Dermatologic Manifestations of Eosinophilic Granulomatosis With Polyangiitis (Churg-Strauss Syndrome)

The diagnosis of eosinophilic granulomatosis with polyangiitis (EGPA) is challenging because of the highly variable presentation and course of the disease. Some patients have only mild manifestations, while others are affected by life-threatening conditions. Some investigators have divided EGPA into 3 phases, as follows[9] :

1. A prodromal phase characterized by allergic manifestations followed by asthma
2. A second phase of marked peripheral blood eosinophilia and eosinophilic tissue infiltration that produces a picture similar to that of Loeffler syndrome, chronic eosinophilic pneumonia, or eosinophilic gastroenteritis
3. A third phase with systemic vasculitis

Pulmonary involvement, neuropathy, and skin lesions are common with each occurring in at least two thirds or more of affected patients. Other systemic features include polyneuropathy (symmetric or mononeuritis multiplex), ischemic bowel disease, nasal perforation, glomerulonephritis, ocular inflammation, coronary arteritis, and cardiomyopathy.[10] Myocardial involvement or congestive heart failure is the most common cause of death. A high eosinophilia count is present in all patients, averaging 1 X 109/L, and approximately two thirds have a positive perinuclear ANCA titer, which targets primarily myeloperoxidase.[11]

More than one classification scheme exists for EGPA, including Lanham’s criteria, which emphasize clinical features, and the Chapel Hill Consensus Conference criteria, which emphasize pathology. A third option is the American College of Rheumatology (ACR) criteria, originally created for epidemiologic and therapeutic studies.

The etiology of eosinophilic granulomatosis with polyangiitis (EGPA) remains unclear. Several triggers are suspected, including environmental factors such as inhaled allergens, infections (bacterial or parasitic), vaccinations, and medications (eg, carbamazepine, quinine, macrolides, corticosteroid-sparing drugs used to treat asthma) all have been implicated. A class of medications that has received particular attention is leukotriene receptor antagonists, which are typically used to treat asthma. It is postulated that the use of these medications may lead to a reduction in patients’ corticosteroid exposure, unmasking EGPA features such as vasculitis. It remains unclear if they are a direct cause or simply associated with the disease.[12] Another possible drug association with EGPA is omalizumab, an anti-immunoglobulin E (IgE) antibody used to treat asthma. Once again, whether omalizumab use is truly responsible for EGPA or simply unmasks it after corticosteroid tapering remains unclear.[13, 14]

A foreign or infectious agent has been suggested to initiate an inflammatory cascade in an individual with a susceptible genetic background. Small sample sizes complicate EGPA genetic association studies. Two studies from Italy and Germany found HLA-DRB1 alleles and HLA-DRB3 and HLA-DR4 associated with EGPA. HLA-DR4 was found to correlate with vasculitic symptoms of the antineutrophil cytoplasmic antibodies (ANCA)‒positive subset.[6]

Frequency

United States

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare and likely underreported disease.

International

EGPA is a rare disease. The annual incidence of the disorder is estimated at 2.4-4 cases per million general population, while among asthma patients, an average of 34.6 cases per million asthma population as been reported.[15]

Race-, sex-, and age-related information

No racial predilection is currently recognized for EGPA.

Sexual predilection for EGPA varies according to the source, with most sources citing a male predominance. The male-to-female ratio is 1.3:1.

EGPA may affect both children and elderly persons. The age of onset is wide (4-75 y), with a mean age of 38 years.[16]

Since the introduction of immunosuppressive therapy, considerable improvement has been gained in patient survival. Five-year survival rates for eosinophilic granulomatosis with polyangiitis (EGPA) range from 68-100% depending on the study. Deaths occurring early in the course of disease are usually attributable to active systemic vasculitis resulting multiorgan failure and/or infection. Long-term adverse effects of therapy and the development of comorbidities account for deaths later in the course of disease.[17]

Treatment with corticosteroids improves patient survival, with long-term overall remission rates nearly 82%. However, 26-28% of patients in remission have relapses. The overall mortality rate in treated patients who relapse is only 3.1%.

A short interval from the onset of asthma to the development of the systemic vasculitis indicates an unfavorable prognosis.

Clinical findings in eosinophilic granulomatosis with polyangiitis (EGPA) vary depending on the phase and organ systems involved.[2, 6, 18]

Allergic (prodromal) phase findings are as follows:

• Upper respiratory tract symptoms affect majority of patients

• Nasal polyps

• Wheezing

• Cough

• Rhinitis

• Recurrent or chronic sinusitis

Eosinophilic (second) phase findings are as follows:

• General - Weight loss, fever, sweats
• Pulmonary - Cough, hemoptysis, rales, rhonchi
• Gastrointestinal - Rebound, masses, obstruction, ascites, bleeding

Vasculitic (third) phase findings are as follows:

• Most commonly affects skin and peripheral nervous system ^[19]
• Constitutional symptoms - Fever, weight loss, adenopathy
• Cardiac - Gallop, pericardial friction rub, jugular venous distension, peripheral edema
• Pulmonary - Rales, rhonchi
• Nervous system - Mononeuritis multiplex affects up to 75% of patients (wrist or foot drop typical), ^[19] mixed sensorimotor peripheral neuropathy (most often in a glove-and-stocking distribution), ^[20] loss of a visual field, cerebral hemorrhage, ^[21] infarction
• Renal - Mild proteinuria and hematuria (more common in those with serologically detectable ANCA)
• Genitourinary - Obstructive uropathy
• Ocular - Episcleritis, panuveitis, marginal corneal ulceration, conjunctival infiltration, retinal infarction
• Musculoskeletal - Joint swelling, muscle tenderness
• Cutaneous - Palpable purpura (50%), subcutaneous nodules (scalp and extensor surfaces on extremities), firm papules on fingertips (may resemble septic emboli), urticaria, livedo reticularis

See the images below.

Magnified view of papules and nodules with central necrosis.

Distal digital purpuric papule.

A representative case of EGPA was reported by Venade et al. A 37-year-old man presented with fever, productive cough, occasional dyspnea, anorexia, and lethargy. The patient was discovered to have leukocytosis and eosinophilia, and he was also determined to be in acute renal failure. Treatment was 3 boluses of methylprednisolone 1 g and commencement of cyclophosphamide therapy with resolution of symptoms and restoration of renal function.[22]

Eosinophilic granulomatosis with polyangiitis (EGPA) is a clinical diagnosis. When present, antineutrophil cytoplasmic antibodies (ANCA) are a major diagnostic finding, but they can be absent. Eosinophilia and histologic vasculitis can also support the diagnosis. Skin, nerve, and muscle biopsy sites yield the highest sensitivities. Several diagnostic criteria have been proposed, including the Lanham, American College of Rheumatology (ACR), and Chapel Hill criteria.[1]

Lanham criteria are as follows:

• Asthma
• Blood eosinophilia exceeding 1,500/µL
• Evidence of vasculitis in two or more organs

ACR criteria are as follows (4 of 6 should be present):

• Asthma
• Eosinophilia
• History of allergy
• Pulmonary infiltrates, non-fixed
• Paranasal sinus abnormalities
• Extravascular eosinophils

The following laboratory studies are warranted in eosinophilic granulomatosis with polyangiitis (EGPA):

• CBC count with erythrocyte sedimentation rate (ESR): Eosinophilia greater than 10% is a diagnostic criterion of the ACR. Treatment with steroids may mask this finding. Anemia, leukocytosis, thrombocytosis, and an elevated ESR usually accompany the vasculitic phase of EGPA.

• Rheumatoid factor (RF) and antinuclear antibody (ANA) testing: Some patients may have weakly positive ANA and/or RF results.

• Antineutrophilic cytoplasmic antibodies (ANCA) testing: Perinuclear ANCA directed predominantly against a myeloperoxidase have been reported in 40-80% of patients with EGPA; however, one study showed that only 13% had positive perinuclear ANCA findings. Because of the low sensitivity of this test, a negative ANCA result does not rule out EGPA. Renal involvement and peripheral neuropathy seem to be increased in ANCA-positive individuals. ANCA is suspected to cause damage to the vascular endothelium, while in ANCA-negative individuals inflammatory mediators and cationic proteins from eosinophils are believed to cause tissue damage. Classic ANCA directed against serine proteinase 3 is positive in approximately 10% of patients with EGPA. High titers of classic ANCA are seen more often with granulomatosis with polyangiitis (Wegener granulomatosis) than with EGPA.

• Systemic vasculitis testing: Screened patients suspected to have systemic vasculitis for cryoglobulins, antiphospholipid antibodies, immunoglobulins (immunoglobulins G, A, E, and M), complement levels (CH50, C3, and C4). Immunoglobulin E levels are usually elevated in persons with EGPA.

• Liver function testing: Serum aspartate aminotransferase and serum alanine aminotransferase levels may indicate liver or muscle involvement. Hepatitis B and C virus serologies are recommended for suspected cases of systemic vasculitis.

• Creatine phosphokinase testing: Creatine phosphokinase levels may indicate muscle or cardiac involvement.

• Gastrointestinal testing: Stool guaiac screening can be performed to test for bleeding.

• BUN and creatinine measurements: Kidney involvement in the form of focal segmental glomerulonephritis may occur, but it is typically mild. Severe kidney involvement is more common in the other systemic vasculitides, such as granulomatosis with polyangiitis (Wegener granulomatosis) and polyarteritis nodosa, than in EGPA.

• Urinalysis: Hematuria and proteinuria have been reported but are usually mild. Severe kidney involvement is more typical of the other systemic vasculitides than of EGPA.[2, 23, 6]

Imaging studies that can be performed in eosinophilic granulomatosis with polyangiitis (EGPA) are as follows:

• Chest radiography: Findings may be abnormal in both the eosinophilic stage and the vasculitic phase. Radiographs typically reveal transient patchy alveolar opacities, nodular infiltrates, or a diffuse interstitial pattern. Bilateral hilar adenopathy has also been reported.[11]

• Sinus radiography: Opacification of the paranasal sinuses is an ACR diagnostic criterion.

• ECG, echocardiography, and cardiac MRI: Cardiac involvement is common in EGPA and may affect the pericardium, myocardium, and endocardium. Pericardial effusion, cardiomyopathy, cardiac valve abnormalities, coronary vasculitis, and granulomatous myocarditis have all been described.[5]

• MRI: CNS involvement is found 25% of time of EGPA cases with neurologic involvement, and, in some case series it accounts for the second most common cause of mortality in this disease.[6]

Any additional testing should be based on clinical history and patient symptoms.

Due to ease of access, the skin, followed by the kidney, are the most frequently selected sites for biopsy. Skin biopsy specimens should be taken from a lesion that has arisen within the last 48 hours. Biopsy specimens for direct immunofluorescence examination should also be obtained from a lesion that has arisen within the last 48 hours.

Biopsy may reveal a variety of histologic changes, including necrotizing vasculitis of small-to-medium vessels, eosinophilic infiltration, and extravascular granulomas. Nodular lesions frequently reveal characteristic extravascular granulomas. These granulomas are not pathognomic for eosinophilic granulomatosis with polyangiitis (EGPA) because they are also found in persons with granulomatosis with polyangiitis (Wegener granulomatosis), polyarteritis nodosa, systemic lupus erythematosus, rheumatoid arthritis, lymphoproliferative disorders, and other immunoreactive disorders. Granulomas are composed of a central core of necrotic eosinophilic debris with degeneration of collagen and surrounded by a peripheral palisade of epithelioid histiocytes with few, if any, giant cells. The non-nodular lesions most often demonstrate a vasculitis or a nonspecific perivascular infiltrate of eosinophils and mononuclear cells without vasculitis.[14]

Granuloma with a central core of eosinophilic debris surrounded by a peripheral palisade of epithelioid histiocytes and eosinophils.

Treatment decisions for eosinophilic granulomatosis with polyangiitis (EGPA) should be based on affected organ systems and the severity of the vasculitis. EGPA is typically a corticosteroid-responsive disease; hence, they are first-line therapeutic agents. EGPA may have an abrupt onset involving multiple organ systems and a relapsing and remitting course. The use of corticosteroids and cyclophosphamide in patients with severe manifestations has greatly improved survival rates and prognosis.[24, 25] Intravenous corticosteroids should be considered for patients with extensive disease. Dramatic responses to therapy may be observed, with improvement in eosinophilia counts, reduction of the erythrocyte sedimentation rate (ESR), and reduction in muscle enzyme levels within 1-2 weeks of the initiation of treatment. Corticosteroids may be tapered once clinical improvement occurs. Importantly, note that patients with EGPA-related neuropathy respond more slowly to treatment. Residual asthma or other symptoms may require the continuation of low-dose prednisone therapy.[10]

Cyclophosphamide should be initiated in severely ill patients who do not respond to initial therapy. Patients with life-threatening disease or those at risk of organ failure are potential candidates. The addition of cyclophosphamide appears to improve outcomes and reduces the incidence of relapses. For patients with systemic disease who are not at risk for major organ failure or death, methotrexate (MTX) may be given as a corticosteroid-sparing agent to reduce the cumulative dose. However, whether methotrexate reduces relapses remains questionable.[24] Other immunomodulatory medications include azathioprine (AZA) and mycophenolate mofetil, which may also be used as corticosteroid-sparing agents. AZA is best used for maintenance therapy rather than for induction of remission in refractory disease. Chlorambucil and plasma exchange have occasionally been used and are most effective when used in combination therapy.[23]

Agents that block tumor necrosis factor (TNF), such as infliximab and etanercept, have been used for a limited period in severe life-threatening cases. These agents, when combined with corticosteroids or other immunomodulatory agents, greatly increase the risk of infection due to immunosuppression. More data are needed to determine whether these drugs have a favorable risk-to-benefit ratio for use in EGPA patients. Another infrequently used therapy is recombinant interferon (IFN) alfa, which can be effective when given on a short-term basis in otherwise refractory cases. One anecdotal case report has described the use of rituximab in a patient with recalcitrant EGPA and another described the use of imatinib mesylate.[23, 26, 27, 28, 29]

Other studies have focused on the inhibition of interleukin 5 (IL-5) or the IL-5 receptor as a potential target for treatment in asthma and asthmatic conditions associated with eosinophilia such as EGPA. IL-5 is a cytokine involved in the regulation of eosinophils, including their maturation, activation, and survival. IL-5 levels have been found to be increased in EGPA patients. Promising anti–IL-5 drugs include mepolizumab and reslizumab. Pilot data with mepolizumab in EGPA patients suggest that its use may allow for reduction of corticosteroid doses, reducing steroid dependence in patients.[30] Controlled trials of mepolizumab are ongoing.[19]

Baldini et al have created a chart reviewing the treatment of EGPA during induction, maintenance, and refractory disease.[24]

Class Summary

These drugs have anti-inflammatory and immunosuppressive properties.

Methylprednisolone (Medrol, Solu-Medrol)

Methylprednisolone is used to treat inflammatory and immune reactions. It may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity.

Prednisolone (Econopred, Articulose-50, Delta-Cortef)

Prednisolone decreases autoimmune reactions, possibly by suppressing key components of the immune system.

Class Summary

These agents modulate immune responses to various stimuli.

Methotrexate (Folex PFS, Rheumatrex)

Methotrexate has an unknown mechanism of action in the treatment of inflammatory reactions; it may affect immune function. Methotrexate ameliorates symptoms of inflammation (eg, pain, swelling, stiffness).

Azathioprine (Imuran)

Azathioprine antagonizes purine metabolism and inhibits the synthesis of DNA, RNA, and proteins. It may decrease the proliferation of immune cells, lowering autoimmune activity.

Cyclosporine (Sandimmune, Neoral)

Cyclosporine is a cyclic polypeptide that suppresses some humoral immunity and, to a greater extent, cell-mediated immune reactions (eg, delayed hypersensitivity, allograft rejection, experimental allergic encephalomyelitis, and graft vs host disease) in many organs. Base dosing on ideal body weight.

Interferon alfa 2b (Interferon alfa-2b, Intron A)

Interferon alfa 2a and 2b are recombinant DNA products. Their mechanism of antitumor activity is not clearly understood; they have direct antiproliferative effects against malignant cells and modulation of host immune response may be important.

Class Summary

These agents are recommended as initial therapy of severe, life-threatening Churg-Strauss syndrome (allergic granulomatosis) and for patients who are not responsive to corticosteroids alone.

Cyclophosphamide (Cytoxan, Neosar)

Cyclophosphamide is chemically related to nitrogen mustards. As an alkylating agent, the mechanism of action of the active metabolites may involve cross-linking of DNA, which may interfere with the growth of normal and neoplastic cells.

Chlorambucil (Leukeran)

Chlorambucil alkylates and cross-links strands of DNA, inhibiting DNA replication and RNA transcription.

Class Summary

These agents are recommended in severe cases when corticosteroids and cyclophosphamide may be insufficient to induce remission.

Infliximab (Remicade)

Infliximab is a monoclonal antibody with human constant and murine variable regions; it neutralizes the biologic activity of TNF-alpha with high binding affinity to the soluble transmembrane forms of TNF-alpha and it inhibits binding of TNF with receptors.

Etanercept (Enbrel)

Etanercept is a fusion protein of the TNF receptor and Fc portion of human IgG-1; it binds TNF and blocks the interaction of TNF-alpha and TNF-beta with cell-surface receptors, rendering TNF biologically inactive.