Immunology

CE/CME No: CR-1608

PROGRAM OVERVIEW
Earn credit by reading this article and successfully completing the posttest and evaluation. Successful completion is defined as a cumulative score of at least 70% correct.

EDUCATIONAL OBJECTIVES
• Describe the pathophysiology and explain the various clinical manifestations of systemic lupus erythematosus (SLE).
• Define the differential diagnosis for SLE.
• List the elements of the laboratory work-up used in the diagnosis of lupus.
• Describe the therapeutic options for patients with SLE.

FACULTY

Michael Felz is an Assistant Professor at Augusta University (formerly Georgia Regents University) in Augusta, Georgia. Mary Bailey Wickham is a PA student in her final year at Augusta University.
The authors have no financial relationships to disclose.

ACCREDITATION STATEMENT

This program has been reviewed and is approved for a maximum of 1.0 hour of American Academy of Physician Assistants (AAPA) Category 1 CME credit by the Physician Assistant Review Panel. [NPs: Both ANCC and the AANP Certification Program recognize AAPA as an approved provider of Category 1 credit.] Approval is valid for one year from the issue date of August 2016.

Article begins on next page >>

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that often goes undiagnosed initially. Timely detection of SLE is important, because prompt treatment can prevent its many major complications—notably, end organ damage. Here’s how to distinguish SLE from other illnesses with similar presentations and how to recognize the complications of undiagnosed SLE, which can progress rapidly and fatally.

Systemic lupus erythematosus (SLE) is a chronic inflammatory disorder that can involve multiple organ systems. The presence of antinuclear antibodies (ANA) is a common marker for this disease. In autoimmune diseases such as SLE, the immune system attacks the cells of healthy tissues throughout the body. Genetic, hormonal, and environmental factors (eg, ultraviolet light, infectious viruses, and even use of certain medications) have been implicated in the pathogenesis.^1-3

It is estimated that 1.5 million people in the United States and up to 5 million people worldwide have SLE.⁴ It is nine to 10 times more prevalent in women—especially those of reproductive age—than menand occurs more frequently in African-American, Hispanic, and Asian women than in non-Hispanic Caucasian women.^1,2,4-6 Siblings of SLE patients are 30 times more likely to develop the disease, compared to individuals without an affected relative.² Increased mortality in persons with SLE is attributed to accelerated atherosclerosis, infection, malignancy, and target organ damage, particularly end-stage renal disease.³ Women ages 33 to 45 with SLE are at increased risk (50x greater) for myocardial infarction due to premature atherosclerosis than age-matched women in the general population.⁷ The life expectancy of SLE ­patients with renal damage is 23.7 years less than that of the general population.⁸

Increased awareness of SLE has led to drastic improvements in associated mortality over the past five decades. The survival rate in the 1950s was 50% at 2 years, while current rates are about 95% at 5 years and about 90% at 10 years.^3,9 These improvements likely reflect earlier diagnosis and treatment on the part of well-informed clinicians, as well as more effective treatment.

SLE MANIFESTATIONS
SLE can affect any organ in the body with a broad spectrum of clinical manifestations, making it a devastatingly deceptive disease. Disease severity may vary by age, by organ involvement, and over time. Onset may be gradual and mild or rapidly progressive with severe organ involvement. Constitutional manifestations such as fatigue, weight loss, anorexia, and low-grade fever often serve as initial complaints. However, these features are common to a variety of infectious and inflammatory conditions, making early SLE easily overlooked and frequently mis­diagnosed. ²

A mix of manifestations involving the joints, skin, mouth, kidneys, lungs, heart, and nervous system offers clues to the diagnosis of SLE (see Table 1). Arthritis is the most common symptom, occurring in 85% to 90% of SLE cases.^1,10 It is typically nonerosive, inflammatory, symmetric or asymmetric, and polyarticular (involving five or more joints)and may be accompanied by constitutional symptoms.^1,2,11 The joints most commonly affected are the proximal interphalangeals, metacarpophalangeals (MCP), knees, and wrists.² Morning stiffness is a common complaint.^1,11 Jaccoud arthropathy, which is characterized by reducible, nonerosive joint subluxations (eg, swan neck deformities, ulnar deviation, boutonniere deformities, and z-shaped thumbs), can be seen in SLE patients.³ When patients present with articular and constitutional symptoms but lack other typical manifestations of SLE, such as skin rash, appropriate measures—for example, arthrocentesis—should be taken to evaluate for infection.¹¹

Cutaneous manifestations are the second most common feature at disease onset, with photosensitivity and malar rash being the most prevalent.¹⁰ Nearly all patients experience skin lesions at some point during the disease course.¹ Diagnostic, or lupus-specific, lesions can be classified into three types: acute, subacute, and chronic.

Acute cutaneous lupus erythematosus (ACLE) is almost always associated with SLE, while subacute cutaneous lupus erythematosus (SCLE) is seen in about 50% of SLE patients.¹² ACLE is usually precipitated by sunlight exposure and includes the classic erythematous, macular, “butterfly” rash located on the malar regions of the face, which may remain for days to weeks.^2,12 Diffuse or discoid alopecia also may develop in ACLE, along with oral ulcers arising in purpuric necrotic lesions on the palate, buccal mucosa, or gums. Generalized erythematous, papular, or urticarial lesions may affect the face, arms, dorsa of the hands, or “V” of the neck.¹²

SCLE tends to be sudden in onset, with annular lesions or psoriasiform plaques on the upper trunk, arms, and dorsa of the hands that often coalesce into polycyclic lesions.¹² These subacute rashes are often associated with anti-SSA/Ro antibodies.

Chronic cutaneous lupus erythematosus is usually characterized by skin disease alone.¹² Discoid lupus is the most common type, with circular scaly plaques with erythematous, hyperpigmented rims and atrophic hypopigmented centers that leave scars.^2,12 It is commonly seen on the face, neck, and scalp.

During the course of SLE, mucous membrane involvement—typically painless oral or nasal ulcers—occurs in 25% to 45% of patients.² Oral lesions are most commonly found on the hard palate and buccal mucosa.^3,12

Lupus nephritis, perhaps the most dangerous manifestation of SLE, conveys high risk for organ failure, a higher mortality rate compared to patients without renal involvement, and lower life expectancy.^8,11 Up to 60% of Asians, African Americans, and Hispanics develop renal disease during the course of their illness.⁸ The dominant feature is proteinuria, typically accompanied by microscopic hematuria.²

Neuropsychiatric SLE (NPSLE) is a clinical manifestation that is poorly understood.¹³ An estimated 28% to 40% of NPSLE manifestations develop prior to or synchronous with the diagnosis, and 63% arise within the first year of diagnosis.¹³ Mild cognitive impairment is the most common manifestation,reported in up to 20% to 30% of SLE patients.^2,13 Seizures and psychosis are reported in 7% to 10% of SLE patients, and psychosis—characterized by hallucinations or delusions—in 3.5%.²

Cardiac findings are common among SLE patients, with an estimated prevalence of 50%, but are rarely the presenting manifestation.¹⁴ Pericarditis with effusion is the most common cardiac manifestation, occurring in 25% of SLE patients.² Advancing atherosclerosis due to chronic inflammation becomes a major cause of mortality in the later years for SLE patients.¹ Compared to the general population, the incidence of myocardial infarction in SLE patients is increased fivefold.¹ Pleuritis is the most common pleuropulmonary manifestation in SLE.¹¹ Pleuritic chest pain with or without a pleural effusion occurs in 45% to 60% of SLE patients.²

Continue for differential diagnoses >>

DIFFERENTIAL DIAGNOSES
The differential diagnosis for SLE includes rheumatoid arthritis (RA), septic arthritis, mixed connective tissue disease (MCTD), Sjögren syndrome, systemic sclerosis (SSc), polymyositis (PM), fibromyalgia, and drug-induced lupus. Symmetrical, inflammatory, polyarticular arthritis with a predilection for the wrist and MCP joints occurs in both RA and SLE.^1,15 And, because the initial articular features of SLE are symmetric arthralgias, patients with SLE are frequently misdiagnosed with RA. The absence of destructive bony erosions on radiographs and large joint effusions, along with the joint reducibility in SLE, can help distinguish it from RA.¹⁶ Asymmetric arthritis, which can be a presenting feature in both RA and SLE, is more commonly seen in the latter. ANA and rheumatoid factor test results can be positive in both disorders, but antibodies to anti-cyclic citrullinated peptides, with a 95% specificity for RA but absent in SLE, distinguish RA from SLE.^1,16

Patients with MCTD display an array of overlapping features of SLE, PM, and SSc, making the diagnosis difficult.¹⁷ Although MCTD can evolve into other connective tissue diseases, such as SLE, it is nonetheless considered a distinct entity.¹⁷ High titers of anti-U1 ribonucleoprotein (anti-U1RNP) antibodies are indicative of MCTD. Anti-U1RNP is rarely detected in SLE and almost never seen in other rheumatic diseases.¹⁷ Typical manifestations of MCTD are Raynaud phenomenon, swollen fingers (referred to as “sausage digits”), and protuberant polyarthritis.¹⁷

Anti-SSA/Ro and anti-SSB/La antibodies, although detectable in SLE patients, are more commonly associated with Sjögren syndrome. In addition, patients with Sjögren syndrome frequently demonstrate signs of keratoconjunctivitis sicca and xerostomia.¹⁶

The clinical features of fibromyalgia include diffuse musculoskeletal pain that readily mimics SLE arthralgias. The 2011 modification of the 2010 American College of Rheumatology (ACR) preliminary diagnostic criteria for fibromyalgia serves as a reliable tool for diagnosing patients with nonspecific, diffuse pain.¹⁸ This 2011 modification includes 19 pain locations and the six self-reported symptoms: fatigue, impaired sleep, headaches, depression, poor cognition, and abdominal pain.¹⁸

SSc, also known as scleroderma, is characterized by skin thickening and/or CREST syndrome (calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia). The presence of anti-Scl-70 and anti-centromere antibodies are noted as well.¹⁶

Finally, a suspicion of SLE mandates an evaluation for drug-induced lupus by assessing the patient’s exposure to culprit medications, such as hydralazine, procainamide, isoniazid, methyldopa, chlorpromazine, quinidine, minocycline, and tumor necrosis factor inhibitiors.^1,11 Four key features point toward drug-induced lupus:
• The female-to-male ratio is nearly equivalent.
• Nephritis and central nervous system (CNS) manifestations are not commonly present.
• Anti–double-stranded DNA (anti-dsDNA) antibodies and hypocomplementemia are absent.
• The clinical features and laboratory abnormalities return to baseline once the offending agent is removed.¹

Anti-histone antibodies are present in approximately 75% of patients with drug-induced lupus but can also be seen in patients with SLE.¹¹

Continue for laboratory work-up >>

LABORATORY WORK-UP
Laboratory abnormalities associated with SLE include anemia, leukopenia, lymphopenia, thrombocytopenia, hypocomplementemia, and proteinuria. A typical work-up includes a routine complete blood count (CBC) with differential, serum creatinine, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), urinalysis with microscopy, and serologic ANA titer.^1,16,19 A CBC with differential may reveal hematologic abnormalities, such as anemia of chronic disease (most commonly) or autoimmune hemolytic anemia, as well as leukopenia and thrombocytopenia due to circulating autoantibodies.³ An elevated ESR and CRP indicate the severity of the systemic inflammation and/or infection. Urinalysis is effective for detecting lupus with renal diseaseand may reveal proteinuria due to renal dysfunction.²

A positive ANA titer indicates widespread activation of the immune system targeted against nuclear and cytoplasmic subparticles. The vast majority of patients with SLE will develop a positive ANA with a high titer at some point during the course of their disease.¹⁶ The ANA is highly sensitive for SLE (93% to 95%) but lacks specificity (57%).²⁰The most common tests for ANA are enzyme-linked immunosorbent assay (ELISA) and indirect immunofluorescence assay (IFA). ELISA is more sensitive in detecting ANA, while IFA is the gold standard due to its high specificity.²¹ Some laboratories may use immunoassay as a screening tool for ANA and then use IFA to confirm positive or equivocal results.²¹ Positive ANA results can be seen in patients with other rheumatologic diseases and in up to 15% of all healthy persons, but with low or borderline titers.²² For these reasons, ANA testing alone is a poor predictor of SLE.

When either the ANA test results are positive or are negative but a strong clinical suspicion for SLE remains, clinicians should order tests for antibodies to extractable nuclear antigens (ENA panel; see Table 2).^3,16 Anti-dsDNA and anti-Smith (anti-Sm) antibodies are both specific for SLE, and levels of anti-dsDNA reflect disease activity in many patients.^1,19 In contrast, anti-dsDNA antibodies are found in fewer than 0.5% of healthy individuals and patients with other autoimmune conditions.¹⁹ Among patients with high levels of anti-dsDNA antibodies and clinically inactive disease, 80% will have active disease within five years after elevated antibodies are detected.¹⁹

Autoantibodies, including ANA, anti-SSA/Ro, anti-SSB/La, and antiphospholipid antibodies, are usually detectable for many years prior to the onset of symptomatic SLE, while others, such as anti-Sm and anti-U1RNP, appear just months before the diagnosis.²³ Patients with positive ANA results who do not meet criteria for SLE are still at risk for lupus and other autoimmune diseases, because complex autoimmune changes occur years before the diagnosis of SLE.²³ These patients should be followed closely.

Continue for making the diagnosis >>

MAKING THE DIAGNOSIS
Diagnosing SLE may prove problematic because of the remarkable variety of relapsing and remitting clinical features, mimicry of similar conditions, and lack of a simple, definitive diagnostic test. Initial diagnosis of SLE depends on the disease manifestation, published criteria, and exclusion of alternative diagnoses. Confirmation requires careful clinical assessment, based on a thorough medical history and complete physical examination, along with specific laboratory testing.^1,16 Biopsy results indicative of lupus nephritis in the presence of ANA or anti-dsDNA antibodies also confirm the diagnosis of SLE.²⁴

Although created for research purposes, ACR classification criteria for SLE, published in 1982 and revised in 1997, have been used for more than 30 years to diagnose lupus (see www.rheumatology.org/Practice-Quality/Clinical-Support/Criteria/ACR-Endorsed-Criteria). In 2012, the Systemic Lupus International Collaborating Clinics (SLICC) group revised the 1997 ACR classification criteria to address major flaws and to improve clinical precision.²⁴ According to SLICC, a definitive diagnosis requires the presence of at least four of 17 criteria, including at least one clinical and one immunologic criterion.²⁴ The SLICC revisions have resulted in fewer misclassifications and provide greater sensitivity but lower specificity in the identification of SLE in comparison to the 1997 ACR criteria.²⁴ To date, no one set of criteria allows for early diagnosis of SLE.

MANAGEMENT OPTIONS
Treatment must be tailored to the patient’s specific organ system involvement. Effective therapy hinges on controlling symptoms and reducing underlying inflammation.²⁵ Four classes of drugs are used: NSAIDs, antimalarial drugs, corticosteroids, and cytotoxic drugs (see Table 3). Most patients benefit from NSAIDs to alleviate minor arthritis and arthralgia symptoms, but the risk for peptic ulcers and nephrotoxicity should be addressed; this may require the concomitant use of gastroprotective agents such as proton pump inhibitors.²⁵ Antimalarials are effective for musculoskeletal symptoms that do not respond to NSAIDs and for cutaneous rashes.¹ The current antimalarial drug of choice is hydroxychloroquine (200 to 400 mg/d po), which has been shown to control SLE manifestations by reducing and preventing disease flares.^1,11,26 It is well tolerated and can be used for the duration of treatment.^11,26 Patients should be informed that this drug’s onset of action is one month.²⁶ In rare cases, this drug can cause retinal toxicity; therefore, SLE patients receiving hydroxychloroquine should be referred to an ophthalmologist for a baseline eye examination and yearly assessments to monitor for this rare adverse effect.^25,26

Low-dose corticosteroids, such as oral prednisolone or methylprednisolone, are employed when NSAIDs and antimalarials fail to control arthritis or cutaneous SLE eruptions.²⁵ Major systemic manifestations that occur during a disease flare—such as severe arthritis, hemolytic anemia, glomerulonephritis, alveolar hemorrhage, pericarditis, pleurisy, or CNS involvement—necessitate high-dose IV corticosteroids in conjunction with immunosuppressive agents.^1,11,25 These high-dose glucocorticoids should be gradually withdrawn as soon as remission is achieved.¹¹ Long-term suppressive therapy with oral corticosteroids in addition to other agents is often needed to preserve organ function.²⁵

The major adverse effects of long-term glucocorticoids are osteoporosis, hypertension, hyperlipidemia, glucose intolerance, and susceptibility to infection. It is recommended that patients taking prednisolone 7.5 mg/d or more undergo a bone mineral density scan every two years.²⁵ Those with T scores below –2.5 should be prescribed bisphosphonates.²⁵

Immunosuppressive agents, such as cyclophosphamide, mycophenolate mofetil, and azathioprine, are used in conjunction with corticosteroids or when syndromes are resistant to corticosteroids.¹ Collaboration between primary care, rheumatology, and nephrology is advisable for patients requiring immunosuppressive or disease-modifying pharmacologic agents.

Two new treatments for SLE are the immunologic agents belimumab and rituximab.⁷ Belimumab, a monoclonal human antibody, is the first medication in the past 50 years that has been approved by the FDA for antibody-positive SLE patients with active lupus unresponsive to standard treatment.^7,27 Rituximab is an anti-CD20 monoclonal antibody, approved by the FDA for non-Hodgkin lymphoma, chronic lymphocytic leukemia, and RA, and is now considered an option for SLE refractory to conventional treatment regimens.^7,27 The efficacy of belimumab and rituximab, and the spectrum of indications for their use, are still under study, but these new therapeutic agents hold promise for the treatment of patients with refractory SLE.

Continue for helping patients live with SLE >>

HELPING PATIENTs LIVE WITH SLE
Patients with SLE have a higher mortality rate, as well as a lower quality of life, compared to the general population.²⁸ The major contributors to a decreased quality of life are fatigue, mood disturbances (eg, depression), and chronic pain.²⁸ Practitioners should advise SLE patients to participate in support groups and psychotherapy to alleviate the anxiety and depression associated with this chronic disease.

For patients with long-standing disease, accelerated atherosclerotic cardiovascular disease adds to morbidity and mortality. For this reason, obesity, hypertension, hyperlipidemia, and smoking are targets for intervention. Lifestyle modifications—such as exercise, smoking cessation, a healthy diet with low saturated fat, stress avoidance, and adequate rest—are recommended.²⁶

Avoiding overexposure to sunlight, by using sunscreen with an SPF of at least 30 and wearing sun-protective clothing, is essential for management of cutaneous lupus.^25,26 Yearly influenza vaccination is appropriate, as are other immunizations (eg, pneumococcal vaccine).²⁶

Advise women of childbearing age with SLE that lupus flares result in a high risk for miscarriage. All women should undergo yearly cervical cancer screening.²⁶

Patients taking long-term glucocorticoids should adopt bone-protective behaviors, including quitting smoking, limiting alcohol intake, partaking in weight-bearing exercise, and consuming dietary calcium and vitamin D.²⁵ Patients taking these drugs should avoid live virus vaccines. Those on immunosuppressive therapy should be warned about the hazardous adverse effects of glucocorticoids.

MONITORING AND FOLLOW-UP
Collaborative efforts between primary care providers and several types of specialty providers can facilitate coordinated interventions in the long-term management of lupus. Rheumatologists are experts in making therapeutic decisions for SLE.

Patients being treated for SLE require routine monitoring to assess disease activity and detect flares. The European League Against Rheumatism (EULAR) guidelines recommend that monitoring include assessment for new clinical manifestations, routine laboratory tests, and immunologic assays, chiefly anti-dsDNA, anti-Sm, and serum complement levels, coupled with one of the validated global activity indices, such as the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI).²⁹

A routine office visit with a physical examination and laboratory testing for CBC with differential, basic metabolic panel, and urinalysis every three months is recommended for patients with stable disease; patients with uncontrolled SLE may require weekly visits.^11,29 Patients taking immunosuppressive drugs should be provided with adverse-effect profiles alerting them to toxicity symptoms and require frequent laboratory monitoring for potential toxicity.¹¹

CONCLUSION
Advances in immunologically targeted serologic tests have shed more light on the underlying pathogenesis of SLE, which in turn has led to improvements in disease detection and monitoring of complications, as well as advances in therapy. Although SLE cannot be cured, emerging therapies targeting different mechanisms of SLE offer hope for patients diagnosed with this complex disease.

CE/CME No: CR-1608

PROGRAM OVERVIEW
Earn credit by reading this article and successfully completing the posttest and evaluation. Successful completion is defined as a cumulative score of at least 70% correct.

EDUCATIONAL OBJECTIVES
• Describe the pathophysiology and explain the various clinical manifestations of systemic lupus erythematosus (SLE).
• Define the differential diagnosis for SLE.
• List the elements of the laboratory work-up used in the diagnosis of lupus.
• Describe the therapeutic options for patients with SLE.

FACULTY

Michael Felz is an Assistant Professor at Augusta University (formerly Georgia Regents University) in Augusta, Georgia. Mary Bailey Wickham is a PA student in her final year at Augusta University.
The authors have no financial relationships to disclose.

ACCREDITATION STATEMENT

This program has been reviewed and is approved for a maximum of 1.0 hour of American Academy of Physician Assistants (AAPA) Category 1 CME credit by the Physician Assistant Review Panel. [NPs: Both ANCC and the AANP Certification Program recognize AAPA as an approved provider of Category 1 credit.] Approval is valid for one year from the issue date of August 2016.

Article begins on next page >>

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that often goes undiagnosed initially. Timely detection of SLE is important, because prompt treatment can prevent its many major complications—notably, end organ damage. Here’s how to distinguish SLE from other illnesses with similar presentations and how to recognize the complications of undiagnosed SLE, which can progress rapidly and fatally.

Systemic lupus erythematosus (SLE) is a chronic inflammatory disorder that can involve multiple organ systems. The presence of antinuclear antibodies (ANA) is a common marker for this disease. In autoimmune diseases such as SLE, the immune system attacks the cells of healthy tissues throughout the body. Genetic, hormonal, and environmental factors (eg, ultraviolet light, infectious viruses, and even use of certain medications) have been implicated in the pathogenesis.^1-3

It is estimated that 1.5 million people in the United States and up to 5 million people worldwide have SLE.⁴ It is nine to 10 times more prevalent in women—especially those of reproductive age—than menand occurs more frequently in African-American, Hispanic, and Asian women than in non-Hispanic Caucasian women.^1,2,4-6 Siblings of SLE patients are 30 times more likely to develop the disease, compared to individuals without an affected relative.² Increased mortality in persons with SLE is attributed to accelerated atherosclerosis, infection, malignancy, and target organ damage, particularly end-stage renal disease.³ Women ages 33 to 45 with SLE are at increased risk (50x greater) for myocardial infarction due to premature atherosclerosis than age-matched women in the general population.⁷ The life expectancy of SLE ­patients with renal damage is 23.7 years less than that of the general population.⁸

Increased awareness of SLE has led to drastic improvements in associated mortality over the past five decades. The survival rate in the 1950s was 50% at 2 years, while current rates are about 95% at 5 years and about 90% at 10 years.^3,9 These improvements likely reflect earlier diagnosis and treatment on the part of well-informed clinicians, as well as more effective treatment.

SLE MANIFESTATIONS
SLE can affect any organ in the body with a broad spectrum of clinical manifestations, making it a devastatingly deceptive disease. Disease severity may vary by age, by organ involvement, and over time. Onset may be gradual and mild or rapidly progressive with severe organ involvement. Constitutional manifestations such as fatigue, weight loss, anorexia, and low-grade fever often serve as initial complaints. However, these features are common to a variety of infectious and inflammatory conditions, making early SLE easily overlooked and frequently mis­diagnosed. ²

A mix of manifestations involving the joints, skin, mouth, kidneys, lungs, heart, and nervous system offers clues to the diagnosis of SLE (see Table 1). Arthritis is the most common symptom, occurring in 85% to 90% of SLE cases.^1,10 It is typically nonerosive, inflammatory, symmetric or asymmetric, and polyarticular (involving five or more joints)and may be accompanied by constitutional symptoms.^1,2,11 The joints most commonly affected are the proximal interphalangeals, metacarpophalangeals (MCP), knees, and wrists.² Morning stiffness is a common complaint.^1,11 Jaccoud arthropathy, which is characterized by reducible, nonerosive joint subluxations (eg, swan neck deformities, ulnar deviation, boutonniere deformities, and z-shaped thumbs), can be seen in SLE patients.³ When patients present with articular and constitutional symptoms but lack other typical manifestations of SLE, such as skin rash, appropriate measures—for example, arthrocentesis—should be taken to evaluate for infection.¹¹

Cutaneous manifestations are the second most common feature at disease onset, with photosensitivity and malar rash being the most prevalent.¹⁰ Nearly all patients experience skin lesions at some point during the disease course.¹ Diagnostic, or lupus-specific, lesions can be classified into three types: acute, subacute, and chronic.

Acute cutaneous lupus erythematosus (ACLE) is almost always associated with SLE, while subacute cutaneous lupus erythematosus (SCLE) is seen in about 50% of SLE patients.¹² ACLE is usually precipitated by sunlight exposure and includes the classic erythematous, macular, “butterfly” rash located on the malar regions of the face, which may remain for days to weeks.^2,12 Diffuse or discoid alopecia also may develop in ACLE, along with oral ulcers arising in purpuric necrotic lesions on the palate, buccal mucosa, or gums. Generalized erythematous, papular, or urticarial lesions may affect the face, arms, dorsa of the hands, or “V” of the neck.¹²

SCLE tends to be sudden in onset, with annular lesions or psoriasiform plaques on the upper trunk, arms, and dorsa of the hands that often coalesce into polycyclic lesions.¹² These subacute rashes are often associated with anti-SSA/Ro antibodies.

Chronic cutaneous lupus erythematosus is usually characterized by skin disease alone.¹² Discoid lupus is the most common type, with circular scaly plaques with erythematous, hyperpigmented rims and atrophic hypopigmented centers that leave scars.^2,12 It is commonly seen on the face, neck, and scalp.

During the course of SLE, mucous membrane involvement—typically painless oral or nasal ulcers—occurs in 25% to 45% of patients.² Oral lesions are most commonly found on the hard palate and buccal mucosa.^3,12

Lupus nephritis, perhaps the most dangerous manifestation of SLE, conveys high risk for organ failure, a higher mortality rate compared to patients without renal involvement, and lower life expectancy.^8,11 Up to 60% of Asians, African Americans, and Hispanics develop renal disease during the course of their illness.⁸ The dominant feature is proteinuria, typically accompanied by microscopic hematuria.²

Neuropsychiatric SLE (NPSLE) is a clinical manifestation that is poorly understood.¹³ An estimated 28% to 40% of NPSLE manifestations develop prior to or synchronous with the diagnosis, and 63% arise within the first year of diagnosis.¹³ Mild cognitive impairment is the most common manifestation,reported in up to 20% to 30% of SLE patients.^2,13 Seizures and psychosis are reported in 7% to 10% of SLE patients, and psychosis—characterized by hallucinations or delusions—in 3.5%.²

Cardiac findings are common among SLE patients, with an estimated prevalence of 50%, but are rarely the presenting manifestation.¹⁴ Pericarditis with effusion is the most common cardiac manifestation, occurring in 25% of SLE patients.² Advancing atherosclerosis due to chronic inflammation becomes a major cause of mortality in the later years for SLE patients.¹ Compared to the general population, the incidence of myocardial infarction in SLE patients is increased fivefold.¹ Pleuritis is the most common pleuropulmonary manifestation in SLE.¹¹ Pleuritic chest pain with or without a pleural effusion occurs in 45% to 60% of SLE patients.²

Continue for differential diagnoses >>

DIFFERENTIAL DIAGNOSES
The differential diagnosis for SLE includes rheumatoid arthritis (RA), septic arthritis, mixed connective tissue disease (MCTD), Sjögren syndrome, systemic sclerosis (SSc), polymyositis (PM), fibromyalgia, and drug-induced lupus. Symmetrical, inflammatory, polyarticular arthritis with a predilection for the wrist and MCP joints occurs in both RA and SLE.^1,15 And, because the initial articular features of SLE are symmetric arthralgias, patients with SLE are frequently misdiagnosed with RA. The absence of destructive bony erosions on radiographs and large joint effusions, along with the joint reducibility in SLE, can help distinguish it from RA.¹⁶ Asymmetric arthritis, which can be a presenting feature in both RA and SLE, is more commonly seen in the latter. ANA and rheumatoid factor test results can be positive in both disorders, but antibodies to anti-cyclic citrullinated peptides, with a 95% specificity for RA but absent in SLE, distinguish RA from SLE.^1,16

Patients with MCTD display an array of overlapping features of SLE, PM, and SSc, making the diagnosis difficult.¹⁷ Although MCTD can evolve into other connective tissue diseases, such as SLE, it is nonetheless considered a distinct entity.¹⁷ High titers of anti-U1 ribonucleoprotein (anti-U1RNP) antibodies are indicative of MCTD. Anti-U1RNP is rarely detected in SLE and almost never seen in other rheumatic diseases.¹⁷ Typical manifestations of MCTD are Raynaud phenomenon, swollen fingers (referred to as “sausage digits”), and protuberant polyarthritis.¹⁷

Anti-SSA/Ro and anti-SSB/La antibodies, although detectable in SLE patients, are more commonly associated with Sjögren syndrome. In addition, patients with Sjögren syndrome frequently demonstrate signs of keratoconjunctivitis sicca and xerostomia.¹⁶

The clinical features of fibromyalgia include diffuse musculoskeletal pain that readily mimics SLE arthralgias. The 2011 modification of the 2010 American College of Rheumatology (ACR) preliminary diagnostic criteria for fibromyalgia serves as a reliable tool for diagnosing patients with nonspecific, diffuse pain.¹⁸ This 2011 modification includes 19 pain locations and the six self-reported symptoms: fatigue, impaired sleep, headaches, depression, poor cognition, and abdominal pain.¹⁸

SSc, also known as scleroderma, is characterized by skin thickening and/or CREST syndrome (calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia). The presence of anti-Scl-70 and anti-centromere antibodies are noted as well.¹⁶

Finally, a suspicion of SLE mandates an evaluation for drug-induced lupus by assessing the patient’s exposure to culprit medications, such as hydralazine, procainamide, isoniazid, methyldopa, chlorpromazine, quinidine, minocycline, and tumor necrosis factor inhibitiors.^1,11 Four key features point toward drug-induced lupus:
• The female-to-male ratio is nearly equivalent.
• Nephritis and central nervous system (CNS) manifestations are not commonly present.
• Anti–double-stranded DNA (anti-dsDNA) antibodies and hypocomplementemia are absent.
• The clinical features and laboratory abnormalities return to baseline once the offending agent is removed.¹

Anti-histone antibodies are present in approximately 75% of patients with drug-induced lupus but can also be seen in patients with SLE.¹¹

Continue for laboratory work-up >>

LABORATORY WORK-UP
Laboratory abnormalities associated with SLE include anemia, leukopenia, lymphopenia, thrombocytopenia, hypocomplementemia, and proteinuria. A typical work-up includes a routine complete blood count (CBC) with differential, serum creatinine, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), urinalysis with microscopy, and serologic ANA titer.^1,16,19 A CBC with differential may reveal hematologic abnormalities, such as anemia of chronic disease (most commonly) or autoimmune hemolytic anemia, as well as leukopenia and thrombocytopenia due to circulating autoantibodies.³ An elevated ESR and CRP indicate the severity of the systemic inflammation and/or infection. Urinalysis is effective for detecting lupus with renal diseaseand may reveal proteinuria due to renal dysfunction.²

A positive ANA titer indicates widespread activation of the immune system targeted against nuclear and cytoplasmic subparticles. The vast majority of patients with SLE will develop a positive ANA with a high titer at some point during the course of their disease.¹⁶ The ANA is highly sensitive for SLE (93% to 95%) but lacks specificity (57%).²⁰The most common tests for ANA are enzyme-linked immunosorbent assay (ELISA) and indirect immunofluorescence assay (IFA). ELISA is more sensitive in detecting ANA, while IFA is the gold standard due to its high specificity.²¹ Some laboratories may use immunoassay as a screening tool for ANA and then use IFA to confirm positive or equivocal results.²¹ Positive ANA results can be seen in patients with other rheumatologic diseases and in up to 15% of all healthy persons, but with low or borderline titers.²² For these reasons, ANA testing alone is a poor predictor of SLE.

When either the ANA test results are positive or are negative but a strong clinical suspicion for SLE remains, clinicians should order tests for antibodies to extractable nuclear antigens (ENA panel; see Table 2).^3,16 Anti-dsDNA and anti-Smith (anti-Sm) antibodies are both specific for SLE, and levels of anti-dsDNA reflect disease activity in many patients.^1,19 In contrast, anti-dsDNA antibodies are found in fewer than 0.5% of healthy individuals and patients with other autoimmune conditions.¹⁹ Among patients with high levels of anti-dsDNA antibodies and clinically inactive disease, 80% will have active disease within five years after elevated antibodies are detected.¹⁹

Autoantibodies, including ANA, anti-SSA/Ro, anti-SSB/La, and antiphospholipid antibodies, are usually detectable for many years prior to the onset of symptomatic SLE, while others, such as anti-Sm and anti-U1RNP, appear just months before the diagnosis.²³ Patients with positive ANA results who do not meet criteria for SLE are still at risk for lupus and other autoimmune diseases, because complex autoimmune changes occur years before the diagnosis of SLE.²³ These patients should be followed closely.

Continue for making the diagnosis >>

MAKING THE DIAGNOSIS
Diagnosing SLE may prove problematic because of the remarkable variety of relapsing and remitting clinical features, mimicry of similar conditions, and lack of a simple, definitive diagnostic test. Initial diagnosis of SLE depends on the disease manifestation, published criteria, and exclusion of alternative diagnoses. Confirmation requires careful clinical assessment, based on a thorough medical history and complete physical examination, along with specific laboratory testing.^1,16 Biopsy results indicative of lupus nephritis in the presence of ANA or anti-dsDNA antibodies also confirm the diagnosis of SLE.²⁴

Although created for research purposes, ACR classification criteria for SLE, published in 1982 and revised in 1997, have been used for more than 30 years to diagnose lupus (see www.rheumatology.org/Practice-Quality/Clinical-Support/Criteria/ACR-Endorsed-Criteria). In 2012, the Systemic Lupus International Collaborating Clinics (SLICC) group revised the 1997 ACR classification criteria to address major flaws and to improve clinical precision.²⁴ According to SLICC, a definitive diagnosis requires the presence of at least four of 17 criteria, including at least one clinical and one immunologic criterion.²⁴ The SLICC revisions have resulted in fewer misclassifications and provide greater sensitivity but lower specificity in the identification of SLE in comparison to the 1997 ACR criteria.²⁴ To date, no one set of criteria allows for early diagnosis of SLE.

MANAGEMENT OPTIONS
Treatment must be tailored to the patient’s specific organ system involvement. Effective therapy hinges on controlling symptoms and reducing underlying inflammation.²⁵ Four classes of drugs are used: NSAIDs, antimalarial drugs, corticosteroids, and cytotoxic drugs (see Table 3). Most patients benefit from NSAIDs to alleviate minor arthritis and arthralgia symptoms, but the risk for peptic ulcers and nephrotoxicity should be addressed; this may require the concomitant use of gastroprotective agents such as proton pump inhibitors.²⁵ Antimalarials are effective for musculoskeletal symptoms that do not respond to NSAIDs and for cutaneous rashes.¹ The current antimalarial drug of choice is hydroxychloroquine (200 to 400 mg/d po), which has been shown to control SLE manifestations by reducing and preventing disease flares.^1,11,26 It is well tolerated and can be used for the duration of treatment.^11,26 Patients should be informed that this drug’s onset of action is one month.²⁶ In rare cases, this drug can cause retinal toxicity; therefore, SLE patients receiving hydroxychloroquine should be referred to an ophthalmologist for a baseline eye examination and yearly assessments to monitor for this rare adverse effect.^25,26

Low-dose corticosteroids, such as oral prednisolone or methylprednisolone, are employed when NSAIDs and antimalarials fail to control arthritis or cutaneous SLE eruptions.²⁵ Major systemic manifestations that occur during a disease flare—such as severe arthritis, hemolytic anemia, glomerulonephritis, alveolar hemorrhage, pericarditis, pleurisy, or CNS involvement—necessitate high-dose IV corticosteroids in conjunction with immunosuppressive agents.^1,11,25 These high-dose glucocorticoids should be gradually withdrawn as soon as remission is achieved.¹¹ Long-term suppressive therapy with oral corticosteroids in addition to other agents is often needed to preserve organ function.²⁵

The major adverse effects of long-term glucocorticoids are osteoporosis, hypertension, hyperlipidemia, glucose intolerance, and susceptibility to infection. It is recommended that patients taking prednisolone 7.5 mg/d or more undergo a bone mineral density scan every two years.²⁵ Those with T scores below –2.5 should be prescribed bisphosphonates.²⁵

Immunosuppressive agents, such as cyclophosphamide, mycophenolate mofetil, and azathioprine, are used in conjunction with corticosteroids or when syndromes are resistant to corticosteroids.¹ Collaboration between primary care, rheumatology, and nephrology is advisable for patients requiring immunosuppressive or disease-modifying pharmacologic agents.

Two new treatments for SLE are the immunologic agents belimumab and rituximab.⁷ Belimumab, a monoclonal human antibody, is the first medication in the past 50 years that has been approved by the FDA for antibody-positive SLE patients with active lupus unresponsive to standard treatment.^7,27 Rituximab is an anti-CD20 monoclonal antibody, approved by the FDA for non-Hodgkin lymphoma, chronic lymphocytic leukemia, and RA, and is now considered an option for SLE refractory to conventional treatment regimens.^7,27 The efficacy of belimumab and rituximab, and the spectrum of indications for their use, are still under study, but these new therapeutic agents hold promise for the treatment of patients with refractory SLE.

Continue for helping patients live with SLE >>

HELPING PATIENTs LIVE WITH SLE
Patients with SLE have a higher mortality rate, as well as a lower quality of life, compared to the general population.²⁸ The major contributors to a decreased quality of life are fatigue, mood disturbances (eg, depression), and chronic pain.²⁸ Practitioners should advise SLE patients to participate in support groups and psychotherapy to alleviate the anxiety and depression associated with this chronic disease.

For patients with long-standing disease, accelerated atherosclerotic cardiovascular disease adds to morbidity and mortality. For this reason, obesity, hypertension, hyperlipidemia, and smoking are targets for intervention. Lifestyle modifications—such as exercise, smoking cessation, a healthy diet with low saturated fat, stress avoidance, and adequate rest—are recommended.²⁶

Avoiding overexposure to sunlight, by using sunscreen with an SPF of at least 30 and wearing sun-protective clothing, is essential for management of cutaneous lupus.^25,26 Yearly influenza vaccination is appropriate, as are other immunizations (eg, pneumococcal vaccine).²⁶

Advise women of childbearing age with SLE that lupus flares result in a high risk for miscarriage. All women should undergo yearly cervical cancer screening.²⁶

Patients taking long-term glucocorticoids should adopt bone-protective behaviors, including quitting smoking, limiting alcohol intake, partaking in weight-bearing exercise, and consuming dietary calcium and vitamin D.²⁵ Patients taking these drugs should avoid live virus vaccines. Those on immunosuppressive therapy should be warned about the hazardous adverse effects of glucocorticoids.

MONITORING AND FOLLOW-UP
Collaborative efforts between primary care providers and several types of specialty providers can facilitate coordinated interventions in the long-term management of lupus. Rheumatologists are experts in making therapeutic decisions for SLE.

Patients being treated for SLE require routine monitoring to assess disease activity and detect flares. The European League Against Rheumatism (EULAR) guidelines recommend that monitoring include assessment for new clinical manifestations, routine laboratory tests, and immunologic assays, chiefly anti-dsDNA, anti-Sm, and serum complement levels, coupled with one of the validated global activity indices, such as the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI).²⁹

A routine office visit with a physical examination and laboratory testing for CBC with differential, basic metabolic panel, and urinalysis every three months is recommended for patients with stable disease; patients with uncontrolled SLE may require weekly visits.^11,29 Patients taking immunosuppressive drugs should be provided with adverse-effect profiles alerting them to toxicity symptoms and require frequent laboratory monitoring for potential toxicity.¹¹

CONCLUSION
Advances in immunologically targeted serologic tests have shed more light on the underlying pathogenesis of SLE, which in turn has led to improvements in disease detection and monitoring of complications, as well as advances in therapy. Although SLE cannot be cured, emerging therapies targeting different mechanisms of SLE offer hope for patients diagnosed with this complex disease.

CE/CME No: CR-1608

PROGRAM OVERVIEW
Earn credit by reading this article and successfully completing the posttest and evaluation. Successful completion is defined as a cumulative score of at least 70% correct.

EDUCATIONAL OBJECTIVES
• Describe the pathophysiology and explain the various clinical manifestations of systemic lupus erythematosus (SLE).
• Define the differential diagnosis for SLE.
• List the elements of the laboratory work-up used in the diagnosis of lupus.
• Describe the therapeutic options for patients with SLE.

FACULTY

Michael Felz is an Assistant Professor at Augusta University (formerly Georgia Regents University) in Augusta, Georgia. Mary Bailey Wickham is a PA student in her final year at Augusta University.
The authors have no financial relationships to disclose.

ACCREDITATION STATEMENT

This program has been reviewed and is approved for a maximum of 1.0 hour of American Academy of Physician Assistants (AAPA) Category 1 CME credit by the Physician Assistant Review Panel. [NPs: Both ANCC and the AANP Certification Program recognize AAPA as an approved provider of Category 1 credit.] Approval is valid for one year from the issue date of August 2016.

Article begins on next page >>

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that often goes undiagnosed initially. Timely detection of SLE is important, because prompt treatment can prevent its many major complications—notably, end organ damage. Here’s how to distinguish SLE from other illnesses with similar presentations and how to recognize the complications of undiagnosed SLE, which can progress rapidly and fatally.

Systemic lupus erythematosus (SLE) is a chronic inflammatory disorder that can involve multiple organ systems. The presence of antinuclear antibodies (ANA) is a common marker for this disease. In autoimmune diseases such as SLE, the immune system attacks the cells of healthy tissues throughout the body. Genetic, hormonal, and environmental factors (eg, ultraviolet light, infectious viruses, and even use of certain medications) have been implicated in the pathogenesis.^1-3

It is estimated that 1.5 million people in the United States and up to 5 million people worldwide have SLE.⁴ It is nine to 10 times more prevalent in women—especially those of reproductive age—than menand occurs more frequently in African-American, Hispanic, and Asian women than in non-Hispanic Caucasian women.^1,2,4-6 Siblings of SLE patients are 30 times more likely to develop the disease, compared to individuals without an affected relative.² Increased mortality in persons with SLE is attributed to accelerated atherosclerosis, infection, malignancy, and target organ damage, particularly end-stage renal disease.³ Women ages 33 to 45 with SLE are at increased risk (50x greater) for myocardial infarction due to premature atherosclerosis than age-matched women in the general population.⁷ The life expectancy of SLE ­patients with renal damage is 23.7 years less than that of the general population.⁸

Increased awareness of SLE has led to drastic improvements in associated mortality over the past five decades. The survival rate in the 1950s was 50% at 2 years, while current rates are about 95% at 5 years and about 90% at 10 years.^3,9 These improvements likely reflect earlier diagnosis and treatment on the part of well-informed clinicians, as well as more effective treatment.

SLE MANIFESTATIONS
SLE can affect any organ in the body with a broad spectrum of clinical manifestations, making it a devastatingly deceptive disease. Disease severity may vary by age, by organ involvement, and over time. Onset may be gradual and mild or rapidly progressive with severe organ involvement. Constitutional manifestations such as fatigue, weight loss, anorexia, and low-grade fever often serve as initial complaints. However, these features are common to a variety of infectious and inflammatory conditions, making early SLE easily overlooked and frequently mis­diagnosed. ²

A mix of manifestations involving the joints, skin, mouth, kidneys, lungs, heart, and nervous system offers clues to the diagnosis of SLE (see Table 1). Arthritis is the most common symptom, occurring in 85% to 90% of SLE cases.^1,10 It is typically nonerosive, inflammatory, symmetric or asymmetric, and polyarticular (involving five or more joints)and may be accompanied by constitutional symptoms.^1,2,11 The joints most commonly affected are the proximal interphalangeals, metacarpophalangeals (MCP), knees, and wrists.² Morning stiffness is a common complaint.^1,11 Jaccoud arthropathy, which is characterized by reducible, nonerosive joint subluxations (eg, swan neck deformities, ulnar deviation, boutonniere deformities, and z-shaped thumbs), can be seen in SLE patients.³ When patients present with articular and constitutional symptoms but lack other typical manifestations of SLE, such as skin rash, appropriate measures—for example, arthrocentesis—should be taken to evaluate for infection.¹¹

Cutaneous manifestations are the second most common feature at disease onset, with photosensitivity and malar rash being the most prevalent.¹⁰ Nearly all patients experience skin lesions at some point during the disease course.¹ Diagnostic, or lupus-specific, lesions can be classified into three types: acute, subacute, and chronic.

Acute cutaneous lupus erythematosus (ACLE) is almost always associated with SLE, while subacute cutaneous lupus erythematosus (SCLE) is seen in about 50% of SLE patients.¹² ACLE is usually precipitated by sunlight exposure and includes the classic erythematous, macular, “butterfly” rash located on the malar regions of the face, which may remain for days to weeks.^2,12 Diffuse or discoid alopecia also may develop in ACLE, along with oral ulcers arising in purpuric necrotic lesions on the palate, buccal mucosa, or gums. Generalized erythematous, papular, or urticarial lesions may affect the face, arms, dorsa of the hands, or “V” of the neck.¹²

SCLE tends to be sudden in onset, with annular lesions or psoriasiform plaques on the upper trunk, arms, and dorsa of the hands that often coalesce into polycyclic lesions.¹² These subacute rashes are often associated with anti-SSA/Ro antibodies.

Chronic cutaneous lupus erythematosus is usually characterized by skin disease alone.¹² Discoid lupus is the most common type, with circular scaly plaques with erythematous, hyperpigmented rims and atrophic hypopigmented centers that leave scars.^2,12 It is commonly seen on the face, neck, and scalp.

During the course of SLE, mucous membrane involvement—typically painless oral or nasal ulcers—occurs in 25% to 45% of patients.² Oral lesions are most commonly found on the hard palate and buccal mucosa.^3,12

Lupus nephritis, perhaps the most dangerous manifestation of SLE, conveys high risk for organ failure, a higher mortality rate compared to patients without renal involvement, and lower life expectancy.^8,11 Up to 60% of Asians, African Americans, and Hispanics develop renal disease during the course of their illness.⁸ The dominant feature is proteinuria, typically accompanied by microscopic hematuria.²

Neuropsychiatric SLE (NPSLE) is a clinical manifestation that is poorly understood.¹³ An estimated 28% to 40% of NPSLE manifestations develop prior to or synchronous with the diagnosis, and 63% arise within the first year of diagnosis.¹³ Mild cognitive impairment is the most common manifestation,reported in up to 20% to 30% of SLE patients.^2,13 Seizures and psychosis are reported in 7% to 10% of SLE patients, and psychosis—characterized by hallucinations or delusions—in 3.5%.²

Cardiac findings are common among SLE patients, with an estimated prevalence of 50%, but are rarely the presenting manifestation.¹⁴ Pericarditis with effusion is the most common cardiac manifestation, occurring in 25% of SLE patients.² Advancing atherosclerosis due to chronic inflammation becomes a major cause of mortality in the later years for SLE patients.¹ Compared to the general population, the incidence of myocardial infarction in SLE patients is increased fivefold.¹ Pleuritis is the most common pleuropulmonary manifestation in SLE.¹¹ Pleuritic chest pain with or without a pleural effusion occurs in 45% to 60% of SLE patients.²

Continue for differential diagnoses >>

DIFFERENTIAL DIAGNOSES
The differential diagnosis for SLE includes rheumatoid arthritis (RA), septic arthritis, mixed connective tissue disease (MCTD), Sjögren syndrome, systemic sclerosis (SSc), polymyositis (PM), fibromyalgia, and drug-induced lupus. Symmetrical, inflammatory, polyarticular arthritis with a predilection for the wrist and MCP joints occurs in both RA and SLE.^1,15 And, because the initial articular features of SLE are symmetric arthralgias, patients with SLE are frequently misdiagnosed with RA. The absence of destructive bony erosions on radiographs and large joint effusions, along with the joint reducibility in SLE, can help distinguish it from RA.¹⁶ Asymmetric arthritis, which can be a presenting feature in both RA and SLE, is more commonly seen in the latter. ANA and rheumatoid factor test results can be positive in both disorders, but antibodies to anti-cyclic citrullinated peptides, with a 95% specificity for RA but absent in SLE, distinguish RA from SLE.^1,16

Patients with MCTD display an array of overlapping features of SLE, PM, and SSc, making the diagnosis difficult.¹⁷ Although MCTD can evolve into other connective tissue diseases, such as SLE, it is nonetheless considered a distinct entity.¹⁷ High titers of anti-U1 ribonucleoprotein (anti-U1RNP) antibodies are indicative of MCTD. Anti-U1RNP is rarely detected in SLE and almost never seen in other rheumatic diseases.¹⁷ Typical manifestations of MCTD are Raynaud phenomenon, swollen fingers (referred to as “sausage digits”), and protuberant polyarthritis.¹⁷

Anti-SSA/Ro and anti-SSB/La antibodies, although detectable in SLE patients, are more commonly associated with Sjögren syndrome. In addition, patients with Sjögren syndrome frequently demonstrate signs of keratoconjunctivitis sicca and xerostomia.¹⁶

The clinical features of fibromyalgia include diffuse musculoskeletal pain that readily mimics SLE arthralgias. The 2011 modification of the 2010 American College of Rheumatology (ACR) preliminary diagnostic criteria for fibromyalgia serves as a reliable tool for diagnosing patients with nonspecific, diffuse pain.¹⁸ This 2011 modification includes 19 pain locations and the six self-reported symptoms: fatigue, impaired sleep, headaches, depression, poor cognition, and abdominal pain.¹⁸

SSc, also known as scleroderma, is characterized by skin thickening and/or CREST syndrome (calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia). The presence of anti-Scl-70 and anti-centromere antibodies are noted as well.¹⁶

Finally, a suspicion of SLE mandates an evaluation for drug-induced lupus by assessing the patient’s exposure to culprit medications, such as hydralazine, procainamide, isoniazid, methyldopa, chlorpromazine, quinidine, minocycline, and tumor necrosis factor inhibitiors.^1,11 Four key features point toward drug-induced lupus:
• The female-to-male ratio is nearly equivalent.
• Nephritis and central nervous system (CNS) manifestations are not commonly present.
• Anti–double-stranded DNA (anti-dsDNA) antibodies and hypocomplementemia are absent.
• The clinical features and laboratory abnormalities return to baseline once the offending agent is removed.¹

Anti-histone antibodies are present in approximately 75% of patients with drug-induced lupus but can also be seen in patients with SLE.¹¹

Continue for laboratory work-up >>

LABORATORY WORK-UP
Laboratory abnormalities associated with SLE include anemia, leukopenia, lymphopenia, thrombocytopenia, hypocomplementemia, and proteinuria. A typical work-up includes a routine complete blood count (CBC) with differential, serum creatinine, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), urinalysis with microscopy, and serologic ANA titer.^1,16,19 A CBC with differential may reveal hematologic abnormalities, such as anemia of chronic disease (most commonly) or autoimmune hemolytic anemia, as well as leukopenia and thrombocytopenia due to circulating autoantibodies.³ An elevated ESR and CRP indicate the severity of the systemic inflammation and/or infection. Urinalysis is effective for detecting lupus with renal diseaseand may reveal proteinuria due to renal dysfunction.²

A positive ANA titer indicates widespread activation of the immune system targeted against nuclear and cytoplasmic subparticles. The vast majority of patients with SLE will develop a positive ANA with a high titer at some point during the course of their disease.¹⁶ The ANA is highly sensitive for SLE (93% to 95%) but lacks specificity (57%).²⁰The most common tests for ANA are enzyme-linked immunosorbent assay (ELISA) and indirect immunofluorescence assay (IFA). ELISA is more sensitive in detecting ANA, while IFA is the gold standard due to its high specificity.²¹ Some laboratories may use immunoassay as a screening tool for ANA and then use IFA to confirm positive or equivocal results.²¹ Positive ANA results can be seen in patients with other rheumatologic diseases and in up to 15% of all healthy persons, but with low or borderline titers.²² For these reasons, ANA testing alone is a poor predictor of SLE.

When either the ANA test results are positive or are negative but a strong clinical suspicion for SLE remains, clinicians should order tests for antibodies to extractable nuclear antigens (ENA panel; see Table 2).^3,16 Anti-dsDNA and anti-Smith (anti-Sm) antibodies are both specific for SLE, and levels of anti-dsDNA reflect disease activity in many patients.^1,19 In contrast, anti-dsDNA antibodies are found in fewer than 0.5% of healthy individuals and patients with other autoimmune conditions.¹⁹ Among patients with high levels of anti-dsDNA antibodies and clinically inactive disease, 80% will have active disease within five years after elevated antibodies are detected.¹⁹

Autoantibodies, including ANA, anti-SSA/Ro, anti-SSB/La, and antiphospholipid antibodies, are usually detectable for many years prior to the onset of symptomatic SLE, while others, such as anti-Sm and anti-U1RNP, appear just months before the diagnosis.²³ Patients with positive ANA results who do not meet criteria for SLE are still at risk for lupus and other autoimmune diseases, because complex autoimmune changes occur years before the diagnosis of SLE.²³ These patients should be followed closely.

Continue for making the diagnosis >>

MAKING THE DIAGNOSIS
Diagnosing SLE may prove problematic because of the remarkable variety of relapsing and remitting clinical features, mimicry of similar conditions, and lack of a simple, definitive diagnostic test. Initial diagnosis of SLE depends on the disease manifestation, published criteria, and exclusion of alternative diagnoses. Confirmation requires careful clinical assessment, based on a thorough medical history and complete physical examination, along with specific laboratory testing.^1,16 Biopsy results indicative of lupus nephritis in the presence of ANA or anti-dsDNA antibodies also confirm the diagnosis of SLE.²⁴

Although created for research purposes, ACR classification criteria for SLE, published in 1982 and revised in 1997, have been used for more than 30 years to diagnose lupus (see www.rheumatology.org/Practice-Quality/Clinical-Support/Criteria/ACR-Endorsed-Criteria). In 2012, the Systemic Lupus International Collaborating Clinics (SLICC) group revised the 1997 ACR classification criteria to address major flaws and to improve clinical precision.²⁴ According to SLICC, a definitive diagnosis requires the presence of at least four of 17 criteria, including at least one clinical and one immunologic criterion.²⁴ The SLICC revisions have resulted in fewer misclassifications and provide greater sensitivity but lower specificity in the identification of SLE in comparison to the 1997 ACR criteria.²⁴ To date, no one set of criteria allows for early diagnosis of SLE.

MANAGEMENT OPTIONS
Treatment must be tailored to the patient’s specific organ system involvement. Effective therapy hinges on controlling symptoms and reducing underlying inflammation.²⁵ Four classes of drugs are used: NSAIDs, antimalarial drugs, corticosteroids, and cytotoxic drugs (see Table 3). Most patients benefit from NSAIDs to alleviate minor arthritis and arthralgia symptoms, but the risk for peptic ulcers and nephrotoxicity should be addressed; this may require the concomitant use of gastroprotective agents such as proton pump inhibitors.²⁵ Antimalarials are effective for musculoskeletal symptoms that do not respond to NSAIDs and for cutaneous rashes.¹ The current antimalarial drug of choice is hydroxychloroquine (200 to 400 mg/d po), which has been shown to control SLE manifestations by reducing and preventing disease flares.^1,11,26 It is well tolerated and can be used for the duration of treatment.^11,26 Patients should be informed that this drug’s onset of action is one month.²⁶ In rare cases, this drug can cause retinal toxicity; therefore, SLE patients receiving hydroxychloroquine should be referred to an ophthalmologist for a baseline eye examination and yearly assessments to monitor for this rare adverse effect.^25,26

Low-dose corticosteroids, such as oral prednisolone or methylprednisolone, are employed when NSAIDs and antimalarials fail to control arthritis or cutaneous SLE eruptions.²⁵ Major systemic manifestations that occur during a disease flare—such as severe arthritis, hemolytic anemia, glomerulonephritis, alveolar hemorrhage, pericarditis, pleurisy, or CNS involvement—necessitate high-dose IV corticosteroids in conjunction with immunosuppressive agents.^1,11,25 These high-dose glucocorticoids should be gradually withdrawn as soon as remission is achieved.¹¹ Long-term suppressive therapy with oral corticosteroids in addition to other agents is often needed to preserve organ function.²⁵

The major adverse effects of long-term glucocorticoids are osteoporosis, hypertension, hyperlipidemia, glucose intolerance, and susceptibility to infection. It is recommended that patients taking prednisolone 7.5 mg/d or more undergo a bone mineral density scan every two years.²⁵ Those with T scores below –2.5 should be prescribed bisphosphonates.²⁵

Immunosuppressive agents, such as cyclophosphamide, mycophenolate mofetil, and azathioprine, are used in conjunction with corticosteroids or when syndromes are resistant to corticosteroids.¹ Collaboration between primary care, rheumatology, and nephrology is advisable for patients requiring immunosuppressive or disease-modifying pharmacologic agents.

Two new treatments for SLE are the immunologic agents belimumab and rituximab.⁷ Belimumab, a monoclonal human antibody, is the first medication in the past 50 years that has been approved by the FDA for antibody-positive SLE patients with active lupus unresponsive to standard treatment.^7,27 Rituximab is an anti-CD20 monoclonal antibody, approved by the FDA for non-Hodgkin lymphoma, chronic lymphocytic leukemia, and RA, and is now considered an option for SLE refractory to conventional treatment regimens.^7,27 The efficacy of belimumab and rituximab, and the spectrum of indications for their use, are still under study, but these new therapeutic agents hold promise for the treatment of patients with refractory SLE.

Continue for helping patients live with SLE >>

HELPING PATIENTs LIVE WITH SLE
Patients with SLE have a higher mortality rate, as well as a lower quality of life, compared to the general population.²⁸ The major contributors to a decreased quality of life are fatigue, mood disturbances (eg, depression), and chronic pain.²⁸ Practitioners should advise SLE patients to participate in support groups and psychotherapy to alleviate the anxiety and depression associated with this chronic disease.

For patients with long-standing disease, accelerated atherosclerotic cardiovascular disease adds to morbidity and mortality. For this reason, obesity, hypertension, hyperlipidemia, and smoking are targets for intervention. Lifestyle modifications—such as exercise, smoking cessation, a healthy diet with low saturated fat, stress avoidance, and adequate rest—are recommended.²⁶

Avoiding overexposure to sunlight, by using sunscreen with an SPF of at least 30 and wearing sun-protective clothing, is essential for management of cutaneous lupus.^25,26 Yearly influenza vaccination is appropriate, as are other immunizations (eg, pneumococcal vaccine).²⁶

Advise women of childbearing age with SLE that lupus flares result in a high risk for miscarriage. All women should undergo yearly cervical cancer screening.²⁶

Patients taking long-term glucocorticoids should adopt bone-protective behaviors, including quitting smoking, limiting alcohol intake, partaking in weight-bearing exercise, and consuming dietary calcium and vitamin D.²⁵ Patients taking these drugs should avoid live virus vaccines. Those on immunosuppressive therapy should be warned about the hazardous adverse effects of glucocorticoids.

MONITORING AND FOLLOW-UP
Collaborative efforts between primary care providers and several types of specialty providers can facilitate coordinated interventions in the long-term management of lupus. Rheumatologists are experts in making therapeutic decisions for SLE.

Patients being treated for SLE require routine monitoring to assess disease activity and detect flares. The European League Against Rheumatism (EULAR) guidelines recommend that monitoring include assessment for new clinical manifestations, routine laboratory tests, and immunologic assays, chiefly anti-dsDNA, anti-Sm, and serum complement levels, coupled with one of the validated global activity indices, such as the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI).²⁹

A routine office visit with a physical examination and laboratory testing for CBC with differential, basic metabolic panel, and urinalysis every three months is recommended for patients with stable disease; patients with uncontrolled SLE may require weekly visits.^11,29 Patients taking immunosuppressive drugs should be provided with adverse-effect profiles alerting them to toxicity symptoms and require frequent laboratory monitoring for potential toxicity.¹¹

CONCLUSION
Advances in immunologically targeted serologic tests have shed more light on the underlying pathogenesis of SLE, which in turn has led to improvements in disease detection and monitoring of complications, as well as advances in therapy. Although SLE cannot be cured, emerging therapies targeting different mechanisms of SLE offer hope for patients diagnosed with this complex disease.

Medicaid status did not significantly affect costs for children who were hospitalized because of asthma, according to Jeffrey H. Silber, MD, and his associates.

In a study of 17,739 matched pairs of children with and without Medicaid who were hospitalized because of asthma, the median cost for Medicaid patients was $4,263; for non-Medicaid patients, it was $4,160. The median difference in cost between Medicaid and non-Medicaid patients was $84, and the mean difference in cost was $49.

Both Medicaid and non-Medicaid patients had similar lengths of stay, with a median of 1 day for both groups. Intensive care unit use was similar, with 10.1% of Medicaid patients visiting the ICU, compared with 10.6% of non-Medicaid patients.

“Our study should serve to provide potential benchmarks for use and reimbursement standards, with implications for care and payment even when children are hospitalized outside the [Pediatric Hospital Information System],” the investigators wrote.

Find the full study in Pediatrics (doi: 10.1542/peds.2016-0371).

[email protected]

Medicaid status did not significantly affect costs for children who were hospitalized because of asthma, according to Jeffrey H. Silber, MD, and his associates.

In a study of 17,739 matched pairs of children with and without Medicaid who were hospitalized because of asthma, the median cost for Medicaid patients was $4,263; for non-Medicaid patients, it was $4,160. The median difference in cost between Medicaid and non-Medicaid patients was $84, and the mean difference in cost was $49.

Both Medicaid and non-Medicaid patients had similar lengths of stay, with a median of 1 day for both groups. Intensive care unit use was similar, with 10.1% of Medicaid patients visiting the ICU, compared with 10.6% of non-Medicaid patients.

“Our study should serve to provide potential benchmarks for use and reimbursement standards, with implications for care and payment even when children are hospitalized outside the [Pediatric Hospital Information System],” the investigators wrote.

Find the full study in Pediatrics (doi: 10.1542/peds.2016-0371).

[email protected]

Medicaid status did not significantly affect costs for children who were hospitalized because of asthma, according to Jeffrey H. Silber, MD, and his associates.

In a study of 17,739 matched pairs of children with and without Medicaid who were hospitalized because of asthma, the median cost for Medicaid patients was $4,263; for non-Medicaid patients, it was $4,160. The median difference in cost between Medicaid and non-Medicaid patients was $84, and the mean difference in cost was $49.

Both Medicaid and non-Medicaid patients had similar lengths of stay, with a median of 1 day for both groups. Intensive care unit use was similar, with 10.1% of Medicaid patients visiting the ICU, compared with 10.6% of non-Medicaid patients.

“Our study should serve to provide potential benchmarks for use and reimbursement standards, with implications for care and payment even when children are hospitalized outside the [Pediatric Hospital Information System],” the investigators wrote.

Find the full study in Pediatrics (doi: 10.1542/peds.2016-0371).

[email protected]

SCOTTSDALE, ARIZ. – Children with severe atopic dermatitis were significantly more likely to log at least 5 hours of screen time a day, and were significantly less likely to exercise than were nonatopic controls, said the lead investigator of a large national study.

“Atopic dermatitis overall was not associated with sedentary behavior. It was severe disease only,” said Mark Strom of the department of dermatology, Northwestern University, Chicago, during an oral presentation at the annual meeting of the Society for Investigative Dermatology. Patients tended to be even more sedentary if they suffered from disturbed sleep in addition to severe eczema, he added.

Heat and sweat worsen the intense itch of atopic dermatitis. Hypothesizing that this would deter affected children from physical activity, Mr. Strom and his associates analyzed data for 131,783 respondents aged 18 and under from the National Survey of Children’s Health. The survey assesses physical activity by asking how many days a week the respondent sweated and breathed hard for at least 20 minutes. Screen time is measured by asking about daily hours spent watching television and playing video games, and sleep quality is assessed by asking how many nights a week the child slept the normal amount for his or her age.

Simply having atopic dermatitis was linked with only a slight increase in the chance of having a sedentary lifestyle after controlling for demographic factors, insurance status, geographic location, and educational level, according to Mr. Strom. Specifically, eczema was significantly associated with a 12% lower odds of having exercised on at least 3 days of the previous week (odds ratio, 0.88). However, severe atopic dermatitis significantly reduced the odds that a child exercised at least one day a week by 61% (OR, 0.39). Furthermore, severe atopic dermatitis was associated with more than double the odds of having at least 5 hours of daily screen time (OR, 2.62). And having either moderate or severe eczema was tied to a significant decrease in the odds of having participated in sports in the past year, Mr. Strom said.

“Atopic dermatitis and sleep disturbance each contribute to sedentary behavior,” he reported. Nonatopic children who did not sleep enough on most nights had nearly double the odds of heavy television and video game use, compared with children who slept more, a significant difference. When poor sleepers also had atopic dermatitis, their odds of heavy screen use more than tripled. Poor sleepers were also significantly less likely to join sports teams, even when they did not have eczema, Mr. Strom said.

“Children with more severe atopic dermatitis may have more profound exacerbations of activity-related symptoms, which would lead to these findings,” he concluded. Future studies should explore whether better symptom control can help improve sedentary behaviors, he added.

The study was sponsored by the Maternal and Child Health Bureau of the U.S. Department of Health and Human Services. Mr. Strom had no disclosures.

SCOTTSDALE, ARIZ. – Children with severe atopic dermatitis were significantly more likely to log at least 5 hours of screen time a day, and were significantly less likely to exercise than were nonatopic controls, said the lead investigator of a large national study.

“Atopic dermatitis overall was not associated with sedentary behavior. It was severe disease only,” said Mark Strom of the department of dermatology, Northwestern University, Chicago, during an oral presentation at the annual meeting of the Society for Investigative Dermatology. Patients tended to be even more sedentary if they suffered from disturbed sleep in addition to severe eczema, he added.

Heat and sweat worsen the intense itch of atopic dermatitis. Hypothesizing that this would deter affected children from physical activity, Mr. Strom and his associates analyzed data for 131,783 respondents aged 18 and under from the National Survey of Children’s Health. The survey assesses physical activity by asking how many days a week the respondent sweated and breathed hard for at least 20 minutes. Screen time is measured by asking about daily hours spent watching television and playing video games, and sleep quality is assessed by asking how many nights a week the child slept the normal amount for his or her age.

Simply having atopic dermatitis was linked with only a slight increase in the chance of having a sedentary lifestyle after controlling for demographic factors, insurance status, geographic location, and educational level, according to Mr. Strom. Specifically, eczema was significantly associated with a 12% lower odds of having exercised on at least 3 days of the previous week (odds ratio, 0.88). However, severe atopic dermatitis significantly reduced the odds that a child exercised at least one day a week by 61% (OR, 0.39). Furthermore, severe atopic dermatitis was associated with more than double the odds of having at least 5 hours of daily screen time (OR, 2.62). And having either moderate or severe eczema was tied to a significant decrease in the odds of having participated in sports in the past year, Mr. Strom said.

“Atopic dermatitis and sleep disturbance each contribute to sedentary behavior,” he reported. Nonatopic children who did not sleep enough on most nights had nearly double the odds of heavy television and video game use, compared with children who slept more, a significant difference. When poor sleepers also had atopic dermatitis, their odds of heavy screen use more than tripled. Poor sleepers were also significantly less likely to join sports teams, even when they did not have eczema, Mr. Strom said.

“Children with more severe atopic dermatitis may have more profound exacerbations of activity-related symptoms, which would lead to these findings,” he concluded. Future studies should explore whether better symptom control can help improve sedentary behaviors, he added.

The study was sponsored by the Maternal and Child Health Bureau of the U.S. Department of Health and Human Services. Mr. Strom had no disclosures.

SCOTTSDALE, ARIZ. – Children with severe atopic dermatitis were significantly more likely to log at least 5 hours of screen time a day, and were significantly less likely to exercise than were nonatopic controls, said the lead investigator of a large national study.

“Atopic dermatitis overall was not associated with sedentary behavior. It was severe disease only,” said Mark Strom of the department of dermatology, Northwestern University, Chicago, during an oral presentation at the annual meeting of the Society for Investigative Dermatology. Patients tended to be even more sedentary if they suffered from disturbed sleep in addition to severe eczema, he added.

Heat and sweat worsen the intense itch of atopic dermatitis. Hypothesizing that this would deter affected children from physical activity, Mr. Strom and his associates analyzed data for 131,783 respondents aged 18 and under from the National Survey of Children’s Health. The survey assesses physical activity by asking how many days a week the respondent sweated and breathed hard for at least 20 minutes. Screen time is measured by asking about daily hours spent watching television and playing video games, and sleep quality is assessed by asking how many nights a week the child slept the normal amount for his or her age.

Simply having atopic dermatitis was linked with only a slight increase in the chance of having a sedentary lifestyle after controlling for demographic factors, insurance status, geographic location, and educational level, according to Mr. Strom. Specifically, eczema was significantly associated with a 12% lower odds of having exercised on at least 3 days of the previous week (odds ratio, 0.88). However, severe atopic dermatitis significantly reduced the odds that a child exercised at least one day a week by 61% (OR, 0.39). Furthermore, severe atopic dermatitis was associated with more than double the odds of having at least 5 hours of daily screen time (OR, 2.62). And having either moderate or severe eczema was tied to a significant decrease in the odds of having participated in sports in the past year, Mr. Strom said.

“Atopic dermatitis and sleep disturbance each contribute to sedentary behavior,” he reported. Nonatopic children who did not sleep enough on most nights had nearly double the odds of heavy television and video game use, compared with children who slept more, a significant difference. When poor sleepers also had atopic dermatitis, their odds of heavy screen use more than tripled. Poor sleepers were also significantly less likely to join sports teams, even when they did not have eczema, Mr. Strom said.

“Children with more severe atopic dermatitis may have more profound exacerbations of activity-related symptoms, which would lead to these findings,” he concluded. Future studies should explore whether better symptom control can help improve sedentary behaviors, he added.

The study was sponsored by the Maternal and Child Health Bureau of the U.S. Department of Health and Human Services. Mr. Strom had no disclosures.

SCOTTSDALE, ARIZ. –Among patients with atopic dermatitis, persistently active disease was significantly more common among females of nonwhite race with a history of atopy than among patients without these characteristics, in an analysis of survey data from the Pediatric Elective Eczema Registry.

Annual household income under $50,000 also was a significant predictor of persistently active eczema, according to Katrina Abuabara, MD, of the department of dermatology, University of California, San Francisco, and her associates, who reported their results in a poster at the annual meeting of the Society for Investigative Dermatology.

Atopic dermatitis often persists into adulthood, but few studies have explored contributors to poor disease control. To help fill that gap, the investigators analyzed 65,237 surveys from the Pediatric Eczema Elective Registry (PEER), which tracks children and young adults aged 2-26 years with physician-diagnosed atopic dermatitis. The average age of the 6,237 patients was 7 years at enrollment (standard deviation, 4 years). They were followed at 6-month intervals for up to 10 years, with an average of about 10 surveys per respondent (standard deviation, 6.3 surveys).

In all, 4,607 patients (74% of the cohort) returned surveys spanning early childhood through their mid-20s. Only 15% of patients had “resolving” disease, meaning that as they aged, they increasingly reported complete disease control for periods of 6 months and longer.

The remaining 85% of patients had persistently active disease. In this group, 54% were female, 77% had a household income under $50,000 per year, 71% were nonwhite, and 75% had a history of atopy. Each of these characteristics significantly increased the odds of persistently active atopic dermatitis in the multivariable model (P less than .05 for each association).

Nonwhite race and history of atopy were the strongest predictors of persistently active disease – each lowered the odds of complete disease control by almost 50% (odds ratio, 0.53). Furthermore, females had 37% lower odds of complete disease control compared with males (OR, 0.63), and individuals with household income under $50,000 had 16% lower odds of complete disease control compared with those with higher annual incomes (OR, 0.84).

The link between lower socioeconomic status and persistently active eczema belies previous findings, the researchers noted. Those studies found that individuals of higher socioeconomic status were at greater risk for developing atopic dermatitis, but “failed to account for the chronic nature of the disease. In contrast, our results suggest that atopic dermatitis persistence may be associated with lower income and nonwhite race, and highlight the importance of longitudinal studies that permit analysis of mechanisms of disease control over time.”

Dr. Abuabara received a grant from the Clinical & Translational Science Institute of UCSF. She had no disclosures.

SCOTTSDALE, ARIZ. –Among patients with atopic dermatitis, persistently active disease was significantly more common among females of nonwhite race with a history of atopy than among patients without these characteristics, in an analysis of survey data from the Pediatric Elective Eczema Registry.

Annual household income under $50,000 also was a significant predictor of persistently active eczema, according to Katrina Abuabara, MD, of the department of dermatology, University of California, San Francisco, and her associates, who reported their results in a poster at the annual meeting of the Society for Investigative Dermatology.

Atopic dermatitis often persists into adulthood, but few studies have explored contributors to poor disease control. To help fill that gap, the investigators analyzed 65,237 surveys from the Pediatric Eczema Elective Registry (PEER), which tracks children and young adults aged 2-26 years with physician-diagnosed atopic dermatitis. The average age of the 6,237 patients was 7 years at enrollment (standard deviation, 4 years). They were followed at 6-month intervals for up to 10 years, with an average of about 10 surveys per respondent (standard deviation, 6.3 surveys).

In all, 4,607 patients (74% of the cohort) returned surveys spanning early childhood through their mid-20s. Only 15% of patients had “resolving” disease, meaning that as they aged, they increasingly reported complete disease control for periods of 6 months and longer.

The remaining 85% of patients had persistently active disease. In this group, 54% were female, 77% had a household income under $50,000 per year, 71% were nonwhite, and 75% had a history of atopy. Each of these characteristics significantly increased the odds of persistently active atopic dermatitis in the multivariable model (P less than .05 for each association).

Nonwhite race and history of atopy were the strongest predictors of persistently active disease – each lowered the odds of complete disease control by almost 50% (odds ratio, 0.53). Furthermore, females had 37% lower odds of complete disease control compared with males (OR, 0.63), and individuals with household income under $50,000 had 16% lower odds of complete disease control compared with those with higher annual incomes (OR, 0.84).

The link between lower socioeconomic status and persistently active eczema belies previous findings, the researchers noted. Those studies found that individuals of higher socioeconomic status were at greater risk for developing atopic dermatitis, but “failed to account for the chronic nature of the disease. In contrast, our results suggest that atopic dermatitis persistence may be associated with lower income and nonwhite race, and highlight the importance of longitudinal studies that permit analysis of mechanisms of disease control over time.”

Dr. Abuabara received a grant from the Clinical & Translational Science Institute of UCSF. She had no disclosures.

SCOTTSDALE, ARIZ. –Among patients with atopic dermatitis, persistently active disease was significantly more common among females of nonwhite race with a history of atopy than among patients without these characteristics, in an analysis of survey data from the Pediatric Elective Eczema Registry.

Annual household income under $50,000 also was a significant predictor of persistently active eczema, according to Katrina Abuabara, MD, of the department of dermatology, University of California, San Francisco, and her associates, who reported their results in a poster at the annual meeting of the Society for Investigative Dermatology.

Atopic dermatitis often persists into adulthood, but few studies have explored contributors to poor disease control. To help fill that gap, the investigators analyzed 65,237 surveys from the Pediatric Eczema Elective Registry (PEER), which tracks children and young adults aged 2-26 years with physician-diagnosed atopic dermatitis. The average age of the 6,237 patients was 7 years at enrollment (standard deviation, 4 years). They were followed at 6-month intervals for up to 10 years, with an average of about 10 surveys per respondent (standard deviation, 6.3 surveys).

In all, 4,607 patients (74% of the cohort) returned surveys spanning early childhood through their mid-20s. Only 15% of patients had “resolving” disease, meaning that as they aged, they increasingly reported complete disease control for periods of 6 months and longer.

The remaining 85% of patients had persistently active disease. In this group, 54% were female, 77% had a household income under $50,000 per year, 71% were nonwhite, and 75% had a history of atopy. Each of these characteristics significantly increased the odds of persistently active atopic dermatitis in the multivariable model (P less than .05 for each association).

Nonwhite race and history of atopy were the strongest predictors of persistently active disease – each lowered the odds of complete disease control by almost 50% (odds ratio, 0.53). Furthermore, females had 37% lower odds of complete disease control compared with males (OR, 0.63), and individuals with household income under $50,000 had 16% lower odds of complete disease control compared with those with higher annual incomes (OR, 0.84).

The link between lower socioeconomic status and persistently active eczema belies previous findings, the researchers noted. Those studies found that individuals of higher socioeconomic status were at greater risk for developing atopic dermatitis, but “failed to account for the chronic nature of the disease. In contrast, our results suggest that atopic dermatitis persistence may be associated with lower income and nonwhite race, and highlight the importance of longitudinal studies that permit analysis of mechanisms of disease control over time.”

Dr. Abuabara received a grant from the Clinical & Translational Science Institute of UCSF. She had no disclosures.

SCOTTSDALE, ARIZ. –Among patients with atopic dermatitis, persistently active disease was significantly more common among females of nonwhite race with a history of atopy than among patients without these characteristics, in an analysis of survey data from the Pediatric Elective Eczema Registry.

Annual household income under $50,000 also was a significant predictor of persistently active eczema, according to Katrina Abuabara, MD, of the department of dermatology, University of California, San Francisco, and her associates, who reported their results in a poster at the annual meeting of the Society for Investigative Dermatology.

Atopic dermatitis often persists into adulthood, but few studies have explored contributors to poor disease control. To help fill that gap, the investigators analyzed 65,237 surveys from the Pediatric Eczema Elective Registry (PEER), which tracks children and young adults aged 2-26 years with physician-diagnosed atopic dermatitis. The average age of the 6,237 patients was 7 years at enrollment (standard deviation, 4 years). They were followed at 6-month intervals for up to 10 years, with an average of about 10 surveys per respondent (standard deviation, 6.3 surveys).

In all, 4,607 patients (74% of the cohort) returned surveys spanning early childhood through their mid-20s. Only 15% of patients had “resolving” disease, meaning that as they aged, they increasingly reported complete disease control for periods of 6 months and longer.

The remaining 85% of patients had persistently active disease. In this group, 54% were female, 77% had a household income under $50,000 per year, 71% were nonwhite, and 75% had a history of atopy. Each of these characteristics significantly increased the odds of persistently active atopic dermatitis in the multivariable model (P less than .05 for each association).

Nonwhite race and history of atopy were the strongest predictors of persistently active disease – each lowered the odds of complete disease control by almost 50% (odds ratio, 0.53). Furthermore, females had 37% lower odds of complete disease control compared with males (OR, 0.63), and individuals with household income under $50,000 had 16% lower odds of complete disease control compared with those with higher annual incomes (OR, 0.84).

The link between lower socioeconomic status and persistently active eczema belies previous findings, the researchers noted. Those studies found that individuals of higher socioeconomic status were at greater risk for developing atopic dermatitis, but “failed to account for the chronic nature of the disease. In contrast, our results suggest that atopic dermatitis persistence may be associated with lower income and nonwhite race, and highlight the importance of longitudinal studies that permit analysis of mechanisms of disease control over time.”

Dr. Abuabara received a grant from the Clinical & Translational Science Institute of UCSF. She had no disclosures.

SCOTTSDALE, ARIZ. –Among patients with atopic dermatitis, persistently active disease was significantly more common among females of nonwhite race with a history of atopy than among patients without these characteristics, in an analysis of survey data from the Pediatric Elective Eczema Registry.

Annual household income under $50,000 also was a significant predictor of persistently active eczema, according to Katrina Abuabara, MD, of the department of dermatology, University of California, San Francisco, and her associates, who reported their results in a poster at the annual meeting of the Society for Investigative Dermatology.

Atopic dermatitis often persists into adulthood, but few studies have explored contributors to poor disease control. To help fill that gap, the investigators analyzed 65,237 surveys from the Pediatric Eczema Elective Registry (PEER), which tracks children and young adults aged 2-26 years with physician-diagnosed atopic dermatitis. The average age of the 6,237 patients was 7 years at enrollment (standard deviation, 4 years). They were followed at 6-month intervals for up to 10 years, with an average of about 10 surveys per respondent (standard deviation, 6.3 surveys).

In all, 4,607 patients (74% of the cohort) returned surveys spanning early childhood through their mid-20s. Only 15% of patients had “resolving” disease, meaning that as they aged, they increasingly reported complete disease control for periods of 6 months and longer.

The remaining 85% of patients had persistently active disease. In this group, 54% were female, 77% had a household income under $50,000 per year, 71% were nonwhite, and 75% had a history of atopy. Each of these characteristics significantly increased the odds of persistently active atopic dermatitis in the multivariable model (P less than .05 for each association).

Nonwhite race and history of atopy were the strongest predictors of persistently active disease – each lowered the odds of complete disease control by almost 50% (odds ratio, 0.53). Furthermore, females had 37% lower odds of complete disease control compared with males (OR, 0.63), and individuals with household income under $50,000 had 16% lower odds of complete disease control compared with those with higher annual incomes (OR, 0.84).

The link between lower socioeconomic status and persistently active eczema belies previous findings, the researchers noted. Those studies found that individuals of higher socioeconomic status were at greater risk for developing atopic dermatitis, but “failed to account for the chronic nature of the disease. In contrast, our results suggest that atopic dermatitis persistence may be associated with lower income and nonwhite race, and highlight the importance of longitudinal studies that permit analysis of mechanisms of disease control over time.”

Dr. Abuabara received a grant from the Clinical & Translational Science Institute of UCSF. She had no disclosures.

SCOTTSDALE, ARIZ. –Among patients with atopic dermatitis, persistently active disease was significantly more common among females of nonwhite race with a history of atopy than among patients without these characteristics, in an analysis of survey data from the Pediatric Elective Eczema Registry.

Annual household income under $50,000 also was a significant predictor of persistently active eczema, according to Katrina Abuabara, MD, of the department of dermatology, University of California, San Francisco, and her associates, who reported their results in a poster at the annual meeting of the Society for Investigative Dermatology.

Atopic dermatitis often persists into adulthood, but few studies have explored contributors to poor disease control. To help fill that gap, the investigators analyzed 65,237 surveys from the Pediatric Eczema Elective Registry (PEER), which tracks children and young adults aged 2-26 years with physician-diagnosed atopic dermatitis. The average age of the 6,237 patients was 7 years at enrollment (standard deviation, 4 years). They were followed at 6-month intervals for up to 10 years, with an average of about 10 surveys per respondent (standard deviation, 6.3 surveys).

In all, 4,607 patients (74% of the cohort) returned surveys spanning early childhood through their mid-20s. Only 15% of patients had “resolving” disease, meaning that as they aged, they increasingly reported complete disease control for periods of 6 months and longer.

The remaining 85% of patients had persistently active disease. In this group, 54% were female, 77% had a household income under $50,000 per year, 71% were nonwhite, and 75% had a history of atopy. Each of these characteristics significantly increased the odds of persistently active atopic dermatitis in the multivariable model (P less than .05 for each association).

Nonwhite race and history of atopy were the strongest predictors of persistently active disease – each lowered the odds of complete disease control by almost 50% (odds ratio, 0.53). Furthermore, females had 37% lower odds of complete disease control compared with males (OR, 0.63), and individuals with household income under $50,000 had 16% lower odds of complete disease control compared with those with higher annual incomes (OR, 0.84).

The link between lower socioeconomic status and persistently active eczema belies previous findings, the researchers noted. Those studies found that individuals of higher socioeconomic status were at greater risk for developing atopic dermatitis, but “failed to account for the chronic nature of the disease. In contrast, our results suggest that atopic dermatitis persistence may be associated with lower income and nonwhite race, and highlight the importance of longitudinal studies that permit analysis of mechanisms of disease control over time.”

Dr. Abuabara received a grant from the Clinical & Translational Science Institute of UCSF. She had no disclosures.

IN THIS ARTICLE

• Conditions associated with increased risk for case disease
• Outcome for the case patient
• Differential diagnosis

A 78-year-old white man with chronic lymphocytic leukemia is admitted to the hospital with worsening cough, shortness of breath, and fever. His medical history is significant for pneumonia caused by Pneumocystis jirovecii in the past year. In the weeks preceding hospital admission, the patient developed an erythematous rash over his trunk (see photographs).

During the man’s hospital stay, this eruption becomes increasingly pruritic and spreads to his proximal extremities. His pulmonary symptoms improve slightly following the initiation of broad-spectrum antibiotic therapy (piperacillin/tazobactam and vancomycin), but CT performed one week after admission reveals worsening pulmonary disease (see image). The radiologist’s differential diagnosis includes neoplasm, fungal infection, Kaposi sarcoma, and autoimmune disease.

A. The patient's back shows a distribution of lesions, with areas of excoriation caused by scratching.	B. A close-up reveals erythematous papules and keratotic papules.

Suspecting that the progressive rash is related to the systemic process, the provider orders a punch biopsy in an effort to reach a diagnosis with minimally invasive studies. When the patient’s clinical status further declines, he undergoes video-assisted thoracoscopic surgery to obtain an excisional biopsy of one of the pulmonary nodules. Subsequent analysis reveals fungal organisms consistent with histoplasmosis. Interestingly, in the histologic review of the skin biopsy, focal acantholytic dyskeratosis—suggestive of Grover disease—is identified.

Continue for discussion >>

DISCUSSION
Grover disease (GD), also known as transient acantholytic dermatosis, is a skin condition of uncertain pathophysiology. Its clinical presentation can be difficult to distinguish from other dermopathies.^1,2

Incidence
GD most commonly appears in fair-skinned persons of late middle age, with men affected at two to three times the rate seen in women.^1,2 Although GD has been documented in patients ranging in age from 4 to 100, this dermopathy is rare in younger patients.^1-3 Persons with a prior history of atopic dermatitis, contact dermatitis, or xerosis cutis are at increased risk for GD—likely due to an increased dermatologic sensitivity to irritants resulting from the aforementioned disorders.^1,4 Risk for GD is also elevated in patients with chronic medical conditions, immunodeficiency, febrile illnesses, or malignancies (see Table 1).^2-5

The true incidence of GD is not known; biopsy-proven GD is uncommon, and specific data on the incidence and prevalence of the condition are lacking. Swiss researchers who reviewed more than 30,000 skin biopsies in the late 1990s noted only 24 diagnosed cases of GD, and similar findings have been reported in the United States.^1,6 However, the variable presentation and often mild nature of GD may result in cases of misdiagnosis, lack of diagnosis, or empiric treatment in the absence of a formal diagnosis.⁷

Causative factors
Although the pathophysiology of GD is uncertain, the most likely cause is an occlusion of the eccrine glands.³ This is followed by acantholysis, or separation of keratinocytes within the epidermis, which in turn leads to the development of vesicular lesions.

Though diagnosed most often in the winter, GD has also been associated with exposure to sunlight, heat, xerosis, and diaphoresis.^1,3 Hospitalized or bedridden patients are at risk for occlusion of the eccrine glands and thus for GD. Use of certain therapies, including sulfadoxine/pyrimethamine (an antimalarial treatment), ionizing radiation, and interleukin-4, may also be precursors for the condition.²

Other exacerbating factors have been suggested, but reports are largely limited to case studies and other anecdotal publications.² Concrete data regarding the etiology and pathophysiology of GD are still relatively scarce.

Clinical presentation
Patients with GD present with pruritic dermatitis on the trunk and proximal extremities, most classically on the anterior chest and mid back.^2,3 The severity of the rash does not necessarily correlate to the degree of pruritus. Some patients report only mild pruritus, while others experience debilitating discomfort and pain. In most cases, erythematous and violaceous papules and vesicles appear first, followed by keratotic erosions.³

GD is a self-limited disorder that often resolves within a few weeks, although some cases will persist for several months.^3,5 Severity and duration of symptoms appear to be correlated with increasing age; elderly patients experience worse pruritus for longer periods than do younger patients.²

Although the condition is sometimes referred to as transient acantholytic dermatosis, there are three typical presentations of GD: transient eruptive, persistent pruritic, and chronic asymptomatic.⁴ Transient eruptive GD presents suddenly, with intense pruritus, and tends to subside over several weeks. Persistent pruritic disease generally causes a milder pruritus, with symptoms that last for several months and are not well controlled by medication. Chronic asymptomatic GD can be difficult to treat medically, yet this form of the disease typically causes little to no irritation and requires minimal therapeutic intervention.⁴

Systemic symptoms of GD have not been observed. Pruritus and rash are the main features in most affected patients. However, pruritic papulovesicular eruptions are commonly seen in other conditions with similar characteristics (see Table 2,^3,4), and GD is comparatively rare. While clinical appearance alone may suggest a diagnosis of GD, further testing may be needed to eliminate other conditions from the differential.

Treatment and prognosis
In the absence of randomized therapeutic trials for GD, there are no strict guidelines for treatment. When irritation, inflammation, and pruritus become bothersome, several interventions may be considered. The first step may consist of efforts to modify aggravating factors, such as dry skin, occlusion, excess heat, and rapid temperature changes. Indeed, for mild cases of GD, this may be all that is required.

The firstline pharmacotherapy for GD is medium- to high-potency topical corticosteroids, which reduce inflammation and pruritus in approximately half of affected patients.^3,6,8 Topical emollients and oral antihistamines can also provide symptom relief. Vitamin D analogues are considered secondline therapy, and retinoids (both topical and systemic) have also been shown to reduce GD severity.^3,4,8

Severe, refractory cases may require more aggressive systemic therapy with corticosteroids or retinoids. For pruritic relief, several weeks of oral corticosteroids may be necessary—and GD may rebound after treatment ceases.^3,4 Therefore, oral corticosteroids should only be considered for severe or persistent cases, since the systemic adverse effects (eg, immunosuppression, weight gain, dysglycemia) of these drugs may outweigh the benefits in patients with GD. Other interventions, including phototherapy and immunosuppressive drugs (eg, etanercept) have also demonstrated benefit in select patients.^4,9,10

The self-limited nature of GD, along with its lack of systemic symptoms, is associated with a generally benign course of disease and no long-term sequelae.^3,5

Continue to outcome for the case patient >>

OUTCOME FOR THE CASE PATIENT
This case involved an immunocompromised patient with systemic symptoms, vasculitic cutaneous lesions, and significant pulmonary disease. The differential diagnosis was extensive, and diagnosis based on clinical grounds alone was extremely challenging. In these circumstances, diagnostic testing was essential to reach a final diagnosis.

In this case, the skin biopsy yielded a diagnosis of GD, and the rash was found to be unrelated to the patient’s systemic and pulmonary symptoms. The providers were then able to focus on the diagnosis of histoplasmosis, with only minimal intervention for the patient’s GD (ie, oral diphenhydramine prn for pruritus).

CONCLUSION
In many cases of GD, skin biopsy can guide providers when the history and physical examination do not yield a clear diagnosis. The histopathology of affected tissue can provide invaluable information about an underlying disease process, particularly in complex cases such as this patient’s. Skin biopsy provides a minimally invasive opportunity to obtain a diagnosis in patients with a condition that affects multiple organ systems, and its use should be considered in disease processes with cutaneous manifestations.

REFERENCES
1. Scheinfeld N, Mones J. Seasonal variation of transient acantholytic dyskeratosis (Grover’s disease). J Am Acad Dermatol. 2006;55(2): 263-268.
2. Parsons JM. Transient acantholytic dermatosis (Grover’s disease): a global perspective. J Am Acad Dermatol. 1996;35(5 part 1):653-666.
3. Weaver J, Bergfeld WF. Grover disease (transient acantholytic dermatosis). Arch Pathol Lab Med. 2009;133(9):1490-1494.
4. Quirk CJ, Heenan PJ. Grover’s disease: 34 years on. Australas J Dermatol. 2004;45(2):83-86.
5. Ippoliti G, Paulli M, Lucioni M, et al. Grover’s disease after heart transplantation: a case report. Case Rep Transplant. 2012;2012:126592.
6. Streit M, Paredes BE, Braathen LR, Brand CU. Transitory acantholytic dermatosis (Grover’s disease): an analysis of the clinical spectrum based on 21 histologically assessed cases [in German]. Hautarzt. 2000;51:244-249.
7. Joshi R, Taneja A. Grover’s disease with acrosyringeal acantholysis: a rare histological presentation of an uncommon disease. Indian J Dermatol. 2014;59(6):621-623.
8. Riemann H, High WA. Grover’s disease (transient and persistent acantholytic dermatosis). UpToDate. 2015. www.uptodate.com/contents/grovers-disease-transient-and-persistent-acantholytic-dermatosis. Accessed June 4, 2016.
9. Breuckmann F, Appelhans C, Altmeyer P, Kreuter A. Medium-dose ultraviolet A1 phototherapy in transient acantholytic dermatosis (Grover’s disease). J Am Acad Dermatol. 2005;52(1):169-170.
10. Norman R, Chau V. Use of etanercept in treating pruritus and preventing new lesions in Grover disease. J Am Acad Dermatol. 2011;64(4):796-798.

IN THIS ARTICLE

• Conditions associated with increased risk for case disease
• Outcome for the case patient
• Differential diagnosis

A 78-year-old white man with chronic lymphocytic leukemia is admitted to the hospital with worsening cough, shortness of breath, and fever. His medical history is significant for pneumonia caused by Pneumocystis jirovecii in the past year. In the weeks preceding hospital admission, the patient developed an erythematous rash over his trunk (see photographs).

During the man’s hospital stay, this eruption becomes increasingly pruritic and spreads to his proximal extremities. His pulmonary symptoms improve slightly following the initiation of broad-spectrum antibiotic therapy (piperacillin/tazobactam and vancomycin), but CT performed one week after admission reveals worsening pulmonary disease (see image). The radiologist’s differential diagnosis includes neoplasm, fungal infection, Kaposi sarcoma, and autoimmune disease.

A. The patient's back shows a distribution of lesions, with areas of excoriation caused by scratching.	B. A close-up reveals erythematous papules and keratotic papules.

Suspecting that the progressive rash is related to the systemic process, the provider orders a punch biopsy in an effort to reach a diagnosis with minimally invasive studies. When the patient’s clinical status further declines, he undergoes video-assisted thoracoscopic surgery to obtain an excisional biopsy of one of the pulmonary nodules. Subsequent analysis reveals fungal organisms consistent with histoplasmosis. Interestingly, in the histologic review of the skin biopsy, focal acantholytic dyskeratosis—suggestive of Grover disease—is identified.

Continue for discussion >>

DISCUSSION
Grover disease (GD), also known as transient acantholytic dermatosis, is a skin condition of uncertain pathophysiology. Its clinical presentation can be difficult to distinguish from other dermopathies.^1,2

Incidence
GD most commonly appears in fair-skinned persons of late middle age, with men affected at two to three times the rate seen in women.^1,2 Although GD has been documented in patients ranging in age from 4 to 100, this dermopathy is rare in younger patients.^1-3 Persons with a prior history of atopic dermatitis, contact dermatitis, or xerosis cutis are at increased risk for GD—likely due to an increased dermatologic sensitivity to irritants resulting from the aforementioned disorders.^1,4 Risk for GD is also elevated in patients with chronic medical conditions, immunodeficiency, febrile illnesses, or malignancies (see Table 1).^2-5

The true incidence of GD is not known; biopsy-proven GD is uncommon, and specific data on the incidence and prevalence of the condition are lacking. Swiss researchers who reviewed more than 30,000 skin biopsies in the late 1990s noted only 24 diagnosed cases of GD, and similar findings have been reported in the United States.^1,6 However, the variable presentation and often mild nature of GD may result in cases of misdiagnosis, lack of diagnosis, or empiric treatment in the absence of a formal diagnosis.⁷

Causative factors
Although the pathophysiology of GD is uncertain, the most likely cause is an occlusion of the eccrine glands.³ This is followed by acantholysis, or separation of keratinocytes within the epidermis, which in turn leads to the development of vesicular lesions.

Though diagnosed most often in the winter, GD has also been associated with exposure to sunlight, heat, xerosis, and diaphoresis.^1,3 Hospitalized or bedridden patients are at risk for occlusion of the eccrine glands and thus for GD. Use of certain therapies, including sulfadoxine/pyrimethamine (an antimalarial treatment), ionizing radiation, and interleukin-4, may also be precursors for the condition.²

Other exacerbating factors have been suggested, but reports are largely limited to case studies and other anecdotal publications.² Concrete data regarding the etiology and pathophysiology of GD are still relatively scarce.

Clinical presentation
Patients with GD present with pruritic dermatitis on the trunk and proximal extremities, most classically on the anterior chest and mid back.^2,3 The severity of the rash does not necessarily correlate to the degree of pruritus. Some patients report only mild pruritus, while others experience debilitating discomfort and pain. In most cases, erythematous and violaceous papules and vesicles appear first, followed by keratotic erosions.³

GD is a self-limited disorder that often resolves within a few weeks, although some cases will persist for several months.^3,5 Severity and duration of symptoms appear to be correlated with increasing age; elderly patients experience worse pruritus for longer periods than do younger patients.²

Although the condition is sometimes referred to as transient acantholytic dermatosis, there are three typical presentations of GD: transient eruptive, persistent pruritic, and chronic asymptomatic.⁴ Transient eruptive GD presents suddenly, with intense pruritus, and tends to subside over several weeks. Persistent pruritic disease generally causes a milder pruritus, with symptoms that last for several months and are not well controlled by medication. Chronic asymptomatic GD can be difficult to treat medically, yet this form of the disease typically causes little to no irritation and requires minimal therapeutic intervention.⁴

Systemic symptoms of GD have not been observed. Pruritus and rash are the main features in most affected patients. However, pruritic papulovesicular eruptions are commonly seen in other conditions with similar characteristics (see Table 2,^3,4), and GD is comparatively rare. While clinical appearance alone may suggest a diagnosis of GD, further testing may be needed to eliminate other conditions from the differential.

Treatment and prognosis
In the absence of randomized therapeutic trials for GD, there are no strict guidelines for treatment. When irritation, inflammation, and pruritus become bothersome, several interventions may be considered. The first step may consist of efforts to modify aggravating factors, such as dry skin, occlusion, excess heat, and rapid temperature changes. Indeed, for mild cases of GD, this may be all that is required.

The firstline pharmacotherapy for GD is medium- to high-potency topical corticosteroids, which reduce inflammation and pruritus in approximately half of affected patients.^3,6,8 Topical emollients and oral antihistamines can also provide symptom relief. Vitamin D analogues are considered secondline therapy, and retinoids (both topical and systemic) have also been shown to reduce GD severity.^3,4,8

Severe, refractory cases may require more aggressive systemic therapy with corticosteroids or retinoids. For pruritic relief, several weeks of oral corticosteroids may be necessary—and GD may rebound after treatment ceases.^3,4 Therefore, oral corticosteroids should only be considered for severe or persistent cases, since the systemic adverse effects (eg, immunosuppression, weight gain, dysglycemia) of these drugs may outweigh the benefits in patients with GD. Other interventions, including phototherapy and immunosuppressive drugs (eg, etanercept) have also demonstrated benefit in select patients.^4,9,10

The self-limited nature of GD, along with its lack of systemic symptoms, is associated with a generally benign course of disease and no long-term sequelae.^3,5

Continue to outcome for the case patient >>

OUTCOME FOR THE CASE PATIENT
This case involved an immunocompromised patient with systemic symptoms, vasculitic cutaneous lesions, and significant pulmonary disease. The differential diagnosis was extensive, and diagnosis based on clinical grounds alone was extremely challenging. In these circumstances, diagnostic testing was essential to reach a final diagnosis.

In this case, the skin biopsy yielded a diagnosis of GD, and the rash was found to be unrelated to the patient’s systemic and pulmonary symptoms. The providers were then able to focus on the diagnosis of histoplasmosis, with only minimal intervention for the patient’s GD (ie, oral diphenhydramine prn for pruritus).

CONCLUSION
In many cases of GD, skin biopsy can guide providers when the history and physical examination do not yield a clear diagnosis. The histopathology of affected tissue can provide invaluable information about an underlying disease process, particularly in complex cases such as this patient’s. Skin biopsy provides a minimally invasive opportunity to obtain a diagnosis in patients with a condition that affects multiple organ systems, and its use should be considered in disease processes with cutaneous manifestations.

REFERENCES
1. Scheinfeld N, Mones J. Seasonal variation of transient acantholytic dyskeratosis (Grover’s disease). J Am Acad Dermatol. 2006;55(2): 263-268.
2. Parsons JM. Transient acantholytic dermatosis (Grover’s disease): a global perspective. J Am Acad Dermatol. 1996;35(5 part 1):653-666.
3. Weaver J, Bergfeld WF. Grover disease (transient acantholytic dermatosis). Arch Pathol Lab Med. 2009;133(9):1490-1494.
4. Quirk CJ, Heenan PJ. Grover’s disease: 34 years on. Australas J Dermatol. 2004;45(2):83-86.
5. Ippoliti G, Paulli M, Lucioni M, et al. Grover’s disease after heart transplantation: a case report. Case Rep Transplant. 2012;2012:126592.
6. Streit M, Paredes BE, Braathen LR, Brand CU. Transitory acantholytic dermatosis (Grover’s disease): an analysis of the clinical spectrum based on 21 histologically assessed cases [in German]. Hautarzt. 2000;51:244-249.
7. Joshi R, Taneja A. Grover’s disease with acrosyringeal acantholysis: a rare histological presentation of an uncommon disease. Indian J Dermatol. 2014;59(6):621-623.
8. Riemann H, High WA. Grover’s disease (transient and persistent acantholytic dermatosis). UpToDate. 2015. www.uptodate.com/contents/grovers-disease-transient-and-persistent-acantholytic-dermatosis. Accessed June 4, 2016.
9. Breuckmann F, Appelhans C, Altmeyer P, Kreuter A. Medium-dose ultraviolet A1 phototherapy in transient acantholytic dermatosis (Grover’s disease). J Am Acad Dermatol. 2005;52(1):169-170.
10. Norman R, Chau V. Use of etanercept in treating pruritus and preventing new lesions in Grover disease. J Am Acad Dermatol. 2011;64(4):796-798.

IN THIS ARTICLE

• Conditions associated with increased risk for case disease
• Outcome for the case patient
• Differential diagnosis

A 78-year-old white man with chronic lymphocytic leukemia is admitted to the hospital with worsening cough, shortness of breath, and fever. His medical history is significant for pneumonia caused by Pneumocystis jirovecii in the past year. In the weeks preceding hospital admission, the patient developed an erythematous rash over his trunk (see photographs).

During the man’s hospital stay, this eruption becomes increasingly pruritic and spreads to his proximal extremities. His pulmonary symptoms improve slightly following the initiation of broad-spectrum antibiotic therapy (piperacillin/tazobactam and vancomycin), but CT performed one week after admission reveals worsening pulmonary disease (see image). The radiologist’s differential diagnosis includes neoplasm, fungal infection, Kaposi sarcoma, and autoimmune disease.

A. The patient's back shows a distribution of lesions, with areas of excoriation caused by scratching.	B. A close-up reveals erythematous papules and keratotic papules.

Suspecting that the progressive rash is related to the systemic process, the provider orders a punch biopsy in an effort to reach a diagnosis with minimally invasive studies. When the patient’s clinical status further declines, he undergoes video-assisted thoracoscopic surgery to obtain an excisional biopsy of one of the pulmonary nodules. Subsequent analysis reveals fungal organisms consistent with histoplasmosis. Interestingly, in the histologic review of the skin biopsy, focal acantholytic dyskeratosis—suggestive of Grover disease—is identified.

Continue for discussion >>

DISCUSSION
Grover disease (GD), also known as transient acantholytic dermatosis, is a skin condition of uncertain pathophysiology. Its clinical presentation can be difficult to distinguish from other dermopathies.^1,2

Incidence
GD most commonly appears in fair-skinned persons of late middle age, with men affected at two to three times the rate seen in women.^1,2 Although GD has been documented in patients ranging in age from 4 to 100, this dermopathy is rare in younger patients.^1-3 Persons with a prior history of atopic dermatitis, contact dermatitis, or xerosis cutis are at increased risk for GD—likely due to an increased dermatologic sensitivity to irritants resulting from the aforementioned disorders.^1,4 Risk for GD is also elevated in patients with chronic medical conditions, immunodeficiency, febrile illnesses, or malignancies (see Table 1).^2-5

The true incidence of GD is not known; biopsy-proven GD is uncommon, and specific data on the incidence and prevalence of the condition are lacking. Swiss researchers who reviewed more than 30,000 skin biopsies in the late 1990s noted only 24 diagnosed cases of GD, and similar findings have been reported in the United States.^1,6 However, the variable presentation and often mild nature of GD may result in cases of misdiagnosis, lack of diagnosis, or empiric treatment in the absence of a formal diagnosis.⁷

Causative factors
Although the pathophysiology of GD is uncertain, the most likely cause is an occlusion of the eccrine glands.³ This is followed by acantholysis, or separation of keratinocytes within the epidermis, which in turn leads to the development of vesicular lesions.

Though diagnosed most often in the winter, GD has also been associated with exposure to sunlight, heat, xerosis, and diaphoresis.^1,3 Hospitalized or bedridden patients are at risk for occlusion of the eccrine glands and thus for GD. Use of certain therapies, including sulfadoxine/pyrimethamine (an antimalarial treatment), ionizing radiation, and interleukin-4, may also be precursors for the condition.²

Other exacerbating factors have been suggested, but reports are largely limited to case studies and other anecdotal publications.² Concrete data regarding the etiology and pathophysiology of GD are still relatively scarce.

Clinical presentation
Patients with GD present with pruritic dermatitis on the trunk and proximal extremities, most classically on the anterior chest and mid back.^2,3 The severity of the rash does not necessarily correlate to the degree of pruritus. Some patients report only mild pruritus, while others experience debilitating discomfort and pain. In most cases, erythematous and violaceous papules and vesicles appear first, followed by keratotic erosions.³

GD is a self-limited disorder that often resolves within a few weeks, although some cases will persist for several months.^3,5 Severity and duration of symptoms appear to be correlated with increasing age; elderly patients experience worse pruritus for longer periods than do younger patients.²

Although the condition is sometimes referred to as transient acantholytic dermatosis, there are three typical presentations of GD: transient eruptive, persistent pruritic, and chronic asymptomatic.⁴ Transient eruptive GD presents suddenly, with intense pruritus, and tends to subside over several weeks. Persistent pruritic disease generally causes a milder pruritus, with symptoms that last for several months and are not well controlled by medication. Chronic asymptomatic GD can be difficult to treat medically, yet this form of the disease typically causes little to no irritation and requires minimal therapeutic intervention.⁴

Systemic symptoms of GD have not been observed. Pruritus and rash are the main features in most affected patients. However, pruritic papulovesicular eruptions are commonly seen in other conditions with similar characteristics (see Table 2,^3,4), and GD is comparatively rare. While clinical appearance alone may suggest a diagnosis of GD, further testing may be needed to eliminate other conditions from the differential.

Treatment and prognosis
In the absence of randomized therapeutic trials for GD, there are no strict guidelines for treatment. When irritation, inflammation, and pruritus become bothersome, several interventions may be considered. The first step may consist of efforts to modify aggravating factors, such as dry skin, occlusion, excess heat, and rapid temperature changes. Indeed, for mild cases of GD, this may be all that is required.

The firstline pharmacotherapy for GD is medium- to high-potency topical corticosteroids, which reduce inflammation and pruritus in approximately half of affected patients.^3,6,8 Topical emollients and oral antihistamines can also provide symptom relief. Vitamin D analogues are considered secondline therapy, and retinoids (both topical and systemic) have also been shown to reduce GD severity.^3,4,8

Severe, refractory cases may require more aggressive systemic therapy with corticosteroids or retinoids. For pruritic relief, several weeks of oral corticosteroids may be necessary—and GD may rebound after treatment ceases.^3,4 Therefore, oral corticosteroids should only be considered for severe or persistent cases, since the systemic adverse effects (eg, immunosuppression, weight gain, dysglycemia) of these drugs may outweigh the benefits in patients with GD. Other interventions, including phototherapy and immunosuppressive drugs (eg, etanercept) have also demonstrated benefit in select patients.^4,9,10

The self-limited nature of GD, along with its lack of systemic symptoms, is associated with a generally benign course of disease and no long-term sequelae.^3,5

Continue to outcome for the case patient >>

OUTCOME FOR THE CASE PATIENT
This case involved an immunocompromised patient with systemic symptoms, vasculitic cutaneous lesions, and significant pulmonary disease. The differential diagnosis was extensive, and diagnosis based on clinical grounds alone was extremely challenging. In these circumstances, diagnostic testing was essential to reach a final diagnosis.

In this case, the skin biopsy yielded a diagnosis of GD, and the rash was found to be unrelated to the patient’s systemic and pulmonary symptoms. The providers were then able to focus on the diagnosis of histoplasmosis, with only minimal intervention for the patient’s GD (ie, oral diphenhydramine prn for pruritus).

CONCLUSION
In many cases of GD, skin biopsy can guide providers when the history and physical examination do not yield a clear diagnosis. The histopathology of affected tissue can provide invaluable information about an underlying disease process, particularly in complex cases such as this patient’s. Skin biopsy provides a minimally invasive opportunity to obtain a diagnosis in patients with a condition that affects multiple organ systems, and its use should be considered in disease processes with cutaneous manifestations.

REFERENCES
1. Scheinfeld N, Mones J. Seasonal variation of transient acantholytic dyskeratosis (Grover’s disease). J Am Acad Dermatol. 2006;55(2): 263-268.
2. Parsons JM. Transient acantholytic dermatosis (Grover’s disease): a global perspective. J Am Acad Dermatol. 1996;35(5 part 1):653-666.
3. Weaver J, Bergfeld WF. Grover disease (transient acantholytic dermatosis). Arch Pathol Lab Med. 2009;133(9):1490-1494.
4. Quirk CJ, Heenan PJ. Grover’s disease: 34 years on. Australas J Dermatol. 2004;45(2):83-86.
5. Ippoliti G, Paulli M, Lucioni M, et al. Grover’s disease after heart transplantation: a case report. Case Rep Transplant. 2012;2012:126592.
6. Streit M, Paredes BE, Braathen LR, Brand CU. Transitory acantholytic dermatosis (Grover’s disease): an analysis of the clinical spectrum based on 21 histologically assessed cases [in German]. Hautarzt. 2000;51:244-249.
7. Joshi R, Taneja A. Grover’s disease with acrosyringeal acantholysis: a rare histological presentation of an uncommon disease. Indian J Dermatol. 2014;59(6):621-623.
8. Riemann H, High WA. Grover’s disease (transient and persistent acantholytic dermatosis). UpToDate. 2015. www.uptodate.com/contents/grovers-disease-transient-and-persistent-acantholytic-dermatosis. Accessed June 4, 2016.
9. Breuckmann F, Appelhans C, Altmeyer P, Kreuter A. Medium-dose ultraviolet A1 phototherapy in transient acantholytic dermatosis (Grover’s disease). J Am Acad Dermatol. 2005;52(1):169-170.
10. Norman R, Chau V. Use of etanercept in treating pruritus and preventing new lesions in Grover disease. J Am Acad Dermatol. 2011;64(4):796-798.

Updated guidelines from the National Institute of Allergy and Infectious Diseases for the early introduction of peanut-containing foods to children at increased risk for peanut allergies are on the horizon, pending final approval.

“Two studies recently showed that infants at high risk of developing peanut allergy [infants with egg allergy and or severe eczema] were much less likely to have peanut allergy at age 5 years if they were able to incorporate peanut regularly into the diet between 4 and 11 months of age,” said Dr. Scott H. Sicherer, the Elliot and Roslyn Jaffe Professor of Pediatrics, Allergy and Immunology, and chief of the division of allergy and immunology in the department of pediatrics at the Icahn School of Medicine at Mount Sinai, New York.

©mates/Fotolia.com

“However, adding peanut to the diet at this age requires caution because these infants may already be allergic to peanut, and so allergy testing and care in adding peanut to the diet with medical supervision is needed in this high-risk group,” noted Dr. Sicherer, a member of the expert panel that worked on the guidelines.

The draft guidelines include 43 clinical recommendations for the diagnosis and management of food allergies in children, according to the NIAID website. In particular, the draft guidelines recommend introducing peanut-containing foods to infants aged 4-6 months who are at increased risk for peanut allergy because of severe eczema and/or egg allergies, after an evaluation with skin prick testing or peanut-specific IgE testing.

“Peanut allergy is relatively common and often persistent, and so a strategy that could prevent the allergy is very important,” Dr. Sicherer said in an interview. “However, peanut can be a choking hazard as peanuts or peanut butter, and so families should talk to their pediatrician about how and when to incorporate peanut into the diet, and whether allergy testing and referral to an allergist is needed.”

Support for the guidelines comes from several large studies with promising results, notably the LEAP (Learning Early about Peanut Allergy) trial. A recent extension of that study, known as LEAP-On (Persistence of Oral Tolerance to Peanut), showed that regular consumption of peanut-containing foods from infancy to 5 years provided ongoing protection against allergies, even 6 years after peanut consumption was discontinued for a 1-year period in 550 children (N Eng J Med. 2016 Apr 14;374:1435-43).

In the original LEAP study, 640 infants aged 4-11 months with severe eczema, egg allergy, or both were randomized to dietary peanut consumption or avoidance (N Engl J Med. 2015 Feb 26;372[9]:803-13). The prevalence of peanut allergy at 5 years of age was approximately 2% in the peanut-consumption group, compared with 14% in the peanut-avoidance group.

Another significant randomized trial, the EAT study (Enquiring About Tolerance) tested not only peanut, but also the early introduction of cooked egg, cow’s milk, sesame, wheat, and fish to 1,303 infants aged 3 months and older in the general population. The study’s strict protocol made adherence difficult, but researchers found a significant 67% reduction in the prevalence of food allergies at age 3 years among the children who followed the protocol, compared with controls, with relative risk reductions of 100% and 75%, respectively, for peanut and egg allergies (N Engl J Med. 2016 May 5;374:1733-43).

The next steps for research should make early introduction of peanut-containing foods even more effective at allergy prevention, Dr. Sicherer noted.

“We need to learn more about how much peanut should be incorporated into the diet, how long the protein has to be kept in the diet to have the best preventative effect, and whether this strategy applies to other foods,” he said.

Updated guidelines from the National Institute of Allergy and Infectious Diseases for the early introduction of peanut-containing foods to children at increased risk for peanut allergies are on the horizon, pending final approval.

“Two studies recently showed that infants at high risk of developing peanut allergy [infants with egg allergy and or severe eczema] were much less likely to have peanut allergy at age 5 years if they were able to incorporate peanut regularly into the diet between 4 and 11 months of age,” said Dr. Scott H. Sicherer, the Elliot and Roslyn Jaffe Professor of Pediatrics, Allergy and Immunology, and chief of the division of allergy and immunology in the department of pediatrics at the Icahn School of Medicine at Mount Sinai, New York.

©mates/Fotolia.com

“However, adding peanut to the diet at this age requires caution because these infants may already be allergic to peanut, and so allergy testing and care in adding peanut to the diet with medical supervision is needed in this high-risk group,” noted Dr. Sicherer, a member of the expert panel that worked on the guidelines.

The draft guidelines include 43 clinical recommendations for the diagnosis and management of food allergies in children, according to the NIAID website. In particular, the draft guidelines recommend introducing peanut-containing foods to infants aged 4-6 months who are at increased risk for peanut allergy because of severe eczema and/or egg allergies, after an evaluation with skin prick testing or peanut-specific IgE testing.

“Peanut allergy is relatively common and often persistent, and so a strategy that could prevent the allergy is very important,” Dr. Sicherer said in an interview. “However, peanut can be a choking hazard as peanuts or peanut butter, and so families should talk to their pediatrician about how and when to incorporate peanut into the diet, and whether allergy testing and referral to an allergist is needed.”

Support for the guidelines comes from several large studies with promising results, notably the LEAP (Learning Early about Peanut Allergy) trial. A recent extension of that study, known as LEAP-On (Persistence of Oral Tolerance to Peanut), showed that regular consumption of peanut-containing foods from infancy to 5 years provided ongoing protection against allergies, even 6 years after peanut consumption was discontinued for a 1-year period in 550 children (N Eng J Med. 2016 Apr 14;374:1435-43).

In the original LEAP study, 640 infants aged 4-11 months with severe eczema, egg allergy, or both were randomized to dietary peanut consumption or avoidance (N Engl J Med. 2015 Feb 26;372[9]:803-13). The prevalence of peanut allergy at 5 years of age was approximately 2% in the peanut-consumption group, compared with 14% in the peanut-avoidance group.

Another significant randomized trial, the EAT study (Enquiring About Tolerance) tested not only peanut, but also the early introduction of cooked egg, cow’s milk, sesame, wheat, and fish to 1,303 infants aged 3 months and older in the general population. The study’s strict protocol made adherence difficult, but researchers found a significant 67% reduction in the prevalence of food allergies at age 3 years among the children who followed the protocol, compared with controls, with relative risk reductions of 100% and 75%, respectively, for peanut and egg allergies (N Engl J Med. 2016 May 5;374:1733-43).

The next steps for research should make early introduction of peanut-containing foods even more effective at allergy prevention, Dr. Sicherer noted.

“We need to learn more about how much peanut should be incorporated into the diet, how long the protein has to be kept in the diet to have the best preventative effect, and whether this strategy applies to other foods,” he said.

Updated guidelines from the National Institute of Allergy and Infectious Diseases for the early introduction of peanut-containing foods to children at increased risk for peanut allergies are on the horizon, pending final approval.

“Two studies recently showed that infants at high risk of developing peanut allergy [infants with egg allergy and or severe eczema] were much less likely to have peanut allergy at age 5 years if they were able to incorporate peanut regularly into the diet between 4 and 11 months of age,” said Dr. Scott H. Sicherer, the Elliot and Roslyn Jaffe Professor of Pediatrics, Allergy and Immunology, and chief of the division of allergy and immunology in the department of pediatrics at the Icahn School of Medicine at Mount Sinai, New York.

©mates/Fotolia.com

“However, adding peanut to the diet at this age requires caution because these infants may already be allergic to peanut, and so allergy testing and care in adding peanut to the diet with medical supervision is needed in this high-risk group,” noted Dr. Sicherer, a member of the expert panel that worked on the guidelines.

The draft guidelines include 43 clinical recommendations for the diagnosis and management of food allergies in children, according to the NIAID website. In particular, the draft guidelines recommend introducing peanut-containing foods to infants aged 4-6 months who are at increased risk for peanut allergy because of severe eczema and/or egg allergies, after an evaluation with skin prick testing or peanut-specific IgE testing.

“Peanut allergy is relatively common and often persistent, and so a strategy that could prevent the allergy is very important,” Dr. Sicherer said in an interview. “However, peanut can be a choking hazard as peanuts or peanut butter, and so families should talk to their pediatrician about how and when to incorporate peanut into the diet, and whether allergy testing and referral to an allergist is needed.”

Support for the guidelines comes from several large studies with promising results, notably the LEAP (Learning Early about Peanut Allergy) trial. A recent extension of that study, known as LEAP-On (Persistence of Oral Tolerance to Peanut), showed that regular consumption of peanut-containing foods from infancy to 5 years provided ongoing protection against allergies, even 6 years after peanut consumption was discontinued for a 1-year period in 550 children (N Eng J Med. 2016 Apr 14;374:1435-43).

In the original LEAP study, 640 infants aged 4-11 months with severe eczema, egg allergy, or both were randomized to dietary peanut consumption or avoidance (N Engl J Med. 2015 Feb 26;372[9]:803-13). The prevalence of peanut allergy at 5 years of age was approximately 2% in the peanut-consumption group, compared with 14% in the peanut-avoidance group.

Another significant randomized trial, the EAT study (Enquiring About Tolerance) tested not only peanut, but also the early introduction of cooked egg, cow’s milk, sesame, wheat, and fish to 1,303 infants aged 3 months and older in the general population. The study’s strict protocol made adherence difficult, but researchers found a significant 67% reduction in the prevalence of food allergies at age 3 years among the children who followed the protocol, compared with controls, with relative risk reductions of 100% and 75%, respectively, for peanut and egg allergies (N Engl J Med. 2016 May 5;374:1733-43).

The next steps for research should make early introduction of peanut-containing foods even more effective at allergy prevention, Dr. Sicherer noted.

“We need to learn more about how much peanut should be incorporated into the diet, how long the protein has to be kept in the diet to have the best preventative effect, and whether this strategy applies to other foods,” he said.

SAN DIEGO – About 90% of patients reported improvement in symptoms of irritable bowel syndrome after avoiding type 4 food allergens identified by skin patch testing, according to an uncontrolled study.

Furthermore, 69% of patients reported at least moderate improvement after eliminating foods to which they reacted, said Dr. Michael Stierstorfer, a dermatologist at East Penn Dermatology in North Wales, Pa., who partnered with gastroenterologists at Temple University to conduct the study. “This raises questions about a possible overlap between IBS and allergic contact enteritis,” the researchers stated in a poster presented at the annual Digestive Disease Week.

Amy Karon/Frontline Medical News

Irritable bowel syndrome is often treatment refractory and tends to elude conventional diagnostics. That was the case for Dr. Stierstorfer, who several years ago developed symptoms of IBS with constipation (IBS-C) that eventually affected him about half the time, he said in an interview. A hydrogen breath test, upper endoscopy, colonoscopy, abdominal/pelvic CT, and tests for gluten-sensitive enteropathy and parasites revealed no abnormalities except decreased small intestinal motility, he said.

But after “flaring badly” twice when he ate Indian food, he began to suspect a cause. “I stopped eating garlic and within a day, I was absolutely fine,” Dr. Stierstorfer said. “The symptoms recurred only if I accidentally ate garlic again.”

Studies had refuted links between IBS and type 1 hypersensitivity but had not explored the role of type 4 (delayed) hypersensitivity in the disorder, Dr. Stierstorfer discovered. “Dermatologists do patch testing all the time for patients with refractory eczema to search for type 4 allergic contact factors that might be causing their rash,” he said. “I performed a patch test of garlic on myself to look for a type 4 allergy, and it was strongly positive. I thought I probably wasn’t the only person walking around with symptoms that mimicked IBS but were really from a type 4 food allergy.”

He tested that idea by skin patch testing 50 patients with IBS symptoms whom he recruited through his dermatology practice. In all, 30 (60%) patients reacted to at least one food allergen, of whom 14 (46%) reported symptomatic improvement after eliminating the suspected triggers from their diets. The findings appeared in the March 2013 Journal of the American Academy of Dermatology (68:377-84).

Next, Dr. Stierstorfer partnered with Dr. Grace Shin, a 3rd-year gastroenterology fellow at Temple University, Philadelphia, and her colleagues. Together, they tested 57 patients with physician-diagnosed IBS with diarrhea (about 43% of patients), IBS with constipation (16%), mixed IBS (30%), or unsubtyped IBS (11%). Patients averaged 41 years of age (standard deviation, 15 years) and 77% were female. Each patient had between 118 and 122 individual allergen patches placed on his or her back. Two days later, the patches were removed and the skin evaluated for macular erythema consistent with a type 4 hypersensitivity reaction. The patients were checked again a day or 2 later to catch any highly delayed reactions.

In all, 56 patients (98%) showed evidence of at least one hypersensitivity, and most reacted to between two and three allergens, Dr. Stierstorfer said. The most commonly identified triggers were cinnamon bark (35 patients; 61%) and sodium bisulfite (26 patients; 46%). At baseline, patients rated their abdominal pain or discomfort at an average of 6.7 on a 10-point severity scale (SD, 2.3 points). After 2-4 weeks of avoiding allergens to which they developed macular edema, they reported a mean 4.4-point improvement in their abdominal symptoms (SD, 2.7 points; P less than .001).

The patients also reported an average 5.8-point improvement on a 10-point scale of global IBS symptom severity (SD, 3.2 points; P less than .001). Overall, 91% of patients reported at least partial relief of abdominal symptoms, while 89% of patients reported at least partial relief of global symptoms, the investigators reported.

Based on these results, “food-related type 4 hypersensitivity reactions may contribute to the pathogenesis of IBS and IBS-like symptoms,” Dr. Shin said in an interview. “The idea of allergic contact enteritis intrigued me, because it made me think that some patients diagnosed with IBS, especially IBS with diarrhea, might benefit from allergy testing when the standard approaches don’t work.”

Another dietary intervention for IBS, the low-FODMAP diet, can help relieve symptoms, “but it’s a hard diet to follow,” Dr. Shin added. “Being able to focus on eliminating one or two things would be easier than eliminating multiple classes of foods that are so common to an American diet.”

Next, the team is planning a controlled trial of the skin patch test. “There is still more validation work to do,” said Dr. Stierstorfer. “But I think this shows that looking at something from a unique perspective – in this case, a dermatologic perspective for a GI problem – can result in a new approach, and potentially an advance in medicine.”

Dr. Shin had no disclosures. Dr. Stierstorfer disclosed financial ties to IBS Centers for Advanced Food Allergy Testing.

SAN DIEGO – About 90% of patients reported improvement in symptoms of irritable bowel syndrome after avoiding type 4 food allergens identified by skin patch testing, according to an uncontrolled study.

Furthermore, 69% of patients reported at least moderate improvement after eliminating foods to which they reacted, said Dr. Michael Stierstorfer, a dermatologist at East Penn Dermatology in North Wales, Pa., who partnered with gastroenterologists at Temple University to conduct the study. “This raises questions about a possible overlap between IBS and allergic contact enteritis,” the researchers stated in a poster presented at the annual Digestive Disease Week.

Amy Karon/Frontline Medical News

Irritable bowel syndrome is often treatment refractory and tends to elude conventional diagnostics. That was the case for Dr. Stierstorfer, who several years ago developed symptoms of IBS with constipation (IBS-C) that eventually affected him about half the time, he said in an interview. A hydrogen breath test, upper endoscopy, colonoscopy, abdominal/pelvic CT, and tests for gluten-sensitive enteropathy and parasites revealed no abnormalities except decreased small intestinal motility, he said.

But after “flaring badly” twice when he ate Indian food, he began to suspect a cause. “I stopped eating garlic and within a day, I was absolutely fine,” Dr. Stierstorfer said. “The symptoms recurred only if I accidentally ate garlic again.”

Studies had refuted links between IBS and type 1 hypersensitivity but had not explored the role of type 4 (delayed) hypersensitivity in the disorder, Dr. Stierstorfer discovered. “Dermatologists do patch testing all the time for patients with refractory eczema to search for type 4 allergic contact factors that might be causing their rash,” he said. “I performed a patch test of garlic on myself to look for a type 4 allergy, and it was strongly positive. I thought I probably wasn’t the only person walking around with symptoms that mimicked IBS but were really from a type 4 food allergy.”

He tested that idea by skin patch testing 50 patients with IBS symptoms whom he recruited through his dermatology practice. In all, 30 (60%) patients reacted to at least one food allergen, of whom 14 (46%) reported symptomatic improvement after eliminating the suspected triggers from their diets. The findings appeared in the March 2013 Journal of the American Academy of Dermatology (68:377-84).

Next, Dr. Stierstorfer partnered with Dr. Grace Shin, a 3rd-year gastroenterology fellow at Temple University, Philadelphia, and her colleagues. Together, they tested 57 patients with physician-diagnosed IBS with diarrhea (about 43% of patients), IBS with constipation (16%), mixed IBS (30%), or unsubtyped IBS (11%). Patients averaged 41 years of age (standard deviation, 15 years) and 77% were female. Each patient had between 118 and 122 individual allergen patches placed on his or her back. Two days later, the patches were removed and the skin evaluated for macular erythema consistent with a type 4 hypersensitivity reaction. The patients were checked again a day or 2 later to catch any highly delayed reactions.

In all, 56 patients (98%) showed evidence of at least one hypersensitivity, and most reacted to between two and three allergens, Dr. Stierstorfer said. The most commonly identified triggers were cinnamon bark (35 patients; 61%) and sodium bisulfite (26 patients; 46%). At baseline, patients rated their abdominal pain or discomfort at an average of 6.7 on a 10-point severity scale (SD, 2.3 points). After 2-4 weeks of avoiding allergens to which they developed macular edema, they reported a mean 4.4-point improvement in their abdominal symptoms (SD, 2.7 points; P less than .001).

The patients also reported an average 5.8-point improvement on a 10-point scale of global IBS symptom severity (SD, 3.2 points; P less than .001). Overall, 91% of patients reported at least partial relief of abdominal symptoms, while 89% of patients reported at least partial relief of global symptoms, the investigators reported.

Based on these results, “food-related type 4 hypersensitivity reactions may contribute to the pathogenesis of IBS and IBS-like symptoms,” Dr. Shin said in an interview. “The idea of allergic contact enteritis intrigued me, because it made me think that some patients diagnosed with IBS, especially IBS with diarrhea, might benefit from allergy testing when the standard approaches don’t work.”

Another dietary intervention for IBS, the low-FODMAP diet, can help relieve symptoms, “but it’s a hard diet to follow,” Dr. Shin added. “Being able to focus on eliminating one or two things would be easier than eliminating multiple classes of foods that are so common to an American diet.”

Next, the team is planning a controlled trial of the skin patch test. “There is still more validation work to do,” said Dr. Stierstorfer. “But I think this shows that looking at something from a unique perspective – in this case, a dermatologic perspective for a GI problem – can result in a new approach, and potentially an advance in medicine.”

Dr. Shin had no disclosures. Dr. Stierstorfer disclosed financial ties to IBS Centers for Advanced Food Allergy Testing.

SAN DIEGO – About 90% of patients reported improvement in symptoms of irritable bowel syndrome after avoiding type 4 food allergens identified by skin patch testing, according to an uncontrolled study.

Furthermore, 69% of patients reported at least moderate improvement after eliminating foods to which they reacted, said Dr. Michael Stierstorfer, a dermatologist at East Penn Dermatology in North Wales, Pa., who partnered with gastroenterologists at Temple University to conduct the study. “This raises questions about a possible overlap between IBS and allergic contact enteritis,” the researchers stated in a poster presented at the annual Digestive Disease Week.

Amy Karon/Frontline Medical News

Irritable bowel syndrome is often treatment refractory and tends to elude conventional diagnostics. That was the case for Dr. Stierstorfer, who several years ago developed symptoms of IBS with constipation (IBS-C) that eventually affected him about half the time, he said in an interview. A hydrogen breath test, upper endoscopy, colonoscopy, abdominal/pelvic CT, and tests for gluten-sensitive enteropathy and parasites revealed no abnormalities except decreased small intestinal motility, he said.

But after “flaring badly” twice when he ate Indian food, he began to suspect a cause. “I stopped eating garlic and within a day, I was absolutely fine,” Dr. Stierstorfer said. “The symptoms recurred only if I accidentally ate garlic again.”

Studies had refuted links between IBS and type 1 hypersensitivity but had not explored the role of type 4 (delayed) hypersensitivity in the disorder, Dr. Stierstorfer discovered. “Dermatologists do patch testing all the time for patients with refractory eczema to search for type 4 allergic contact factors that might be causing their rash,” he said. “I performed a patch test of garlic on myself to look for a type 4 allergy, and it was strongly positive. I thought I probably wasn’t the only person walking around with symptoms that mimicked IBS but were really from a type 4 food allergy.”

He tested that idea by skin patch testing 50 patients with IBS symptoms whom he recruited through his dermatology practice. In all, 30 (60%) patients reacted to at least one food allergen, of whom 14 (46%) reported symptomatic improvement after eliminating the suspected triggers from their diets. The findings appeared in the March 2013 Journal of the American Academy of Dermatology (68:377-84).

Next, Dr. Stierstorfer partnered with Dr. Grace Shin, a 3rd-year gastroenterology fellow at Temple University, Philadelphia, and her colleagues. Together, they tested 57 patients with physician-diagnosed IBS with diarrhea (about 43% of patients), IBS with constipation (16%), mixed IBS (30%), or unsubtyped IBS (11%). Patients averaged 41 years of age (standard deviation, 15 years) and 77% were female. Each patient had between 118 and 122 individual allergen patches placed on his or her back. Two days later, the patches were removed and the skin evaluated for macular erythema consistent with a type 4 hypersensitivity reaction. The patients were checked again a day or 2 later to catch any highly delayed reactions.

In all, 56 patients (98%) showed evidence of at least one hypersensitivity, and most reacted to between two and three allergens, Dr. Stierstorfer said. The most commonly identified triggers were cinnamon bark (35 patients; 61%) and sodium bisulfite (26 patients; 46%). At baseline, patients rated their abdominal pain or discomfort at an average of 6.7 on a 10-point severity scale (SD, 2.3 points). After 2-4 weeks of avoiding allergens to which they developed macular edema, they reported a mean 4.4-point improvement in their abdominal symptoms (SD, 2.7 points; P less than .001).

The patients also reported an average 5.8-point improvement on a 10-point scale of global IBS symptom severity (SD, 3.2 points; P less than .001). Overall, 91% of patients reported at least partial relief of abdominal symptoms, while 89% of patients reported at least partial relief of global symptoms, the investigators reported.

Based on these results, “food-related type 4 hypersensitivity reactions may contribute to the pathogenesis of IBS and IBS-like symptoms,” Dr. Shin said in an interview. “The idea of allergic contact enteritis intrigued me, because it made me think that some patients diagnosed with IBS, especially IBS with diarrhea, might benefit from allergy testing when the standard approaches don’t work.”

Another dietary intervention for IBS, the low-FODMAP diet, can help relieve symptoms, “but it’s a hard diet to follow,” Dr. Shin added. “Being able to focus on eliminating one or two things would be easier than eliminating multiple classes of foods that are so common to an American diet.”

Next, the team is planning a controlled trial of the skin patch test. “There is still more validation work to do,” said Dr. Stierstorfer. “But I think this shows that looking at something from a unique perspective – in this case, a dermatologic perspective for a GI problem – can result in a new approach, and potentially an advance in medicine.”

Dr. Shin had no disclosures. Dr. Stierstorfer disclosed financial ties to IBS Centers for Advanced Food Allergy Testing.

A previously healthy 32-year-old man presented to the emergency room with a persistent, nonpruritic rash on his trunk, which had suddenly appeared 2 days after he ate Chinese food.

Physical examination revealed multiple crosslinked linear plaques that appeared like scratches over his chest, back, and shoulders (Figures 1 and 2). He had no dermatographism, and his scalp, nails, palms, and soles were not affected. He had no signs of lymphadenopathy or systemic involvement.

Basic blood and urinary laboratory testing, blood cultures, and serologic studies showed normal or negative results.

Given the presentation and results of initial testing, his rash was diagnosed as flagellate erythema, likely due to shiitake mushroom intake. The diagnosis does not require histopathologic confirmation.

The rash resolved spontaneously over the next 2 weeks with use of a topical emollient and without scarring or residual hyperpigmentation.

FLAGELLATE ERYTHEMA

Flagellate erythema is a peculiar cutaneous eruption characterized by the progressive or sudden onset of parallel linear or curvilinear plaques, most commonly on the trunk. The plaques are typically arranged in a scratch pattern resembling marks left by the lashes of a whip.¹ In contrast to other itchy dermatoses and neurotic excoriations that may present with self-induced linear marks, flagellate erythema appears spontaneously.

Drug-related causes, disease associations

Originally described in association with bleomycin treatment, flagellate erythema is currently considered a distinct feature of several dermatologic and systemic disorders, and therefore the ability to recognize it is valuable in daily practice.² In addition to bleomycin analogues and anticancer agents such as peplomycin,¹ bendamustine,³ and docetaxel,⁴ physicians should consider shiitake dermatitis⁵ and other less commonly reported associations such as dermatomyositis,⁶ lupus,⁷ Still disease,⁸ and parvovirus infection.⁹

Diagnostic features

The diagnosis of flagellate erythema is mainly based on the morphologic features of the clinical lesions.¹ Shiitake dermatitis and flagellate erythema related to rheumatologic disease usually present with more inflammatory and erythematous plaques. Chemotherapy-induced flagellate rash typically has a violaceous or purpuric coloration, which tends to leave noticeable hyperpigmentation for several months.²

Skin biopsy may be necessary to distinguish it from similar-looking dermatoses with different histologic findings, such as dermatographism, phytophotodermatitis, erythema gyratum repens, and factitious dermatoses, which may require specific treatments or be related to important underlying pathology.^1,2

Treatment

Treatment includes both specific treatment of the underlying cause and symptomatic care of the skin with topical emollients and, in cases of associated pruritus, oral antihistamines. The patient should also be reassured about the self-healing nature of shiitake dermatitis rash.⁵

A previously healthy 32-year-old man presented to the emergency room with a persistent, nonpruritic rash on his trunk, which had suddenly appeared 2 days after he ate Chinese food.

Physical examination revealed multiple crosslinked linear plaques that appeared like scratches over his chest, back, and shoulders (Figures 1 and 2). He had no dermatographism, and his scalp, nails, palms, and soles were not affected. He had no signs of lymphadenopathy or systemic involvement.

Basic blood and urinary laboratory testing, blood cultures, and serologic studies showed normal or negative results.

Given the presentation and results of initial testing, his rash was diagnosed as flagellate erythema, likely due to shiitake mushroom intake. The diagnosis does not require histopathologic confirmation.

The rash resolved spontaneously over the next 2 weeks with use of a topical emollient and without scarring or residual hyperpigmentation.

FLAGELLATE ERYTHEMA

Flagellate erythema is a peculiar cutaneous eruption characterized by the progressive or sudden onset of parallel linear or curvilinear plaques, most commonly on the trunk. The plaques are typically arranged in a scratch pattern resembling marks left by the lashes of a whip.¹ In contrast to other itchy dermatoses and neurotic excoriations that may present with self-induced linear marks, flagellate erythema appears spontaneously.

Drug-related causes, disease associations

Originally described in association with bleomycin treatment, flagellate erythema is currently considered a distinct feature of several dermatologic and systemic disorders, and therefore the ability to recognize it is valuable in daily practice.² In addition to bleomycin analogues and anticancer agents such as peplomycin,¹ bendamustine,³ and docetaxel,⁴ physicians should consider shiitake dermatitis⁵ and other less commonly reported associations such as dermatomyositis,⁶ lupus,⁷ Still disease,⁸ and parvovirus infection.⁹

Diagnostic features

The diagnosis of flagellate erythema is mainly based on the morphologic features of the clinical lesions.¹ Shiitake dermatitis and flagellate erythema related to rheumatologic disease usually present with more inflammatory and erythematous plaques. Chemotherapy-induced flagellate rash typically has a violaceous or purpuric coloration, which tends to leave noticeable hyperpigmentation for several months.²

Skin biopsy may be necessary to distinguish it from similar-looking dermatoses with different histologic findings, such as dermatographism, phytophotodermatitis, erythema gyratum repens, and factitious dermatoses, which may require specific treatments or be related to important underlying pathology.^1,2

Treatment

Treatment includes both specific treatment of the underlying cause and symptomatic care of the skin with topical emollients and, in cases of associated pruritus, oral antihistamines. The patient should also be reassured about the self-healing nature of shiitake dermatitis rash.⁵

A previously healthy 32-year-old man presented to the emergency room with a persistent, nonpruritic rash on his trunk, which had suddenly appeared 2 days after he ate Chinese food.

Physical examination revealed multiple crosslinked linear plaques that appeared like scratches over his chest, back, and shoulders (Figures 1 and 2). He had no dermatographism, and his scalp, nails, palms, and soles were not affected. He had no signs of lymphadenopathy or systemic involvement.

Basic blood and urinary laboratory testing, blood cultures, and serologic studies showed normal or negative results.

Given the presentation and results of initial testing, his rash was diagnosed as flagellate erythema, likely due to shiitake mushroom intake. The diagnosis does not require histopathologic confirmation.

The rash resolved spontaneously over the next 2 weeks with use of a topical emollient and without scarring or residual hyperpigmentation.

FLAGELLATE ERYTHEMA

Flagellate erythema is a peculiar cutaneous eruption characterized by the progressive or sudden onset of parallel linear or curvilinear plaques, most commonly on the trunk. The plaques are typically arranged in a scratch pattern resembling marks left by the lashes of a whip.¹ In contrast to other itchy dermatoses and neurotic excoriations that may present with self-induced linear marks, flagellate erythema appears spontaneously.

Drug-related causes, disease associations

Originally described in association with bleomycin treatment, flagellate erythema is currently considered a distinct feature of several dermatologic and systemic disorders, and therefore the ability to recognize it is valuable in daily practice.² In addition to bleomycin analogues and anticancer agents such as peplomycin,¹ bendamustine,³ and docetaxel,⁴ physicians should consider shiitake dermatitis⁵ and other less commonly reported associations such as dermatomyositis,⁶ lupus,⁷ Still disease,⁸ and parvovirus infection.⁹

Diagnostic features

The diagnosis of flagellate erythema is mainly based on the morphologic features of the clinical lesions.¹ Shiitake dermatitis and flagellate erythema related to rheumatologic disease usually present with more inflammatory and erythematous plaques. Chemotherapy-induced flagellate rash typically has a violaceous or purpuric coloration, which tends to leave noticeable hyperpigmentation for several months.²

Skin biopsy may be necessary to distinguish it from similar-looking dermatoses with different histologic findings, such as dermatographism, phytophotodermatitis, erythema gyratum repens, and factitious dermatoses, which may require specific treatments or be related to important underlying pathology.^1,2

Treatment

Treatment includes both specific treatment of the underlying cause and symptomatic care of the skin with topical emollients and, in cases of associated pruritus, oral antihistamines. The patient should also be reassured about the self-healing nature of shiitake dermatitis rash.⁵