and women who are obese, have PCOS, or had a late first pregnancy.^3-10

Many fibroids are asymptomatic, and are found incidentally on sonographic examination performed for other reasons; in one-third of affected patients, the fibroids result in heavy menstrual bleeding.¹⁰ Intermenstrual bleeding and postcoital bleeding can occur, but are not common symptoms with fibroids. Consider other causes of AUB, such as endometrial polyps, when these symptoms are present.

Treatment of fibroids is medical or surgical. Medical management is a reasonable first-line option, especially in women who have not completed childbearing and who have small (<3 cm in diameter) fibroids. Options include a combination OC, NSAIDs, tranexamic acid, and, when the uterine cavity is not distorted, an LNG-IUD.^4,10,11

For women with larger fibroids, those for whom the aforementioned medical treatments are unsuccessful, and those who are seeking more definitive treatment, uterine artery embolization, myomectomy, or hysterectomy can be considered.

› Uterine artery embolization is performed by an interventional radiologist under local anesthesia and, if necessary, moderate sedation.¹² After the procedure, fibroids decrease in size due to avascular necrosis, but the remainder of the myometrium is relatively unaffected because collateral blood supply develops.^13,14 Patients might experience abdominal cramping for 2 or 3 days following the procedure, which can be managed with an oral NSAID.¹² Approximately 90% of women treated with embolization note improvement in AUB by 3 months after the procedure.¹⁵ Uterine artery embolization is not recommended in women who have not completed childbearing.^12,16,17

Continue to: Myomectomy

› Myomectomy (removal of the leiomyoma) is the surgical treatment of choice for women who want to maintain fertility. Depending on the size and location of the fibroid(s), myomectomy can be performed as an open surgical procedure, laparoscopically, or hysteroscopically. At the discretion of the surgeon, leuprolide acetate, a gonadotropin-releasing hormone agonist, can be prescribed for 3 months before myomectomy to reduce intraoperative blood loss by decreasing the vascularity of the fibroids.^4,18 Reduction in bleeding is reported in 70% to 90% of patients who undergo myomectomy.¹⁹

› Hysterectomy, the definitive treatment for uterine fibroids, should be reserved for women who have completed childbearing and who have failed (or have a contraindication to) other treatment options.

Malignancy/hyperplasia. EMB should be performed when endometrial malignancy/hyperplasia is suspected. As noted, endometrial cancer should be considered as a diagnostic possibility in women >45 years, in younger women with risk factors, and in women who have failed to respond to medical treatment for other suspected causes of AUB.⁵

When hyperplasia without atypia is diagnosed, the LNG-IUD or oral progesterone is an acceptable treatment option; note that fewer women who have an LNG-IUD eventually require hysterectomy, compared to women who take oral hormone therapy for AUB.²⁰ When hyperplasia with atypia is diagnosed, hysterectomy is the treatment of choice. If a woman wishes to maintain fertility, however, oral progesterone therapy can be offered.²¹

When the diagnosis is cancer, the patient should be referred to a gynecologic oncologist for staging and treatment. Treatment varies depending on stage, but generally requires hysterectomy including bilateral salpingo-oophorectomy, with possible chemotherapy or radiation, or both.²²

Continue to: CASE 1

CASE 1

Ms. R undergoes a sonogram that reveals a 4-cm fibroid in the uterine fundus that has not distorted the uterine cavity. Although she has completed childbearing, Ms. R is not interested in a surgical procedure at this time. You recommend insertion of an LNG-IUD; she accepts your advice.

CASE 2

Claire G, 27 years old, with a body mass index of 41,* complains of irregular menses for several months. Her menstrual cycle is irregular, as is the duration of menses and amount of bleeding. She has some mild fatigue without dizziness.

Endometrial biopsy should be part of the initial evaluation of abnormal uterine bleeding in all women >45 years and in younger women who have risk factors for endometrial cancer.

The physical exam is notable for mild hirsutism, without abnormalities on pelvic examination. Lab testing reveals iron-deficiency anemia; a pregnancy test is negative.

The questions that were raised by Ms. R’s case challenge you here, too: What is the appropriate workup of Ms. G’s bleeding? Once the cause is confirmed, how should you treat her?

Nonstructural AUB: The “COEIN” mnemonic

In the absence of abnormalities on a pelvic exam, and after excluding endometrial malignancy/hyperplasia in patients with the aforementioned risk factors, a nonstructural cause of AUB should be considered (TABLE 1).³ In women 20 to 40 years of age, the primary common cause of nonstructural uterine bleeding is ovulatory dysfunction, most often caused by PCOS or anovulatory bleeding.

Continue to: For nonstructual causes of AUB...

For nonstructural causes of AUB, the recommended laboratory workup varies with the suspected diagnosis. In addition, recently pregnant women should have a quantitative assay of β human chorionic gonadotropin to evaluate for trophoblastic disease.^5,23

Imaging is not usually recommended when the cause of AUB is suspected to be nonstructural. However, when PCOS is suspected, TVUS can be used to confirm the presence of polycystic ovaries.²³

As noted, EMB should be performed when AUB is present in women >45 years, in patients of any age group who fail to respond to medical therapy, and in those at increased risk for endometrial cancer.

Coagulopathy. When heavy bleeding has been present since the onset of menarche, inherited bleeding disorders must be considered, the most common of which is von Willebrand disease, a disorder of platelet adhesion.²⁴ It is estimated that just under 50% of adolescents with abnormal uterine bleeding have a coagulopathy, most often a platelet function disorder.²⁵ Additional clues to the presence of a coagulation disorder include a family history of bleeding disorder, a personal history of bleeding problems associated with surgery, and a history of iron-deficiency anemia.²⁶ Abnormal uterine bleeding might resolve with treatment of the underlying coagulopathy; if it does not, consider consultation with a hematologist before prescribing an NSAID or an OC.

Heavy bleeding in patients taking an anticoagulant falls into the category of coagulopathy-related AUB. No further workup is generally needed for these women.³

Continue to: Ovulatory dysfunction

Ovulatory dysfunction. Abnormal uterine bleeding caused by ovulatory dysfunction is generally due to PCOS or anovulatory bleeding. Other causes, beyond the scope of this discussion, include hypothyroidism, hyperandrogenism, female athlete triad, stress, and hyperprolactinemia.

› Polycystic ovary syndrome. A diagnosis of PCOS is made using any of several recognized criteria. The commonly used Rotterdam 2003 criteria²⁷ require that at least 2 of the following be present to make a diagnosis of PCOS:

• oligo-ovulation or anovulation
• hyperandrogenism

• polycystic ovaries seen on ultrasonography.

In addition, women with PCOS are frequently obese, show signs of insulin resistance (diabetes, prediabetes, acanthosis nigricans), or hyperandrogenism (hirsutism, acne). Even if these latter findings are not present at diagnosis, women with PCOS are at risk for a metabolic disorder. Once a diagnosis of PCOS has been established, therefore, screening tests for diabetes and cardiac risk factors (eg, dyslipidemia) should be performed.^28.29

Hysterectomy is the definitive treatment for uterine fibroids, but is reserved for women who have completed childbearing and failed (or have a contraindication to) other options.

To evaluate for hyperandrogenism, free testosterone should be measured using a high-sensitivity immunoassay in all women in whom PCOS is suspected. Because of a higher prevalence of nonclassical (ie, late-onset) congenital adrenal hyperplasia (CAH) in women of Ashkenazi Jewish (estimated prevalence, 3.7%), Hispanic (1.9%), Slavic (1.6%), and Italian (0.3%) descent, screening for CAH as a possible cause of hyperandrogenism is also recommended, by a test of a morning 17-hydroxyprogesterone level.^23,29,30 (Note: The general Caucasian population has an estimated prevalence of nonclassical CAH of 0.1%.³⁰)

Treatment of PCOS should be individualized, based on a patient’s symptoms and comorbidities. For overweight and obese women, weight loss, exercise, and metformin (1500-2000 mg/d) are the mainstays of therapy, and might reduce AUB.^29,31 If these measures do not reduce AUB, other options include an OC, an LNG-IUD, and NSAIDs.

Continue to: Information on treating other PCOS-related symptoms...

Information on treating other PCOS-related symptoms (acne, hirsutism) is available from many sources²⁹; these treatments do not typically help the patient’s AUB, however, and are therefore not addressed in this article.

› Anovulatory bleeding. In adolescence, the most common cause of AUB is anovulation resulting from immaturity of the hypothalamic–pituitary–ovarian axis. During anovulatory cycles, the imbalance of estrogen and progesterone creates a fragile endometrium, leading to unpredictable bleeding and irregular cycles. Other less common causes of AUB, such as ovarian or adrenal tumor, should be considered in adolescents who have hirsutism but do not meet the criteria for PCOS.⁵

Endometrial dysfunction as the cause of abnormal uterine bleeding stems from aberrations in biochemical pathways— making it difficult to confirm by lab analysis or histology.

When seeing an adolescent for evaluation of AUB, be aware that emotional barriers might be present that make it difficult for her to talk about menses and sexual activity. Be patient and normalize the patient’s symptoms when appropriate. Pelvic exam can be deferred, especially in adolescents who have not yet had vaginal intercourse. When AUB occurs in an adolescent and the cause is thought to be immaturity of the hypothalamic–pituitary–ovarian axis, there is no need for laboratory testing or imaging studies, other than excluding hypothyroidism and pregnancy as the cause.

Oral contraceptives, NSAIDs, tranexamic acid, and the LNG-IUD are all options for treating patients who have anovulatory bleeding^4,5 (TABLE 3). An OC has a major advantage for adolescents because it alleviates other complaints related to adolescent hormonal changes, such as acne, and provides contraception when taken on a regular basis.

Alternatively, the LNG-IUD has the benefit of ease of use once inserted, while still providing the added benefit of contraception. In women who have not yet had vaginal intercourse, an intrauterine device might not be the first choice of treatment, however, and should be prescribed only after discussion with the patient. For both OCs and the LNG-IUD, myths surrounding the use of these medications must be addressed with the patient and, if she is a minor, her parents or guardian.³²

Continue to: NSAIDS can be effective because...

NSAIDs can be effective because they reduce bleeding by causing vasoconstriction, but they provide the greatest benefit when started before menses, which can be difficult for a patient who has irregular cycles.

Endometrial causes of AUB should be suspected when a patient has heavy menstrual bleeding with regular menstrual cycles and no other causes can be identified. Endometrial dysfunction as the cause of AUB stems from aberrations in the biochemical pathways of endometrial hemostasis and repair, and therefore is difficult to confirm by laboratory analysis or histologic evaluation.³ Medical management focuses on alleviating heavy menstrual bleeding (TABLE 3).

Iatrogenic. The most common type of iatrogenic AUB is unscheduled bleeding, also known as breakthrough bleeding, that occurs during hormonal treatment with an OC or during the first few months after insertion of an LNG-IUD or contraceptive implant.³ In most cases, no specific treatment is required; bleeding resolves upon continued use of the contraceptive.

Not yet classified. This category is difficult to define; it was created for causes of AUB that have not yet been identified and remain unclear. For example, a condition known as chronic endometritis is under study as a possible cause of AUB, but has not been assigned to a PALM–COEIN category.³ As more data become available and understanding of pathophysiologic mechanisms lead to better definitions of disease, this and other poorly understood conditions will be moved to an appropriate category in the FIGO classification system.

CASE 2

Ms. G is given a diagnosis of PCOS, based on her history. You recommend weight loss and exercise; screen her for diabetes and dyslipidemia; and prescribe metformin.

ACKNOWLEDGMENT
Barry D. Weiss, MD, University of Arizona College of Medicine, Department of Family and Community Medicine, Tucson, assisted with the editing of this manuscript.

CORRESPONDENCE
Melody A. Jordahl-Iafrato, MD, Community Hospital East Family Medicine Residency, 10122 East 10th Street, Suite 100, Indianapolis, IN 46229; [email protected].

Menstrual bleeding is considered normal when it occurs regularly (every 21-35 days), lasts 4 to 8 days, and is not associated with heavy bleeding.¹ During the first few years after menarche, it is normal for girls to experience irregular menstrual cycles but, by the third year, 60% to 80% of girls have an adult pattern of menstrual bleeding.²

Menstrual flow without normal volume, duration, regularity, or frequency is considered abnormal uterine bleeding (AUB). The condition is considered acute if there is need for immediate intervention. In the absence of the need for immediate intervention, recurrent AUB is classified as chronic.³ Chronic AUB is the focus of this article.

Invaluable tool: The FIGO classification

In 2011, the International Federation of Gynecology and Obstetrics (FIGO) proposed what is known as the PALM–COEIN AUB classification system (TABLE 1).³ This mnemonic system divides AUB into 2 broad types:

• structural causes, recalled by “PALM” (Polyps, Adenomyosis, Leiomyoma, and Malignancy/hyperplasia)
• nonstructural causes, recalled by “COEIN” (Coagulopathy, Ovulatory dysfunction, Endometrial, Iatrogenic, and Not yet classified).

The PALM–COEIN system also uses descriptive terminology (heavy bleeding, intermenstrual bleeding) to characterize the bleeding pattern.³ The American College of Obstetricians and Gynecologists has adopted this classification system and recommends that such historically used terminology as “dysfunctional uterine bleeding,” “menorrhagia,” and “metrorrhagia” be abandoned.¹

The initial workup of all causes of chronic uterine bleeding begins with a history; physical examination, including pelvic exam; and laboratory testing, including a urine pregnancy test, complete blood count, and a test of thyroid-stimulating hormone (TABLE 2). The need for additional laboratory testing, imaging, or endometrial biopsy depends on the suspected cause of AUB, detailed stepwise in FIGURE 1 (women <18 years) and FIGURE 2 (≥18 years).

We first briefly review the 9 categories of AUB in the PALM–COEIN system; discuss the most common causes in more detail; and review common treatment options (TABLE 3).

CASE 1

Marsha R, a 41-year-old-woman, complains of heavy menstrual bleeding for the past year that has become worse over the past 2 months. Her menstrual cycles have occurred every 28 days and last 10 days; she uses 10 to 12 pads a day.

Continue to: Recently, Ms. R reports...

Recently, Ms. R reports, she has been bleeding continuously for 14 days, with episodes of lighter bleeding followed by heavier bleeding. She also complains of fatigue.

Bimanual examination is notable for an enlarged uterus.

How would you proceed with the workup of this patient, to determine the cause of her bleeding and tailor management accordingly?

Structural AUB: The “PALM” mnemonic

A structural cause of AUB must be considered when you encounter an abnormality on physical exam (TABLE 1).³ In obese women or other patients in whom the physical exam is difficult, historical clues—including postcoital bleeding, intermenstrual bleeding, or pelvic pain or pressure—also suggest a structural abnormality.⁴

Transvaginal ultrasonography (TVUS) is the initial method of evaluation when a structural abnormality is suspected.^1,4 However, although TVUS is excellent at visualizing the myometrium, lesions within the uterine cavity can be missed. If intracavitary pathology, such as submucosal fibroids or endometrial polyps, is suspected, additional imaging with saline infusion sonohysterography (SIS) should be performed. If a cavitary abnormality is confirmed, hysteroscopy is indicated.¹ Magnetic resonance imaging (MRI) is reserved for cases in which a uterine cavity abnormality is found on TVUS but cannot be further characterized by SIS or hysteroscopy.¹

Continue to: Endometrial biopsy...

Endometrial biopsy (EMB) is indicated as part of the initial evaluation of AUB in all women >45 years and in younger women who have risk factors for endometrial cancer, including polycystic ovary syndrome (PCOS), obesity, and hereditary nonpolyposis colorectal cancer. Such biopsy is necessary in these women whether or not another condition is the cause of the AUB and regardless of findings on TVUS.^1-4 Endometrial biopsy should also be performed in women with AUB that persists despite medical management. If office EMB is nondiagnostic, hysteroscopy or SIS can be used to obtain tissue samples for further evaluation.⁵

Emotional barriers might exist in an adolescent being evaluated for abnormal uterine bleeding that make it difficult for her to talk about menses and sexual activity.

Polyps. An endometrial polyp is a benign growth of endometrial tissue that is covered with epithelial cells. Polyps are often diagnosed by EMB or TVUS when these techniques are performed as part of the workup for AUB.⁶ Endometrial polyps are found more commonly in postmenopausal women, but should be considered as a cause of AUB in premenopausal women, too, especially those with intermenstrual bleeding or postcoital bleeding (or both) that is unresponsive to medical management.⁷ Risk factors for polyps include older age, obesity, and treatment with tamoxifen.⁷ The usual treatment for symptomatic endometrial polyps is removal by operative hysteroscopy.⁷

Adenomyosis. Ectopic endometrial tissue in the myometrium that leads to hypertrophy of the myometrium and uterine enlargement is known as adenomyosis. The disorder is most often diagnosed in women 40 to 50 years of age, who commonly complain of heavy uterine bleeding (40%-60% of cases) and dysmenorrhea (65%).⁸ Although definitive diagnosis is made histologically at hysterectomy, TVUS and MRI can be useful tools to help narrow the differential diagnosis in women with unexplained AUB.

According to a systematic review,⁹ the sensitivity and specificity of imaging in the diagnosis of adenomyosis is 72% and 81%, respectively, for TVUS and 77% and 89%, respectively, for MRI. Needle biopsy, performed hysteroscopically or laparoscopically, is less useful because the technique has low sensitivity (reported variously as 8%-56%) in diagnosing adenomyosis.⁸

Treatment options for adenomyosis are medical management with agents that reduce bleeding (eg, a combination oral contraceptive [OC], nonsteroidal anti-inflammatory drugs [NSAIDs], the antifibrinolytic tranexamic acid, and, when there is no distortion of the uterine cavity, a levonorgestrel intrauterine device [LNG-IUD]); uterine artery embolization; and hysterectomy.⁸

Continue to: Leiomyoma

Leiomyoma. Uterine fibroids, or leiomyomas, are benign, fibromuscular solid tumors, thought to be hormone-dependent because many regress after menopause. In women of reproductive age, uterine fibroids are the most common cause of structural AUB, with a cumulative incidence of 70% to 80% among women in this age group.^3,10 Fibroids are more common in African-American women, women who experienced early menarche, and women who are obese, have PCOS, or had a late first pregnancy.^3-10

Many fibroids are asymptomatic, and are found incidentally on sonographic examination performed for other reasons; in one-third of affected patients, the fibroids result in heavy menstrual bleeding.¹⁰ Intermenstrual bleeding and postcoital bleeding can occur, but are not common symptoms with fibroids. Consider other causes of AUB, such as endometrial polyps, when these symptoms are present.

Treatment of fibroids is medical or surgical. Medical management is a reasonable first-line option, especially in women who have not completed childbearing and who have small (<3 cm in diameter) fibroids. Options include a combination OC, NSAIDs, tranexamic acid, and, when the uterine cavity is not distorted, an LNG-IUD.^4,10,11

For women with larger fibroids, those for whom the aforementioned medical treatments are unsuccessful, and those who are seeking more definitive treatment, uterine artery embolization, myomectomy, or hysterectomy can be considered.

› Uterine artery embolization is performed by an interventional radiologist under local anesthesia and, if necessary, moderate sedation.¹² After the procedure, fibroids decrease in size due to avascular necrosis, but the remainder of the myometrium is relatively unaffected because collateral blood supply develops.^13,14 Patients might experience abdominal cramping for 2 or 3 days following the procedure, which can be managed with an oral NSAID.¹² Approximately 90% of women treated with embolization note improvement in AUB by 3 months after the procedure.¹⁵ Uterine artery embolization is not recommended in women who have not completed childbearing.^12,16,17

Continue to: Myomectomy

› Myomectomy (removal of the leiomyoma) is the surgical treatment of choice for women who want to maintain fertility. Depending on the size and location of the fibroid(s), myomectomy can be performed as an open surgical procedure, laparoscopically, or hysteroscopically. At the discretion of the surgeon, leuprolide acetate, a gonadotropin-releasing hormone agonist, can be prescribed for 3 months before myomectomy to reduce intraoperative blood loss by decreasing the vascularity of the fibroids.^4,18 Reduction in bleeding is reported in 70% to 90% of patients who undergo myomectomy.¹⁹

› Hysterectomy, the definitive treatment for uterine fibroids, should be reserved for women who have completed childbearing and who have failed (or have a contraindication to) other treatment options.

Malignancy/hyperplasia. EMB should be performed when endometrial malignancy/hyperplasia is suspected. As noted, endometrial cancer should be considered as a diagnostic possibility in women >45 years, in younger women with risk factors, and in women who have failed to respond to medical treatment for other suspected causes of AUB.⁵

When hyperplasia without atypia is diagnosed, the LNG-IUD or oral progesterone is an acceptable treatment option; note that fewer women who have an LNG-IUD eventually require hysterectomy, compared to women who take oral hormone therapy for AUB.²⁰ When hyperplasia with atypia is diagnosed, hysterectomy is the treatment of choice. If a woman wishes to maintain fertility, however, oral progesterone therapy can be offered.²¹

When the diagnosis is cancer, the patient should be referred to a gynecologic oncologist for staging and treatment. Treatment varies depending on stage, but generally requires hysterectomy including bilateral salpingo-oophorectomy, with possible chemotherapy or radiation, or both.²²

Continue to: CASE 1

CASE 1

Ms. R undergoes a sonogram that reveals a 4-cm fibroid in the uterine fundus that has not distorted the uterine cavity. Although she has completed childbearing, Ms. R is not interested in a surgical procedure at this time. You recommend insertion of an LNG-IUD; she accepts your advice.

CASE 2

Claire G, 27 years old, with a body mass index of 41,* complains of irregular menses for several months. Her menstrual cycle is irregular, as is the duration of menses and amount of bleeding. She has some mild fatigue without dizziness.

Endometrial biopsy should be part of the initial evaluation of abnormal uterine bleeding in all women >45 years and in younger women who have risk factors for endometrial cancer.

The physical exam is notable for mild hirsutism, without abnormalities on pelvic examination. Lab testing reveals iron-deficiency anemia; a pregnancy test is negative.

The questions that were raised by Ms. R’s case challenge you here, too: What is the appropriate workup of Ms. G’s bleeding? Once the cause is confirmed, how should you treat her?

Nonstructural AUB: The “COEIN” mnemonic

In the absence of abnormalities on a pelvic exam, and after excluding endometrial malignancy/hyperplasia in patients with the aforementioned risk factors, a nonstructural cause of AUB should be considered (TABLE 1).³ In women 20 to 40 years of age, the primary common cause of nonstructural uterine bleeding is ovulatory dysfunction, most often caused by PCOS or anovulatory bleeding.

Continue to: For nonstructual causes of AUB...

For nonstructural causes of AUB, the recommended laboratory workup varies with the suspected diagnosis. In addition, recently pregnant women should have a quantitative assay of β human chorionic gonadotropin to evaluate for trophoblastic disease.^5,23

Imaging is not usually recommended when the cause of AUB is suspected to be nonstructural. However, when PCOS is suspected, TVUS can be used to confirm the presence of polycystic ovaries.²³

As noted, EMB should be performed when AUB is present in women >45 years, in patients of any age group who fail to respond to medical therapy, and in those at increased risk for endometrial cancer.

Coagulopathy. When heavy bleeding has been present since the onset of menarche, inherited bleeding disorders must be considered, the most common of which is von Willebrand disease, a disorder of platelet adhesion.²⁴ It is estimated that just under 50% of adolescents with abnormal uterine bleeding have a coagulopathy, most often a platelet function disorder.²⁵ Additional clues to the presence of a coagulation disorder include a family history of bleeding disorder, a personal history of bleeding problems associated with surgery, and a history of iron-deficiency anemia.²⁶ Abnormal uterine bleeding might resolve with treatment of the underlying coagulopathy; if it does not, consider consultation with a hematologist before prescribing an NSAID or an OC.

Heavy bleeding in patients taking an anticoagulant falls into the category of coagulopathy-related AUB. No further workup is generally needed for these women.³

Continue to: Ovulatory dysfunction

Ovulatory dysfunction. Abnormal uterine bleeding caused by ovulatory dysfunction is generally due to PCOS or anovulatory bleeding. Other causes, beyond the scope of this discussion, include hypothyroidism, hyperandrogenism, female athlete triad, stress, and hyperprolactinemia.

› Polycystic ovary syndrome. A diagnosis of PCOS is made using any of several recognized criteria. The commonly used Rotterdam 2003 criteria²⁷ require that at least 2 of the following be present to make a diagnosis of PCOS:

• oligo-ovulation or anovulation
• hyperandrogenism

• polycystic ovaries seen on ultrasonography.

In addition, women with PCOS are frequently obese, show signs of insulin resistance (diabetes, prediabetes, acanthosis nigricans), or hyperandrogenism (hirsutism, acne). Even if these latter findings are not present at diagnosis, women with PCOS are at risk for a metabolic disorder. Once a diagnosis of PCOS has been established, therefore, screening tests for diabetes and cardiac risk factors (eg, dyslipidemia) should be performed.^28.29

Hysterectomy is the definitive treatment for uterine fibroids, but is reserved for women who have completed childbearing and failed (or have a contraindication to) other options.

To evaluate for hyperandrogenism, free testosterone should be measured using a high-sensitivity immunoassay in all women in whom PCOS is suspected. Because of a higher prevalence of nonclassical (ie, late-onset) congenital adrenal hyperplasia (CAH) in women of Ashkenazi Jewish (estimated prevalence, 3.7%), Hispanic (1.9%), Slavic (1.6%), and Italian (0.3%) descent, screening for CAH as a possible cause of hyperandrogenism is also recommended, by a test of a morning 17-hydroxyprogesterone level.^23,29,30 (Note: The general Caucasian population has an estimated prevalence of nonclassical CAH of 0.1%.³⁰)

Treatment of PCOS should be individualized, based on a patient’s symptoms and comorbidities. For overweight and obese women, weight loss, exercise, and metformin (1500-2000 mg/d) are the mainstays of therapy, and might reduce AUB.^29,31 If these measures do not reduce AUB, other options include an OC, an LNG-IUD, and NSAIDs.

Continue to: Information on treating other PCOS-related symptoms...

Information on treating other PCOS-related symptoms (acne, hirsutism) is available from many sources²⁹; these treatments do not typically help the patient’s AUB, however, and are therefore not addressed in this article.

› Anovulatory bleeding. In adolescence, the most common cause of AUB is anovulation resulting from immaturity of the hypothalamic–pituitary–ovarian axis. During anovulatory cycles, the imbalance of estrogen and progesterone creates a fragile endometrium, leading to unpredictable bleeding and irregular cycles. Other less common causes of AUB, such as ovarian or adrenal tumor, should be considered in adolescents who have hirsutism but do not meet the criteria for PCOS.⁵

Endometrial dysfunction as the cause of abnormal uterine bleeding stems from aberrations in biochemical pathways— making it difficult to confirm by lab analysis or histology.

When seeing an adolescent for evaluation of AUB, be aware that emotional barriers might be present that make it difficult for her to talk about menses and sexual activity. Be patient and normalize the patient’s symptoms when appropriate. Pelvic exam can be deferred, especially in adolescents who have not yet had vaginal intercourse. When AUB occurs in an adolescent and the cause is thought to be immaturity of the hypothalamic–pituitary–ovarian axis, there is no need for laboratory testing or imaging studies, other than excluding hypothyroidism and pregnancy as the cause.

Oral contraceptives, NSAIDs, tranexamic acid, and the LNG-IUD are all options for treating patients who have anovulatory bleeding^4,5 (TABLE 3). An OC has a major advantage for adolescents because it alleviates other complaints related to adolescent hormonal changes, such as acne, and provides contraception when taken on a regular basis.

Alternatively, the LNG-IUD has the benefit of ease of use once inserted, while still providing the added benefit of contraception. In women who have not yet had vaginal intercourse, an intrauterine device might not be the first choice of treatment, however, and should be prescribed only after discussion with the patient. For both OCs and the LNG-IUD, myths surrounding the use of these medications must be addressed with the patient and, if she is a minor, her parents or guardian.³²

Continue to: NSAIDS can be effective because...

NSAIDs can be effective because they reduce bleeding by causing vasoconstriction, but they provide the greatest benefit when started before menses, which can be difficult for a patient who has irregular cycles.

Endometrial causes of AUB should be suspected when a patient has heavy menstrual bleeding with regular menstrual cycles and no other causes can be identified. Endometrial dysfunction as the cause of AUB stems from aberrations in the biochemical pathways of endometrial hemostasis and repair, and therefore is difficult to confirm by laboratory analysis or histologic evaluation.³ Medical management focuses on alleviating heavy menstrual bleeding (TABLE 3).

Iatrogenic. The most common type of iatrogenic AUB is unscheduled bleeding, also known as breakthrough bleeding, that occurs during hormonal treatment with an OC or during the first few months after insertion of an LNG-IUD or contraceptive implant.³ In most cases, no specific treatment is required; bleeding resolves upon continued use of the contraceptive.

Not yet classified. This category is difficult to define; it was created for causes of AUB that have not yet been identified and remain unclear. For example, a condition known as chronic endometritis is under study as a possible cause of AUB, but has not been assigned to a PALM–COEIN category.³ As more data become available and understanding of pathophysiologic mechanisms lead to better definitions of disease, this and other poorly understood conditions will be moved to an appropriate category in the FIGO classification system.

CASE 2

Ms. G is given a diagnosis of PCOS, based on her history. You recommend weight loss and exercise; screen her for diabetes and dyslipidemia; and prescribe metformin.

ACKNOWLEDGMENT
Barry D. Weiss, MD, University of Arizona College of Medicine, Department of Family and Community Medicine, Tucson, assisted with the editing of this manuscript.

CORRESPONDENCE
Melody A. Jordahl-Iafrato, MD, Community Hospital East Family Medicine Residency, 10122 East 10th Street, Suite 100, Indianapolis, IN 46229; [email protected].

Here are 5 articles from the March issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):

1. Endometriosis surgery: Women can expect years-long benefits

To take the posttest, go to: https://bit.ly/2Ez8mdu
Expires January 3, 2019

2. Cerebral small vessel disease progression linked to MCI in hypertensive patients

To take the posttest, go to: https://bit.ly/2ExDV7o
Expires January 4, 2019

3. Adult atopic dermatitis is fraught with dermatologic comorbidities

To take the posttest, go to: https://bit.ly/2Vl7E9a
Expires January 11, 2019

4. Antidepressants tied to greater hip fracture incidence in older adults

To take the posttest, go to: https://bit.ly/2GRfMeH
Expires January 4, 2019

5. Researchers exploring ways to mitigate aging’s impact on diabetes

To take the posttest, go to: https://bit.ly/2tFxF7v
Expires January 8, 2019

Here are 5 articles from the March issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):

1. Endometriosis surgery: Women can expect years-long benefits

To take the posttest, go to: https://bit.ly/2Ez8mdu
Expires January 3, 2019

2. Cerebral small vessel disease progression linked to MCI in hypertensive patients

To take the posttest, go to: https://bit.ly/2ExDV7o
Expires January 4, 2019

3. Adult atopic dermatitis is fraught with dermatologic comorbidities

To take the posttest, go to: https://bit.ly/2Vl7E9a
Expires January 11, 2019

4. Antidepressants tied to greater hip fracture incidence in older adults

To take the posttest, go to: https://bit.ly/2GRfMeH
Expires January 4, 2019

5. Researchers exploring ways to mitigate aging’s impact on diabetes

To take the posttest, go to: https://bit.ly/2tFxF7v
Expires January 8, 2019

Here are 5 articles from the March issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):

1. Endometriosis surgery: Women can expect years-long benefits

To take the posttest, go to: https://bit.ly/2Ez8mdu
Expires January 3, 2019

2. Cerebral small vessel disease progression linked to MCI in hypertensive patients

To take the posttest, go to: https://bit.ly/2ExDV7o
Expires January 4, 2019

3. Adult atopic dermatitis is fraught with dermatologic comorbidities

To take the posttest, go to: https://bit.ly/2Vl7E9a
Expires January 11, 2019

4. Antidepressants tied to greater hip fracture incidence in older adults

To take the posttest, go to: https://bit.ly/2GRfMeH
Expires January 4, 2019

5. Researchers exploring ways to mitigate aging’s impact on diabetes

To take the posttest, go to: https://bit.ly/2tFxF7v
Expires January 8, 2019

DALLAS – The time is right to bring big data and high-horsepower computation to the thorniest problems in multiple sclerosis (MS) research, said Jennifer Graves, MD, who cochaired the closing session at the meeting held by the Americas Committee for Research and Treatment in Multiple Sclerosis. The session focused on harnessing machine learning, deep learning, and the newest noninvasive observational techniques to move research and clinical care forward.

“We’ve reached a point in MS research where we’re hitting some stumbling blocks. And a lot of those stumbling blocks are related to how well and how precisely we can measure phenotype in MS. The reason that’s important is that our next frontier is treating progressive MS – and what that requires is finding things that let us know what’s happening at the biological level, so that we can screen drugs faster. We can’t afford to have 3- to 5-year clinical trials. ... Because our patients can’t wait,” said Dr. Graves, an associate professor of neuroscience at the University of California, San Diego.

“We can use all sorts of big data sources, whether it’s the rich imaging data we get on patients when they go into the MRI scanner, whether it’s wearable sensors,” or even newer technology, Dr. Graves said. “We can use technology to give us the sensitivity that we’ve been missing.”

Wearable technology, including accelerometers, can track physical activity that tracks with outcomes in MS, she added. As the tech armament increases, so will data available for analysis and correlation.

However, the key to progress will be to focus on technology that measures change over time. “This is the key: sensitivity to change over time. A lot of things can be associated with disability,” said Dr. Graves, but the key is tracking what changes in an individual patient with disease progression, “so that we can detect treatment effects or side effects.”

[email protected]

DALLAS – The time is right to bring big data and high-horsepower computation to the thorniest problems in multiple sclerosis (MS) research, said Jennifer Graves, MD, who cochaired the closing session at the meeting held by the Americas Committee for Research and Treatment in Multiple Sclerosis. The session focused on harnessing machine learning, deep learning, and the newest noninvasive observational techniques to move research and clinical care forward.

“We’ve reached a point in MS research where we’re hitting some stumbling blocks. And a lot of those stumbling blocks are related to how well and how precisely we can measure phenotype in MS. The reason that’s important is that our next frontier is treating progressive MS – and what that requires is finding things that let us know what’s happening at the biological level, so that we can screen drugs faster. We can’t afford to have 3- to 5-year clinical trials. ... Because our patients can’t wait,” said Dr. Graves, an associate professor of neuroscience at the University of California, San Diego.

“We can use all sorts of big data sources, whether it’s the rich imaging data we get on patients when they go into the MRI scanner, whether it’s wearable sensors,” or even newer technology, Dr. Graves said. “We can use technology to give us the sensitivity that we’ve been missing.”

Wearable technology, including accelerometers, can track physical activity that tracks with outcomes in MS, she added. As the tech armament increases, so will data available for analysis and correlation.

However, the key to progress will be to focus on technology that measures change over time. “This is the key: sensitivity to change over time. A lot of things can be associated with disability,” said Dr. Graves, but the key is tracking what changes in an individual patient with disease progression, “so that we can detect treatment effects or side effects.”

[email protected]

DALLAS – The time is right to bring big data and high-horsepower computation to the thorniest problems in multiple sclerosis (MS) research, said Jennifer Graves, MD, who cochaired the closing session at the meeting held by the Americas Committee for Research and Treatment in Multiple Sclerosis. The session focused on harnessing machine learning, deep learning, and the newest noninvasive observational techniques to move research and clinical care forward.

“We’ve reached a point in MS research where we’re hitting some stumbling blocks. And a lot of those stumbling blocks are related to how well and how precisely we can measure phenotype in MS. The reason that’s important is that our next frontier is treating progressive MS – and what that requires is finding things that let us know what’s happening at the biological level, so that we can screen drugs faster. We can’t afford to have 3- to 5-year clinical trials. ... Because our patients can’t wait,” said Dr. Graves, an associate professor of neuroscience at the University of California, San Diego.

“We can use all sorts of big data sources, whether it’s the rich imaging data we get on patients when they go into the MRI scanner, whether it’s wearable sensors,” or even newer technology, Dr. Graves said. “We can use technology to give us the sensitivity that we’ve been missing.”

Wearable technology, including accelerometers, can track physical activity that tracks with outcomes in MS, she added. As the tech armament increases, so will data available for analysis and correlation.

However, the key to progress will be to focus on technology that measures change over time. “This is the key: sensitivity to change over time. A lot of things can be associated with disability,” said Dr. Graves, but the key is tracking what changes in an individual patient with disease progression, “so that we can detect treatment effects or side effects.”

[email protected]

DALLAS – In a cohort of patients with multiple sclerosis, a history of migraine was associated with more severe disability and significantly slower walking speeds, researchers reported at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.

“Traditional migraine risk factors such as obesity, anxiety, and depression were also overrepresented in our cohort” of patients with multiple sclerosis (MS) and migraine, said Anne M. Damian, MD, of Johns Hopkins University, Baltimore, and her research colleagues.

Migraine is common in patients with MS, but whether migraine plays a role in MS disease course or MS symptom severity is unknown. Dr. Damian and her colleagues conducted an observational study to examine the associations between migraine history, disability, and neurologic function in patients with MS and whether migraine tends to occur with other comorbid conditions in MS.

They analyzed data from 289 patients (79% female; mean age, 49.2 years) patients with MS who completed the Multiple Sclerosis Performance Test (MSPT), an iPad version of the MS Functional Composite. MS outcome measures included disability (such as the Patient Determined Disease Steps) and objective neurologic outcomes (such as walking speed, manual dexterity, and processing speed). Patients also completed a questionnaire about comorbidities, including history of physician-diagnosed migraine, diabetes, hypertension, hypercholesterolemia, heart disease, sleep apnea, depression, and anxiety.

The researchers used generalized linear models adjusted for age, sex, MS subtype, MS duration, years of education, and body mass index to evaluate the association between history of migraine and MS outcomes.

Compared with patients with MS without migraine, migraineurs (n = 65) tended to be younger (mean age, 44.3 years vs. 50.4 years) and were more likely to be overweight or obese (73.9% vs. 51.6%). In addition, patients with MS and migraine were more likely to have a history of depression (46.2% vs. 24.2%), anxiety (30.8% vs. 18.8%), and severe rather than mild disability (odds ratio, 3.08; 95% confidence, 1.04-9.20). Migraine also was associated with significantly slower walking speeds (9.08% slower; 95% CI, 0.82%-18.77%). Migraine was not associated with processing speed or manual dexterity, however.

If an association between migraine history and worse MS disability is confirmed, migraine history may be a factor that neurologists could consider when making MS treatment decisions, Dr. Damian said. The researchers noted that migraine was reported by patients and not detected using a validated questionnaire. Future studies should investigate whether MS lesions on MRI differ in migraineurs and whether migraine predicts future neurologic disability in patients with MS.

Collection of the MSPT outcomes was sponsored by Biogen.

[email protected]

SOURCE: Damian AM et al. ACTRIMS Forum 2019, Abstract 78.

DALLAS – In a cohort of patients with multiple sclerosis, a history of migraine was associated with more severe disability and significantly slower walking speeds, researchers reported at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.

“Traditional migraine risk factors such as obesity, anxiety, and depression were also overrepresented in our cohort” of patients with multiple sclerosis (MS) and migraine, said Anne M. Damian, MD, of Johns Hopkins University, Baltimore, and her research colleagues.

Migraine is common in patients with MS, but whether migraine plays a role in MS disease course or MS symptom severity is unknown. Dr. Damian and her colleagues conducted an observational study to examine the associations between migraine history, disability, and neurologic function in patients with MS and whether migraine tends to occur with other comorbid conditions in MS.

They analyzed data from 289 patients (79% female; mean age, 49.2 years) patients with MS who completed the Multiple Sclerosis Performance Test (MSPT), an iPad version of the MS Functional Composite. MS outcome measures included disability (such as the Patient Determined Disease Steps) and objective neurologic outcomes (such as walking speed, manual dexterity, and processing speed). Patients also completed a questionnaire about comorbidities, including history of physician-diagnosed migraine, diabetes, hypertension, hypercholesterolemia, heart disease, sleep apnea, depression, and anxiety.

The researchers used generalized linear models adjusted for age, sex, MS subtype, MS duration, years of education, and body mass index to evaluate the association between history of migraine and MS outcomes.

Compared with patients with MS without migraine, migraineurs (n = 65) tended to be younger (mean age, 44.3 years vs. 50.4 years) and were more likely to be overweight or obese (73.9% vs. 51.6%). In addition, patients with MS and migraine were more likely to have a history of depression (46.2% vs. 24.2%), anxiety (30.8% vs. 18.8%), and severe rather than mild disability (odds ratio, 3.08; 95% confidence, 1.04-9.20). Migraine also was associated with significantly slower walking speeds (9.08% slower; 95% CI, 0.82%-18.77%). Migraine was not associated with processing speed or manual dexterity, however.

If an association between migraine history and worse MS disability is confirmed, migraine history may be a factor that neurologists could consider when making MS treatment decisions, Dr. Damian said. The researchers noted that migraine was reported by patients and not detected using a validated questionnaire. Future studies should investigate whether MS lesions on MRI differ in migraineurs and whether migraine predicts future neurologic disability in patients with MS.

Collection of the MSPT outcomes was sponsored by Biogen.

[email protected]

SOURCE: Damian AM et al. ACTRIMS Forum 2019, Abstract 78.

DALLAS – In a cohort of patients with multiple sclerosis, a history of migraine was associated with more severe disability and significantly slower walking speeds, researchers reported at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.

“Traditional migraine risk factors such as obesity, anxiety, and depression were also overrepresented in our cohort” of patients with multiple sclerosis (MS) and migraine, said Anne M. Damian, MD, of Johns Hopkins University, Baltimore, and her research colleagues.

Migraine is common in patients with MS, but whether migraine plays a role in MS disease course or MS symptom severity is unknown. Dr. Damian and her colleagues conducted an observational study to examine the associations between migraine history, disability, and neurologic function in patients with MS and whether migraine tends to occur with other comorbid conditions in MS.

They analyzed data from 289 patients (79% female; mean age, 49.2 years) patients with MS who completed the Multiple Sclerosis Performance Test (MSPT), an iPad version of the MS Functional Composite. MS outcome measures included disability (such as the Patient Determined Disease Steps) and objective neurologic outcomes (such as walking speed, manual dexterity, and processing speed). Patients also completed a questionnaire about comorbidities, including history of physician-diagnosed migraine, diabetes, hypertension, hypercholesterolemia, heart disease, sleep apnea, depression, and anxiety.

The researchers used generalized linear models adjusted for age, sex, MS subtype, MS duration, years of education, and body mass index to evaluate the association between history of migraine and MS outcomes.

Compared with patients with MS without migraine, migraineurs (n = 65) tended to be younger (mean age, 44.3 years vs. 50.4 years) and were more likely to be overweight or obese (73.9% vs. 51.6%). In addition, patients with MS and migraine were more likely to have a history of depression (46.2% vs. 24.2%), anxiety (30.8% vs. 18.8%), and severe rather than mild disability (odds ratio, 3.08; 95% confidence, 1.04-9.20). Migraine also was associated with significantly slower walking speeds (9.08% slower; 95% CI, 0.82%-18.77%). Migraine was not associated with processing speed or manual dexterity, however.

If an association between migraine history and worse MS disability is confirmed, migraine history may be a factor that neurologists could consider when making MS treatment decisions, Dr. Damian said. The researchers noted that migraine was reported by patients and not detected using a validated questionnaire. Future studies should investigate whether MS lesions on MRI differ in migraineurs and whether migraine predicts future neurologic disability in patients with MS.

Collection of the MSPT outcomes was sponsored by Biogen.

[email protected]

SOURCE: Damian AM et al. ACTRIMS Forum 2019, Abstract 78.

Pain is becoming a fact of life for more and more people, and they are turning to opioids to treat it, according to a survey sponsored by the National Center for Complementary and Integrative Health.

Researchers looked at nearly 2 decades-worth of cumulative data from the Medical Expenditure Panel Survey (MEPS). They found that since 1997/1998, pain prevalence in US adults rose by 25%.

In 1997/1998, about 33% of American adults had at ≤ 1 painful health condition. In 2013/2014, that proportion was 41%. For about 68 million people, moderate-to-severe pain was interfering with normal work activities. And those people were turning more often to strong opioids—eg, fentanyl, morphine, oxycodone—for help. Use of opioids to manage pain more than doubled in just 10 years: from 4.1 million (11.5%) in 2001/2002 to 10.5 million (24.3%) in 2013/2014.

People with severe pain-related interference also were more likely to have had > 4 opioid prescriptions and to have visited a doctor’s office > 6 times for pain compared with those with minimal pain-related interference.

Opioid use peaked between 2005 and 2012, but since 2012, opioid use has slightly declined. The researchers say this ties to a reduction in use of weak opioids and in the number of patients reporting only 1 opioid prescription.

The survey also found some small downward shifts in health care visits. Ambulatory office visits plateaued between 2001/2002 and 2007/2008 and decreased through 2013/2014. The researchers also found small but statistically significant drops in pain-related emergency department visits and overnight hospital stays.

The researchers say their findings suggest more education about the risk/benefit ratio of opioids “appears warranted.”

Pain is becoming a fact of life for more and more people, and they are turning to opioids to treat it, according to a survey sponsored by the National Center for Complementary and Integrative Health.

Researchers looked at nearly 2 decades-worth of cumulative data from the Medical Expenditure Panel Survey (MEPS). They found that since 1997/1998, pain prevalence in US adults rose by 25%.

In 1997/1998, about 33% of American adults had at ≤ 1 painful health condition. In 2013/2014, that proportion was 41%. For about 68 million people, moderate-to-severe pain was interfering with normal work activities. And those people were turning more often to strong opioids—eg, fentanyl, morphine, oxycodone—for help. Use of opioids to manage pain more than doubled in just 10 years: from 4.1 million (11.5%) in 2001/2002 to 10.5 million (24.3%) in 2013/2014.

People with severe pain-related interference also were more likely to have had > 4 opioid prescriptions and to have visited a doctor’s office > 6 times for pain compared with those with minimal pain-related interference.

Opioid use peaked between 2005 and 2012, but since 2012, opioid use has slightly declined. The researchers say this ties to a reduction in use of weak opioids and in the number of patients reporting only 1 opioid prescription.

The survey also found some small downward shifts in health care visits. Ambulatory office visits plateaued between 2001/2002 and 2007/2008 and decreased through 2013/2014. The researchers also found small but statistically significant drops in pain-related emergency department visits and overnight hospital stays.

The researchers say their findings suggest more education about the risk/benefit ratio of opioids “appears warranted.”

Pain is becoming a fact of life for more and more people, and they are turning to opioids to treat it, according to a survey sponsored by the National Center for Complementary and Integrative Health.

Researchers looked at nearly 2 decades-worth of cumulative data from the Medical Expenditure Panel Survey (MEPS). They found that since 1997/1998, pain prevalence in US adults rose by 25%.

In 1997/1998, about 33% of American adults had at ≤ 1 painful health condition. In 2013/2014, that proportion was 41%. For about 68 million people, moderate-to-severe pain was interfering with normal work activities. And those people were turning more often to strong opioids—eg, fentanyl, morphine, oxycodone—for help. Use of opioids to manage pain more than doubled in just 10 years: from 4.1 million (11.5%) in 2001/2002 to 10.5 million (24.3%) in 2013/2014.

People with severe pain-related interference also were more likely to have had > 4 opioid prescriptions and to have visited a doctor’s office > 6 times for pain compared with those with minimal pain-related interference.

Opioid use peaked between 2005 and 2012, but since 2012, opioid use has slightly declined. The researchers say this ties to a reduction in use of weak opioids and in the number of patients reporting only 1 opioid prescription.

The survey also found some small downward shifts in health care visits. Ambulatory office visits plateaued between 2001/2002 and 2007/2008 and decreased through 2013/2014. The researchers also found small but statistically significant drops in pain-related emergency department visits and overnight hospital stays.

The researchers say their findings suggest more education about the risk/benefit ratio of opioids “appears warranted.”

New research has revealed considerable disparity between rheumatologists’ clinical diagnosis of fibromyalgia and fibromyalgia criteria-based diagnosis, particularly the most recent revision of criteria from 2011 that rely on patients’ self-report of symptoms.

Frederick Wolfe, MD, of the National Data Bank for Rheumatic Diseases and the University of Kansas, Wichita, and his colleagues reported in Arthritis Care & Research that clinicians failed to identify almost half of cases that met the 2011 modification of the American College of Rheumatology’s self-report criteria for fibromyalgia during a 3-month period at Rush Medical College, Chicago. This led them to conclude that the “overall agreement between clinicians’ diagnosis of fibromyalgia and diagnosis by fibromyalgia criteria is only fair.”

The findings call into question studies of fibromyalgia based on ICD-10 diagnosis, according to the authors.

Several widely accepted criteria sets have provided definitions and methods of diagnosis, but a number of studies have suggested that fibromyalgia is overdiagnosed, the authors wrote.

“In the current study, we consider underdiagnosis as well as the form of overdiagnosis that lead to diagnosis when fibromyalgia criteria are not satisfied and symptoms are insufficient for diagnosis,” they added.

The research included 497 consecutive patients attending the Rush Medical College rheumatology clinic who completed a questionnaire assessing fibromyalgia diagnostic variables used in the ACR 2010 preliminary diagnostic criteria for fibromyalgia and its 2011 modification for self-report immediately prior to being seen at the clinic. Clinicians were not given instructions on how any diseases were to be diagnosed, including no instructions on using 2011 fibromyalgia criteria.


The results showed that 121 (24.3%) of the patients satisfied the 2011 fibromyalgia criteria. The agreement between clinicians and criteria was 79.2%, but agreement beyond chance was considered “fair” based on a kappa score of 0.41 and a probabilistic benchmark interval of 0.21-0.40. The researchers wrote that this benchmark represents “the probability for each coefficient of falling into the selected benchmark interval along with the cumulative probability of exceeding the predetermined threshold associated with the interval.”

A total of 104 (20.9%) received a clinician ICD-10 diagnosis of fibromyalgia, but only 61 (58.7%) actually satisfied criteria. Physicians failed to identify 60 (49.6%) criteria-positive patients and incorrectly identified 43 (11.4%) criteria-negative patients.

In a subset of 88 patients with RA, agreement was 84.1%, and the kappa score was 0.32, indicating “slight to fair” agreement (probabilistic benchmark interval, 0.00-0.20). Among 13 RA patients with criteria-positive fibromyalgia, 5 were identified by clinicians; among those who were criteria negative, 6 were deemed positive by clinicians.

The authors noted than “even worse” results were obtained in patients with systemic lupus erythematosus, where the agreement between criteria and clinician ICD diagnosis yielded a kappa value of 0.08. In patients with osteoarthritis, the kappa score was 0.51 (probabilistic benchmark interval, 0.21-0.40).

Overall, the results showed that women and patients with more symptoms but fewer pain areas were more likely to receive a clinician’s diagnosis than to satisfy fibromyalgia criteria. “Clinicians gave greater weight in making a diagnosis to being a woman and having increased symptoms and were willing to diagnose patients with lower WPI [Widespread Pain Index] and PSD [polysymptomatic distress] scores,” the researchers noted.

Dr. Wolfe and his associates wrote that it is unclear why the physicians in the study who misclassified fibromyalgia and missed patients with the diagnosis did not do better. “They may have simply misdiagnosed the condition or not accepted the use of the formal diagnostic system as necessary or clinically useful for identifying fibromyalgia in routine care.”

The researchers noted that it is likely that diagnosis in the community by general physicians, for whom the criteria are not as well known, is even more inaccurate. “It is likely that misdiagnosis is a public health problem and one that can lead to overdiagnosis and overtreatment as well as to inappropriate treatment of individuals not recognized to have fibromyalgia symptoms.”

No disclosures or funding were reported.

SOURCE: Wolfe F et al. Arthritis Care Res. 2019 Feb 6. doi: 10.1002/acr.23731.

New research has revealed considerable disparity between rheumatologists’ clinical diagnosis of fibromyalgia and fibromyalgia criteria-based diagnosis, particularly the most recent revision of criteria from 2011 that rely on patients’ self-report of symptoms.

Frederick Wolfe, MD, of the National Data Bank for Rheumatic Diseases and the University of Kansas, Wichita, and his colleagues reported in Arthritis Care & Research that clinicians failed to identify almost half of cases that met the 2011 modification of the American College of Rheumatology’s self-report criteria for fibromyalgia during a 3-month period at Rush Medical College, Chicago. This led them to conclude that the “overall agreement between clinicians’ diagnosis of fibromyalgia and diagnosis by fibromyalgia criteria is only fair.”

The findings call into question studies of fibromyalgia based on ICD-10 diagnosis, according to the authors.

Several widely accepted criteria sets have provided definitions and methods of diagnosis, but a number of studies have suggested that fibromyalgia is overdiagnosed, the authors wrote.

“In the current study, we consider underdiagnosis as well as the form of overdiagnosis that lead to diagnosis when fibromyalgia criteria are not satisfied and symptoms are insufficient for diagnosis,” they added.

The research included 497 consecutive patients attending the Rush Medical College rheumatology clinic who completed a questionnaire assessing fibromyalgia diagnostic variables used in the ACR 2010 preliminary diagnostic criteria for fibromyalgia and its 2011 modification for self-report immediately prior to being seen at the clinic. Clinicians were not given instructions on how any diseases were to be diagnosed, including no instructions on using 2011 fibromyalgia criteria.


The results showed that 121 (24.3%) of the patients satisfied the 2011 fibromyalgia criteria. The agreement between clinicians and criteria was 79.2%, but agreement beyond chance was considered “fair” based on a kappa score of 0.41 and a probabilistic benchmark interval of 0.21-0.40. The researchers wrote that this benchmark represents “the probability for each coefficient of falling into the selected benchmark interval along with the cumulative probability of exceeding the predetermined threshold associated with the interval.”

A total of 104 (20.9%) received a clinician ICD-10 diagnosis of fibromyalgia, but only 61 (58.7%) actually satisfied criteria. Physicians failed to identify 60 (49.6%) criteria-positive patients and incorrectly identified 43 (11.4%) criteria-negative patients.

In a subset of 88 patients with RA, agreement was 84.1%, and the kappa score was 0.32, indicating “slight to fair” agreement (probabilistic benchmark interval, 0.00-0.20). Among 13 RA patients with criteria-positive fibromyalgia, 5 were identified by clinicians; among those who were criteria negative, 6 were deemed positive by clinicians.

The authors noted than “even worse” results were obtained in patients with systemic lupus erythematosus, where the agreement between criteria and clinician ICD diagnosis yielded a kappa value of 0.08. In patients with osteoarthritis, the kappa score was 0.51 (probabilistic benchmark interval, 0.21-0.40).

Overall, the results showed that women and patients with more symptoms but fewer pain areas were more likely to receive a clinician’s diagnosis than to satisfy fibromyalgia criteria. “Clinicians gave greater weight in making a diagnosis to being a woman and having increased symptoms and were willing to diagnose patients with lower WPI [Widespread Pain Index] and PSD [polysymptomatic distress] scores,” the researchers noted.

Dr. Wolfe and his associates wrote that it is unclear why the physicians in the study who misclassified fibromyalgia and missed patients with the diagnosis did not do better. “They may have simply misdiagnosed the condition or not accepted the use of the formal diagnostic system as necessary or clinically useful for identifying fibromyalgia in routine care.”

The researchers noted that it is likely that diagnosis in the community by general physicians, for whom the criteria are not as well known, is even more inaccurate. “It is likely that misdiagnosis is a public health problem and one that can lead to overdiagnosis and overtreatment as well as to inappropriate treatment of individuals not recognized to have fibromyalgia symptoms.”

No disclosures or funding were reported.

SOURCE: Wolfe F et al. Arthritis Care Res. 2019 Feb 6. doi: 10.1002/acr.23731.

New research has revealed considerable disparity between rheumatologists’ clinical diagnosis of fibromyalgia and fibromyalgia criteria-based diagnosis, particularly the most recent revision of criteria from 2011 that rely on patients’ self-report of symptoms.

Frederick Wolfe, MD, of the National Data Bank for Rheumatic Diseases and the University of Kansas, Wichita, and his colleagues reported in Arthritis Care & Research that clinicians failed to identify almost half of cases that met the 2011 modification of the American College of Rheumatology’s self-report criteria for fibromyalgia during a 3-month period at Rush Medical College, Chicago. This led them to conclude that the “overall agreement between clinicians’ diagnosis of fibromyalgia and diagnosis by fibromyalgia criteria is only fair.”

The findings call into question studies of fibromyalgia based on ICD-10 diagnosis, according to the authors.

Several widely accepted criteria sets have provided definitions and methods of diagnosis, but a number of studies have suggested that fibromyalgia is overdiagnosed, the authors wrote.

“In the current study, we consider underdiagnosis as well as the form of overdiagnosis that lead to diagnosis when fibromyalgia criteria are not satisfied and symptoms are insufficient for diagnosis,” they added.

The research included 497 consecutive patients attending the Rush Medical College rheumatology clinic who completed a questionnaire assessing fibromyalgia diagnostic variables used in the ACR 2010 preliminary diagnostic criteria for fibromyalgia and its 2011 modification for self-report immediately prior to being seen at the clinic. Clinicians were not given instructions on how any diseases were to be diagnosed, including no instructions on using 2011 fibromyalgia criteria.


The results showed that 121 (24.3%) of the patients satisfied the 2011 fibromyalgia criteria. The agreement between clinicians and criteria was 79.2%, but agreement beyond chance was considered “fair” based on a kappa score of 0.41 and a probabilistic benchmark interval of 0.21-0.40. The researchers wrote that this benchmark represents “the probability for each coefficient of falling into the selected benchmark interval along with the cumulative probability of exceeding the predetermined threshold associated with the interval.”

A total of 104 (20.9%) received a clinician ICD-10 diagnosis of fibromyalgia, but only 61 (58.7%) actually satisfied criteria. Physicians failed to identify 60 (49.6%) criteria-positive patients and incorrectly identified 43 (11.4%) criteria-negative patients.

In a subset of 88 patients with RA, agreement was 84.1%, and the kappa score was 0.32, indicating “slight to fair” agreement (probabilistic benchmark interval, 0.00-0.20). Among 13 RA patients with criteria-positive fibromyalgia, 5 were identified by clinicians; among those who were criteria negative, 6 were deemed positive by clinicians.

The authors noted than “even worse” results were obtained in patients with systemic lupus erythematosus, where the agreement between criteria and clinician ICD diagnosis yielded a kappa value of 0.08. In patients with osteoarthritis, the kappa score was 0.51 (probabilistic benchmark interval, 0.21-0.40).

Overall, the results showed that women and patients with more symptoms but fewer pain areas were more likely to receive a clinician’s diagnosis than to satisfy fibromyalgia criteria. “Clinicians gave greater weight in making a diagnosis to being a woman and having increased symptoms and were willing to diagnose patients with lower WPI [Widespread Pain Index] and PSD [polysymptomatic distress] scores,” the researchers noted.

Dr. Wolfe and his associates wrote that it is unclear why the physicians in the study who misclassified fibromyalgia and missed patients with the diagnosis did not do better. “They may have simply misdiagnosed the condition or not accepted the use of the formal diagnostic system as necessary or clinically useful for identifying fibromyalgia in routine care.”

The researchers noted that it is likely that diagnosis in the community by general physicians, for whom the criteria are not as well known, is even more inaccurate. “It is likely that misdiagnosis is a public health problem and one that can lead to overdiagnosis and overtreatment as well as to inappropriate treatment of individuals not recognized to have fibromyalgia symptoms.”

No disclosures or funding were reported.

SOURCE: Wolfe F et al. Arthritis Care Res. 2019 Feb 6. doi: 10.1002/acr.23731.

Oxygen is a highly effective treatment for cluster headache with few complications, according to patient survey results published in the February issue of Headache. According to the results, triptans also are highly effective, with some side effects. Newer medications deserve further study, the researchers said.

To assess the effectiveness and adverse effects of acute cluster headache medications in a large international sample, Stuart M. Pearson, a researcher in the department of psychology at the University of West Georgia in Carrollton, and his coauthors analyzed data from the Cluster Headache Questionnaire. Respondents from more than 50 countries completed the online survey; most were from the United States, the United Kingdom, and Canada. The survey included questions about cluster headache diagnostic criteria and medication effectiveness, complications, and access to medications.

In all, 3,251 subjects participated in the questionnaire, and 2,193 respondents met criteria for the study; 1,604 had cluster headache, and 589 had probable cluster headache. Among the respondents with cluster headache, 68.8% were male, 78.0% had episodic cluster headache, and the average age was 46 years. More than half of respondents reported complete or very effective treatment for triptans (54%) and oxygen (also 54%). The proportion of respondents who reported that ergot derivatives, caffeine or energy drinks, and intranasal ketamine were completely or very effective ranged from 14% to 25%. Patients were less likely to report high levels of efficacy for opioids (6%), intranasal capsaicin (5%), and intranasal lidocaine (2%).

Participants experienced few complications from oxygen, with 99% reporting no or minimal physical and medical complications, and 97% reporting no or minimal psychological and emotional complications. Patients also reported few complications from intranasal lidocaine, intranasal ketamine, intranasal capsaicin, and caffeine and energy drinks. For triptans, 74% of respondents reported no or minimal physical and medical complications, and 85% reported no or minimal psychological and emotional complications.

Among the 139 participants with cluster headache who were aged 65 years or older, responses were similar to those for the entire population. In addition, the 589 respondents with probable cluster headache reported similar efficacy data, compared with respondents with a full diagnosis of cluster headache.

“Oxygen in particular had a high rate of complete effectiveness, a low rate of ineffectiveness, and a low rate of physical, medical, emotional, and psychological side effects,” the investigators said. “However, respondents reported that it was difficult to obtain.”

Limited insurance coverage of oxygen may affect access, even though the treatment has a Level A recommendation for the acute treatment of cluster headache in the American Headache Society guidelines, the authors said. Physicians also may pose a barrier. A prior study found that 12% of providers did not prescribe oxygen for cluster headache because they doubted its efficacy or did not know about it. In addition, there may be concerns that the treatment could be a fire hazard in a patient population that has high rates of smoking, the researchers said.

Limitations of the study include the survey’s use of nonvalidated questions, the lack of a formal clinical diagnosis of cluster headache, and the grouping of all triptans, rather than assessing individual triptan medications, such as sumatriptan subcutaneous, alone.

The study received funding from Autonomic Technologies and Clusterbusters. One of the authors has served as a paid consultant to Eli Lilly as a member of the data monitoring committee for clinical trials of galcanezumab for cluster headache and migraine.

This article was updated 3/7/2019.

[email protected]

SOURCE: Pearson SM et al. Headache. 2019 Jan 11. doi: 10.1111/head.13473.

Oxygen is a highly effective treatment for cluster headache with few complications, according to patient survey results published in the February issue of Headache. According to the results, triptans also are highly effective, with some side effects. Newer medications deserve further study, the researchers said.

To assess the effectiveness and adverse effects of acute cluster headache medications in a large international sample, Stuart M. Pearson, a researcher in the department of psychology at the University of West Georgia in Carrollton, and his coauthors analyzed data from the Cluster Headache Questionnaire. Respondents from more than 50 countries completed the online survey; most were from the United States, the United Kingdom, and Canada. The survey included questions about cluster headache diagnostic criteria and medication effectiveness, complications, and access to medications.

In all, 3,251 subjects participated in the questionnaire, and 2,193 respondents met criteria for the study; 1,604 had cluster headache, and 589 had probable cluster headache. Among the respondents with cluster headache, 68.8% were male, 78.0% had episodic cluster headache, and the average age was 46 years. More than half of respondents reported complete or very effective treatment for triptans (54%) and oxygen (also 54%). The proportion of respondents who reported that ergot derivatives, caffeine or energy drinks, and intranasal ketamine were completely or very effective ranged from 14% to 25%. Patients were less likely to report high levels of efficacy for opioids (6%), intranasal capsaicin (5%), and intranasal lidocaine (2%).

Participants experienced few complications from oxygen, with 99% reporting no or minimal physical and medical complications, and 97% reporting no or minimal psychological and emotional complications. Patients also reported few complications from intranasal lidocaine, intranasal ketamine, intranasal capsaicin, and caffeine and energy drinks. For triptans, 74% of respondents reported no or minimal physical and medical complications, and 85% reported no or minimal psychological and emotional complications.

Among the 139 participants with cluster headache who were aged 65 years or older, responses were similar to those for the entire population. In addition, the 589 respondents with probable cluster headache reported similar efficacy data, compared with respondents with a full diagnosis of cluster headache.

“Oxygen in particular had a high rate of complete effectiveness, a low rate of ineffectiveness, and a low rate of physical, medical, emotional, and psychological side effects,” the investigators said. “However, respondents reported that it was difficult to obtain.”

Limited insurance coverage of oxygen may affect access, even though the treatment has a Level A recommendation for the acute treatment of cluster headache in the American Headache Society guidelines, the authors said. Physicians also may pose a barrier. A prior study found that 12% of providers did not prescribe oxygen for cluster headache because they doubted its efficacy or did not know about it. In addition, there may be concerns that the treatment could be a fire hazard in a patient population that has high rates of smoking, the researchers said.

Limitations of the study include the survey’s use of nonvalidated questions, the lack of a formal clinical diagnosis of cluster headache, and the grouping of all triptans, rather than assessing individual triptan medications, such as sumatriptan subcutaneous, alone.

The study received funding from Autonomic Technologies and Clusterbusters. One of the authors has served as a paid consultant to Eli Lilly as a member of the data monitoring committee for clinical trials of galcanezumab for cluster headache and migraine.

This article was updated 3/7/2019.

[email protected]

SOURCE: Pearson SM et al. Headache. 2019 Jan 11. doi: 10.1111/head.13473.

Oxygen is a highly effective treatment for cluster headache with few complications, according to patient survey results published in the February issue of Headache. According to the results, triptans also are highly effective, with some side effects. Newer medications deserve further study, the researchers said.

To assess the effectiveness and adverse effects of acute cluster headache medications in a large international sample, Stuart M. Pearson, a researcher in the department of psychology at the University of West Georgia in Carrollton, and his coauthors analyzed data from the Cluster Headache Questionnaire. Respondents from more than 50 countries completed the online survey; most were from the United States, the United Kingdom, and Canada. The survey included questions about cluster headache diagnostic criteria and medication effectiveness, complications, and access to medications.

In all, 3,251 subjects participated in the questionnaire, and 2,193 respondents met criteria for the study; 1,604 had cluster headache, and 589 had probable cluster headache. Among the respondents with cluster headache, 68.8% were male, 78.0% had episodic cluster headache, and the average age was 46 years. More than half of respondents reported complete or very effective treatment for triptans (54%) and oxygen (also 54%). The proportion of respondents who reported that ergot derivatives, caffeine or energy drinks, and intranasal ketamine were completely or very effective ranged from 14% to 25%. Patients were less likely to report high levels of efficacy for opioids (6%), intranasal capsaicin (5%), and intranasal lidocaine (2%).

Participants experienced few complications from oxygen, with 99% reporting no or minimal physical and medical complications, and 97% reporting no or minimal psychological and emotional complications. Patients also reported few complications from intranasal lidocaine, intranasal ketamine, intranasal capsaicin, and caffeine and energy drinks. For triptans, 74% of respondents reported no or minimal physical and medical complications, and 85% reported no or minimal psychological and emotional complications.

Among the 139 participants with cluster headache who were aged 65 years or older, responses were similar to those for the entire population. In addition, the 589 respondents with probable cluster headache reported similar efficacy data, compared with respondents with a full diagnosis of cluster headache.

“Oxygen in particular had a high rate of complete effectiveness, a low rate of ineffectiveness, and a low rate of physical, medical, emotional, and psychological side effects,” the investigators said. “However, respondents reported that it was difficult to obtain.”

Limited insurance coverage of oxygen may affect access, even though the treatment has a Level A recommendation for the acute treatment of cluster headache in the American Headache Society guidelines, the authors said. Physicians also may pose a barrier. A prior study found that 12% of providers did not prescribe oxygen for cluster headache because they doubted its efficacy or did not know about it. In addition, there may be concerns that the treatment could be a fire hazard in a patient population that has high rates of smoking, the researchers said.

Limitations of the study include the survey’s use of nonvalidated questions, the lack of a formal clinical diagnosis of cluster headache, and the grouping of all triptans, rather than assessing individual triptan medications, such as sumatriptan subcutaneous, alone.

The study received funding from Autonomic Technologies and Clusterbusters. One of the authors has served as a paid consultant to Eli Lilly as a member of the data monitoring committee for clinical trials of galcanezumab for cluster headache and migraine.

This article was updated 3/7/2019.

[email protected]

SOURCE: Pearson SM et al. Headache. 2019 Jan 11. doi: 10.1111/head.13473.

There is a higher prevalence of opioid prescribing and opioid-related overdose deaths concentrated in regions with mostly low-income, white residents, compared with regions with high income and the lowest proportion of white residents, according to a new analysis of data on people living in California.

sdominick/iStock/Getty Images

The findings of this study provide further evidence that the opioid epidemic affects a large proportion of low-income white communities (JAMA Intern Med. 2019 Feb 11. doi: 10.1001/jamainternmed.2018.6721).

“Whereas most epidemics predominate within social minority groups and previous US drug epidemics have typically been concentrated in nonwhite communities, the current opioid crisis is largely found among lower-income and majority-white communities,” Joseph Friedman, MPH, from the University of California, Los Angeles, and his colleagues wrote in their study. “Our analysis suggests that, at least in California, an important determinant of this phenomenon may be that white individuals have a higher level of exposure than nonwhite individuals to opioid prescriptions on a per capita basis through the health care system.”

Mr. Friedman and his colleagues analyzed 29.7 million prescription drug records from California’s Controlled Substance Utilization Review and Evaluation System in and examined the prevalence of opioids, benzodiazepines, and stimulants by race, ethnicity, and income level in 1,760 zip codes during 2011-2015. The researchers estimated the prevalence of opioid prescriptions in each zip code by calculating the number of people per zip code receiving an opioid prescription divided by the population of the zip code during each year.

Overall, 23.6% of California residents received at least one opioid prescription each year of the study. The researchers found 44.2% of individuals in zip codes with the lowest income but highest proportion of white residents and 16.1% of individuals in areas with the highest income and lowest proportion of white residents had received a minimum of one opioid prescription each year. The prevalence of stimulant prescriptions was 3.8% in zip codes with high income, and a high proportion of white population, compared with a prevalence of 0.6% in areas with low income and a low proportion of white residents. The researchers noted there was no association between income and benzodiazepine prescription, but the prevalence of benzodiazepine prescriptions was 15.7% in zip codes with the highest proportion of white residents, compared with 7.0% in zip codes with a low proportion of white residents.

During the same time period, there were 9,534 opioid overdose deaths in California from causes such as fentanyl, synthetic opioids, and prescription opioids. “Overdose deaths were highly concentrated in lower-income and mostly white areas,” Mr. Friedman and his colleagues wrote. “We observed an approximate 10-fold difference in overdose rates across the race/ethnicity–income gradient in California.”

Although the number of opioids prescribed each year has decreased since 2012, in a research letter published in the same issue noted that the rate of prescribing is still higher than it was in 1999 (JAMA Intern Med. 2019 Feb 11. doi: 10.1001/jamainternmed.2018.6989). The authors also pointed out increases in the duration of opioid prescriptions and wide regional variations in opioid prescribing rates.

In their study, Gery P. Guy Jr., PhD, and his colleagues used data from the IQVIA Xponent database from approximately 50,400 retail pharmacies and discovered the average morphine milligram equivalent (MME) per capita had decreased from 641.4 MME per capita in 2015 to 512.6 MME per capita in 2017 (20.1%). The number of opioid prescriptions also decreased from 6.7 per 100 persons in 2015 to 5.0 per 100 persons in 2017 (25.3%). However, during 2015-2017, the average duration of opioid prescriptions increased from 17.7 days to 18.3 days (3.4%), while the median duration increased during the same time from 15.0 days to 20.0 days (33.3%).

While 74.7% of counties reduced the number of opioids prescribed during 2015-2017 and there also were reductions in the rate of high-dose prescribing (76.6%) and overall prescribing rates (74.7%), Dr. Guy of the Centers for Disease Control and Prevention and his colleagues found “substantial variation” in 2017 prescription rates at the county level, with opioids prescribed at 1,061.0 MME per capita at the highest quartile, compared with 182.8 MME per capita at the lowest quartile.

“Recent reductions could be related to policies and strategies aimed at reducing inappropriate prescribing, increased awareness of the risks associated with opioids, and release of the CDC Guideline for Prescribing Opioids for Chronic Pain–United States, 2016,” Dr. Guy and his colleagues noted.

In an additional article published in the same JAMA Internal Medicine issue, Bennett Allen, a research associate at the New York City Department of Health and Mental Hygiene and his colleagues examined the rate of opioid overdose deaths for non-Hispanic white, non-Hispanic black, Hispanic, and undefined other races in New York (JAMA Intern Med. 2019 Feb 11. doi: 10.1001/jamainternmed.2018.7700). They identified 1,487 deaths in 2017, which included 556 white (37.0%), 421 black (28.0%), 455 Hispanic (31.0%), and 55 undefined (4.0%) opioid overdose deaths. There was a higher rate of fentanyl and/or heroin overdose deaths from younger (aged 15-34 years) white New Yorkers (22.2/100,000 persons; 95% confidence interval, 19.0-25.5), compared with younger black New Yorkers (5.8/100,000; 95% CI, 4.0-8.2) and Hispanic (9.7/100,000; 95% CI, 7.6-12.1).

Among older residents (aged 55-84 years), Mr. Allen and his colleagues found higher rates of fentanyl and/or heroin overdose for black New Yorkers (25.4/100,000 persons; 95% CI, 20.9-30.0), compared with older white New Yorkers (9.4/100,000 persons; 95% CI, 7.3-11.8), as well as significantly higher rates of cocaine overdose (25.4/100,000 persons; 95% CI, 20.9-30.0), compared with white (5.1/100,000 persons; 95% CI, 3.6-7.0) and Hispanic residents (11.8/100,000 persons; 95% CI, 8.9-15.4).

“The distinct age distribution and drug involvement of overdose deaths among New York City blacks, Latinos, and whites, along with complementary evidence about drug use trajectories, highlight the need for heterogeneous approaches to treatment and the equitable allocation of treatment and health care resources to reach diverse populations at risk of overdose,” Mr. Allen and his colleagues wrote.

Dr. Schriger reported support from Korein Foundation for his time working on the study by Friedman et al. The other authors reported no conflicts of interest.

There is a higher prevalence of opioid prescribing and opioid-related overdose deaths concentrated in regions with mostly low-income, white residents, compared with regions with high income and the lowest proportion of white residents, according to a new analysis of data on people living in California.

sdominick/iStock/Getty Images

The findings of this study provide further evidence that the opioid epidemic affects a large proportion of low-income white communities (JAMA Intern Med. 2019 Feb 11. doi: 10.1001/jamainternmed.2018.6721).

“Whereas most epidemics predominate within social minority groups and previous US drug epidemics have typically been concentrated in nonwhite communities, the current opioid crisis is largely found among lower-income and majority-white communities,” Joseph Friedman, MPH, from the University of California, Los Angeles, and his colleagues wrote in their study. “Our analysis suggests that, at least in California, an important determinant of this phenomenon may be that white individuals have a higher level of exposure than nonwhite individuals to opioid prescriptions on a per capita basis through the health care system.”

Mr. Friedman and his colleagues analyzed 29.7 million prescription drug records from California’s Controlled Substance Utilization Review and Evaluation System in and examined the prevalence of opioids, benzodiazepines, and stimulants by race, ethnicity, and income level in 1,760 zip codes during 2011-2015. The researchers estimated the prevalence of opioid prescriptions in each zip code by calculating the number of people per zip code receiving an opioid prescription divided by the population of the zip code during each year.

Overall, 23.6% of California residents received at least one opioid prescription each year of the study. The researchers found 44.2% of individuals in zip codes with the lowest income but highest proportion of white residents and 16.1% of individuals in areas with the highest income and lowest proportion of white residents had received a minimum of one opioid prescription each year. The prevalence of stimulant prescriptions was 3.8% in zip codes with high income, and a high proportion of white population, compared with a prevalence of 0.6% in areas with low income and a low proportion of white residents. The researchers noted there was no association between income and benzodiazepine prescription, but the prevalence of benzodiazepine prescriptions was 15.7% in zip codes with the highest proportion of white residents, compared with 7.0% in zip codes with a low proportion of white residents.

During the same time period, there were 9,534 opioid overdose deaths in California from causes such as fentanyl, synthetic opioids, and prescription opioids. “Overdose deaths were highly concentrated in lower-income and mostly white areas,” Mr. Friedman and his colleagues wrote. “We observed an approximate 10-fold difference in overdose rates across the race/ethnicity–income gradient in California.”

Although the number of opioids prescribed each year has decreased since 2012, in a research letter published in the same issue noted that the rate of prescribing is still higher than it was in 1999 (JAMA Intern Med. 2019 Feb 11. doi: 10.1001/jamainternmed.2018.6989). The authors also pointed out increases in the duration of opioid prescriptions and wide regional variations in opioid prescribing rates.

In their study, Gery P. Guy Jr., PhD, and his colleagues used data from the IQVIA Xponent database from approximately 50,400 retail pharmacies and discovered the average morphine milligram equivalent (MME) per capita had decreased from 641.4 MME per capita in 2015 to 512.6 MME per capita in 2017 (20.1%). The number of opioid prescriptions also decreased from 6.7 per 100 persons in 2015 to 5.0 per 100 persons in 2017 (25.3%). However, during 2015-2017, the average duration of opioid prescriptions increased from 17.7 days to 18.3 days (3.4%), while the median duration increased during the same time from 15.0 days to 20.0 days (33.3%).

While 74.7% of counties reduced the number of opioids prescribed during 2015-2017 and there also were reductions in the rate of high-dose prescribing (76.6%) and overall prescribing rates (74.7%), Dr. Guy of the Centers for Disease Control and Prevention and his colleagues found “substantial variation” in 2017 prescription rates at the county level, with opioids prescribed at 1,061.0 MME per capita at the highest quartile, compared with 182.8 MME per capita at the lowest quartile.

“Recent reductions could be related to policies and strategies aimed at reducing inappropriate prescribing, increased awareness of the risks associated with opioids, and release of the CDC Guideline for Prescribing Opioids for Chronic Pain–United States, 2016,” Dr. Guy and his colleagues noted.

In an additional article published in the same JAMA Internal Medicine issue, Bennett Allen, a research associate at the New York City Department of Health and Mental Hygiene and his colleagues examined the rate of opioid overdose deaths for non-Hispanic white, non-Hispanic black, Hispanic, and undefined other races in New York (JAMA Intern Med. 2019 Feb 11. doi: 10.1001/jamainternmed.2018.7700). They identified 1,487 deaths in 2017, which included 556 white (37.0%), 421 black (28.0%), 455 Hispanic (31.0%), and 55 undefined (4.0%) opioid overdose deaths. There was a higher rate of fentanyl and/or heroin overdose deaths from younger (aged 15-34 years) white New Yorkers (22.2/100,000 persons; 95% confidence interval, 19.0-25.5), compared with younger black New Yorkers (5.8/100,000; 95% CI, 4.0-8.2) and Hispanic (9.7/100,000; 95% CI, 7.6-12.1).

Among older residents (aged 55-84 years), Mr. Allen and his colleagues found higher rates of fentanyl and/or heroin overdose for black New Yorkers (25.4/100,000 persons; 95% CI, 20.9-30.0), compared with older white New Yorkers (9.4/100,000 persons; 95% CI, 7.3-11.8), as well as significantly higher rates of cocaine overdose (25.4/100,000 persons; 95% CI, 20.9-30.0), compared with white (5.1/100,000 persons; 95% CI, 3.6-7.0) and Hispanic residents (11.8/100,000 persons; 95% CI, 8.9-15.4).

“The distinct age distribution and drug involvement of overdose deaths among New York City blacks, Latinos, and whites, along with complementary evidence about drug use trajectories, highlight the need for heterogeneous approaches to treatment and the equitable allocation of treatment and health care resources to reach diverse populations at risk of overdose,” Mr. Allen and his colleagues wrote.

Dr. Schriger reported support from Korein Foundation for his time working on the study by Friedman et al. The other authors reported no conflicts of interest.

There is a higher prevalence of opioid prescribing and opioid-related overdose deaths concentrated in regions with mostly low-income, white residents, compared with regions with high income and the lowest proportion of white residents, according to a new analysis of data on people living in California.

sdominick/iStock/Getty Images

The findings of this study provide further evidence that the opioid epidemic affects a large proportion of low-income white communities (JAMA Intern Med. 2019 Feb 11. doi: 10.1001/jamainternmed.2018.6721).

“Whereas most epidemics predominate within social minority groups and previous US drug epidemics have typically been concentrated in nonwhite communities, the current opioid crisis is largely found among lower-income and majority-white communities,” Joseph Friedman, MPH, from the University of California, Los Angeles, and his colleagues wrote in their study. “Our analysis suggests that, at least in California, an important determinant of this phenomenon may be that white individuals have a higher level of exposure than nonwhite individuals to opioid prescriptions on a per capita basis through the health care system.”

Mr. Friedman and his colleagues analyzed 29.7 million prescription drug records from California’s Controlled Substance Utilization Review and Evaluation System in and examined the prevalence of opioids, benzodiazepines, and stimulants by race, ethnicity, and income level in 1,760 zip codes during 2011-2015. The researchers estimated the prevalence of opioid prescriptions in each zip code by calculating the number of people per zip code receiving an opioid prescription divided by the population of the zip code during each year.

Overall, 23.6% of California residents received at least one opioid prescription each year of the study. The researchers found 44.2% of individuals in zip codes with the lowest income but highest proportion of white residents and 16.1% of individuals in areas with the highest income and lowest proportion of white residents had received a minimum of one opioid prescription each year. The prevalence of stimulant prescriptions was 3.8% in zip codes with high income, and a high proportion of white population, compared with a prevalence of 0.6% in areas with low income and a low proportion of white residents. The researchers noted there was no association between income and benzodiazepine prescription, but the prevalence of benzodiazepine prescriptions was 15.7% in zip codes with the highest proportion of white residents, compared with 7.0% in zip codes with a low proportion of white residents.

During the same time period, there were 9,534 opioid overdose deaths in California from causes such as fentanyl, synthetic opioids, and prescription opioids. “Overdose deaths were highly concentrated in lower-income and mostly white areas,” Mr. Friedman and his colleagues wrote. “We observed an approximate 10-fold difference in overdose rates across the race/ethnicity–income gradient in California.”

Although the number of opioids prescribed each year has decreased since 2012, in a research letter published in the same issue noted that the rate of prescribing is still higher than it was in 1999 (JAMA Intern Med. 2019 Feb 11. doi: 10.1001/jamainternmed.2018.6989). The authors also pointed out increases in the duration of opioid prescriptions and wide regional variations in opioid prescribing rates.

In their study, Gery P. Guy Jr., PhD, and his colleagues used data from the IQVIA Xponent database from approximately 50,400 retail pharmacies and discovered the average morphine milligram equivalent (MME) per capita had decreased from 641.4 MME per capita in 2015 to 512.6 MME per capita in 2017 (20.1%). The number of opioid prescriptions also decreased from 6.7 per 100 persons in 2015 to 5.0 per 100 persons in 2017 (25.3%). However, during 2015-2017, the average duration of opioid prescriptions increased from 17.7 days to 18.3 days (3.4%), while the median duration increased during the same time from 15.0 days to 20.0 days (33.3%).

While 74.7% of counties reduced the number of opioids prescribed during 2015-2017 and there also were reductions in the rate of high-dose prescribing (76.6%) and overall prescribing rates (74.7%), Dr. Guy of the Centers for Disease Control and Prevention and his colleagues found “substantial variation” in 2017 prescription rates at the county level, with opioids prescribed at 1,061.0 MME per capita at the highest quartile, compared with 182.8 MME per capita at the lowest quartile.

“Recent reductions could be related to policies and strategies aimed at reducing inappropriate prescribing, increased awareness of the risks associated with opioids, and release of the CDC Guideline for Prescribing Opioids for Chronic Pain–United States, 2016,” Dr. Guy and his colleagues noted.

In an additional article published in the same JAMA Internal Medicine issue, Bennett Allen, a research associate at the New York City Department of Health and Mental Hygiene and his colleagues examined the rate of opioid overdose deaths for non-Hispanic white, non-Hispanic black, Hispanic, and undefined other races in New York (JAMA Intern Med. 2019 Feb 11. doi: 10.1001/jamainternmed.2018.7700). They identified 1,487 deaths in 2017, which included 556 white (37.0%), 421 black (28.0%), 455 Hispanic (31.0%), and 55 undefined (4.0%) opioid overdose deaths. There was a higher rate of fentanyl and/or heroin overdose deaths from younger (aged 15-34 years) white New Yorkers (22.2/100,000 persons; 95% confidence interval, 19.0-25.5), compared with younger black New Yorkers (5.8/100,000; 95% CI, 4.0-8.2) and Hispanic (9.7/100,000; 95% CI, 7.6-12.1).

Among older residents (aged 55-84 years), Mr. Allen and his colleagues found higher rates of fentanyl and/or heroin overdose for black New Yorkers (25.4/100,000 persons; 95% CI, 20.9-30.0), compared with older white New Yorkers (9.4/100,000 persons; 95% CI, 7.3-11.8), as well as significantly higher rates of cocaine overdose (25.4/100,000 persons; 95% CI, 20.9-30.0), compared with white (5.1/100,000 persons; 95% CI, 3.6-7.0) and Hispanic residents (11.8/100,000 persons; 95% CI, 8.9-15.4).

“The distinct age distribution and drug involvement of overdose deaths among New York City blacks, Latinos, and whites, along with complementary evidence about drug use trajectories, highlight the need for heterogeneous approaches to treatment and the equitable allocation of treatment and health care resources to reach diverse populations at risk of overdose,” Mr. Allen and his colleagues wrote.

Dr. Schriger reported support from Korein Foundation for his time working on the study by Friedman et al. The other authors reported no conflicts of interest.