Are You Confident of the Diagnosis?
What you should be alert for in the history
Specific cutaneous lesions in Wegener’s granulomatosis (WG) occur in about 15% of patients at some time in the disease course. Most often skin lesions develop concurrently with systemic symptoms or after systemic symptoms but may be the first manifestation of disease in 10 to 20% of those who develop skin lesions. Most patients with skin lesions have more than one organ involved and may present with epistaxis, pulmonary nodules or renal disease.
Characteristic findings on physical examination
The most common skin lesion is palpable purpura of the lower extremities and sometimes the upper extremities (Figure 1). Ulcerations strongly resembling or identical to pyoderma gangrenosum may develop on the extremities or even the face (Figure 2).
The periauricular area seems to be a favored location on the face. Small papules, clustered about the elbows, knees or extensor surfaces of the fingers can also be seen. Other manifestations include livedo and erythema-nodosum-like lesions. Gingival hyperplasia with purpura is a characteristic finding. Oral ulcerations may also develop.
Expected results of diagnostic studies
Skin biopsies show leukocytoclastic vasculitis when purpuric lesions are biopsied (Figure 3). Ulcerations may demonstrate vasculitis, including granulomatous vasculitis or may show granulomatous inflammation without vasculitis. Papules most often demonstrate palisaded granulomatous inflammation closely resembling that seen in Churg-Strauss granulomas, either with or without leukocytoclastic change.
Serum tests for ANCA are most often positive in patients with active skin lesions. The most common pattern is the cytoplasmic pattern utilizing indirect immunofluoresence (c-ANCA) and Proteinase-3 as the target antigen by solid phase ELISA test. This c-ANCA/PR3 pattern is seen in approximately 75% of patients with skin lesions and WG. Other ’atypical’ ANCA patterns may be seen at times and approximately 20% may have the perinuclear pattern (p-ANCA) and myeloperoxidase (MPO) target (p-ANCA/MPO).
ANCA may be positive even before patients develop systemic lesions, aiding in the overall early diagnosis of disease. The final diagnosis must be confirmed by tissue biopsies of affected organs and correlation with the clinical findings in addition to ANCA testing.
Diagnosis confirmation requires careful correlation of the clinical findings with tissue histopathology and appropriate laboratory tests. Depending on the organ involved these tests may include CT scans, bronchoscopy, inspections and biopsy of the upper airways, renal evaluation and other.
WG must be differentiated from other systemic vasculitis syndromes including Churg-Strauss granulomatosis, polyarteritis nodosum, and others. Skin lesions may closely mimic pyoderma gangrenosum both clinically and microscopically.
Reports of cocaine-induced ANCA positive ulcerative diseases have surfaced. These patients may have clinical lesions that closely resemble the rhino/sinus or oral ulceration seen in WG. Careful correlation of the clinical findings can most often separate these patients from those with WG. Subtle differences in the ANCA targets also exist.
Other more recent reports of widespread livedo and acral purpura due to vascular coagulation similar to that seen in livedoid vasculitis but with a much more rapid, widespread and intense onset have been linked to cocaine laced with levamasole. Acral accentuation including ear involvement is most often seen in these latter conditions. Careful history taking and examination of all organs helps to distinguish this entity from WG. These two cocaine-related disorders emphasize that the diagnosis of WG should not be made on the basis of ANCA testing alone.
Who is at Risk for Developing this Disease?
The cause for WG is not known although some patients may have antecedent upper respiratory tract or sinus infections. Both genders are affected and the mean age of patients with skin lesions is the late 40’s.
What is the Cause of the Disease?
The etiology of WG is not known although the presence of PR3 ANCA and MPO ANCA’s are thought to correlate with disease activity and can be used in some (not all) patients to follow disease progress and efficacy of treatment. WG, like other vasculitides is thought to represent mainly an immune complex disease in a genetically predisposed host followed by a cascade of inflammatory events.
Infections especially of the upper respiratory tract and/or environmental allergens including silica may serve as triggering factors. Drug-induced cases have been reported especially to propylthiouracil.
In animal studies, PR3 and MPO have been shown to induce and promote inflammation with fixation of antibody, release of cytokines and chemokines, causing vascular adhesion followed by vessel damage. Likely various stimuli create the pro-inflammatory environment in which a genetically susceptible host will respond with inflammation that encompasses both a granulomatous component and vasculitis.
B-lymphocytes are involved in the production and maintenance of antibodies and T-lymphocytes including T-regulatory cells modify the inflammatory response including formation of granuloma.
Systemic Implications and Complications
Most patients with cutaneous lesions either have, or will shortly develop in days to weeks, systemic involvement. Organs involved include the upper airway, the lungs, the ears, eye, nerves, kidney and skin. A complete examination of all these systems and a thorough general medical evaluation is a must. Pulmonary nodules and hemorrhage may complicate the disease. Secondary infection is a risk either due to the disease or related to the use of immunosuppressive medications for treatment.
Therapy of WG requires a coordinated effort of medical specialists familiar with this disease. Treatment of the most affected and most critically involved organ is of key importance. Skin lesions most often respond in parallel to improvements overall. Systemic therapies should not be administered by dermatologists alone in the presence of internal organ involvement as remission as early as possible and maintenance of remission are of key importance.
Use gentle antiseptic compresses (dilute white vinegar or equivalent) to remove necrotic material from ulcers when present and to prevent secondary infection. Use whirlpool or gentle manual debridement for larger ulcers.
Oral prednisone is most often used in combination with steroid sparing medications and medications aimed at remission. The dose is most often at 1 mg/kg daily at the onset and tapered over several months depending on response.
Cyclophosphamide (2 mg/kg daily) in adults is still used for most patients until remission and continued for months to a year or as needed. It remains the gold standard for therapy in those with multi-organ or life-threatening disease.
Azathioprine (2 mg/kg daily) may be considered as an alternative if needed due to intolerance of cyclophosphamide in induction or it may be used to maintain remission.
Methotrexate (20 to 25 mg weekly for adults) may be used as a medication to maintain remission but may not be as effective as cyclophosphamide in this respect.
Mycophenolate mofetil has been reported to be effective in the maintenance of remission but controlled studies show a preference toward azathioprine or to methotrexate in maintaining remission.
Trimethoprim/sulfamethoxazole (160/800 mg daily) may be used in some patients with mainly sinus disease to maintain remission. It is most often used as well for pneumocystis jiroveci (carinii) prophylaxis at standard doses in those who are not allergic.
Rituximab has shown promise in inducing remissions and may be used in selected cases for relapse. Large multi-center trials have confirmed its effectiveness. In the induction of remission it has been used with cyclophosphamide. It is given as weekly infusions at a dose of 375 mg/m2 and often over a 4 week period of time.
Plasma exchange (up to 7 exchanges) may play a role in life threatening or treatment resistant disease and is most often given in conjunction with other more standard therapies above.
Optimal Therapeutic Approach for this Disease
According to current practice, the treatment of choice for most patients with WG is the combination of prednisone (1 mg/kg daily) together with cyclophosphamide (2 mg/kg daily). This combination has yielded the best results for remission and achieving maintenance of remission. Rituximab shows promise in this area as well.
Supportive topical skin care is of help in avoiding secondary infection and relieving pain. Treatments must be coordinated with specialists with expertise in the treatment of this disease and according to organ involvement. Co-morbidities such as intolerance of medications, allergy or diabetes and infection may alter the induction treatment choice or maintenance treatments.
From the cutaneous standpoint the endpoint should be the clearing of purpura or healing of ulcerations, papules or nodules. Recurrence of any of these specific skin lesions indicates new activity of the disease. Periodic blood testing for ANCA may forewarn of a flare in patients who were ANCA positive. Some patients, especially those with upper airway disease, may be maintained on trimethoprim/sulfamethoxasole.
Unusual Clinical Scenarios to Consider in Patient Management
WG is an uncommon disease and specific skin lesions are therefore uncommon in clinical practice. Careful clinical and pathologic correlations are required since neither the clinical skin lesions nor the microscopic patterns are diagnostic in isolation. Therefore, room for diagnostic error is great. The addition of ANCA testing has helped to improve diagnostic accuracy and may be helpful in following the course of the disease as well.
Keep in mind that several other conditions, including cocaine abuse, may mimic WG clinically and require careful consideration. Always consider confounding diagnoses such as infection (especially with fungi or a typcial mycobacteria) and take appropriate tissue-based cultures (not swabs). Consider secondary infection especially in patients who respond otherwise to therapy but whose skin lesions persist or worsen. Subglottic stenosis is a complication of WG and requires surveillance to detect and treat.
What is the Evidence?
Finan, MC, Winkelmann, RK. “The cutaneous extravascular necrotizing granuloma (Chrug-Strauss granuloma) and systemic disease: a review of 27 cases”. Medicine (Baltimore). vol. 62. 1983. pp. 142-158. (A classic reference detailing the various diseases where the extravascular necrotizing granuloma can be seen in addition to Chrug-Strauss vasculitis.)
Langford, CA, Specks, U, Gibson, GJ. “Wegener’s granulomatosis and other vasculitides”. Respiratory Medicine. 2003. pp. 1621-1642. (A very thorough discussion of the clinical features, including complications, the pathophysiology and treatment of several ANCA-associated vasculitides including Churg-Strauss and Wegener’s granulomatoses.)
Daoud, MS, Gibson, LE, DeRemee, RA, Specks, U, el-Azhary, RA, Su, WP. “Wegener’s granulomatosis: clinical, histopathologic and immunopathologic features of thirty patients”. J Am Acad Dermatol. vol. 31. 1994. pp. 605-612. (A larger review of patients who have been diagnosed with Wegener’s granulomatosis and then looking at specific skin lesions clinically with microscopic correlations.)
Comfere, NI, Macaron, NC, Gibson, LE. “Cutaneous manifestations of Wegener’s granulomatosis: a clinicopathologic study of 17 patients and correlation to antineutrophil cytoplasmic antibody status”. J Cutan Pathol. vol. 34. 2007. pp. 1-9. (A recent review of patients diagnosed in the ANCA era correlating ANCA status with specific skin lesions with emphasis on the microscopic pattern.)
Gibson, LE, Specks, U, Homburger, H. “Clinical utility of ANCA tests for the dermatologist”. Int J Dermatol. vol. 42. 2003. pp. 859-869. (A review of ANCA testing with correlation to various skin diseases looking at the specificity for diagnosis with ANCA.)
Peikert, T, Finkielman, JD, Hummel, AM, McKenney, ME, Gregorini, G, Trimarchi, M. “Functional characterization of antineutrophil cytoplasmic antibodies in patients with cocaine-induced midline destructive lesions”. Arthritis and Rheum. vol. 58. 2008. pp. 1546-1551. (A good discussion of the ANCA seen in patients with nasal or oral ulceration due to cocaine use and differentiation from the ANCA of Wegener’s granulomatosis.)
Walsh, NM, Green, PJ, Burlingame, RW, Pasternak, S, Hanly, JG. “Cocaine-related retiform purpura: evidence to incriminate the adulterant, levamisole”. J Cutan Pathol. vol. 37. 2010. pp. 1212-1219. (A relatively recent development of dramatic purpuric lesions developing in persons using cocaine and thought to be closely linked to the adulterant used to cut the cocaine, levamisole.)
Stone, JH, Merkel, PA, Spiera, R, Seo, P, Langford, CA, Hoffman, Gary S.. “Rituximab versus cyclophosphamide for ANCA-associated vasculitis”. N Engl J Med. vol. 363. 2010. pp. 221-232. (One of the largest cooperative, multi-centered, controlled studies of treatment of ANCA-associated vasculitis to date. Using cyclophosphamide as the standard, rituximab was shown to have a potential role in therapy, especially in relapsing patients.)
Chen, M, Kallenberg, CG. “ANCA-associated vasculitides-advances in pathogenesis and treatment”. Nat Rev Rheumatol. vol. 6. 2010. pp. 653-664. (A very up to date review of the clinical features, differential diagnoses, pathophysiology and treatment of ANCA-associated illnesses. Recent therapeutic trials are summarized and referenced.)
Vega, LE, Espinoza, LR. “Predictors of Poor Outcome in ANCA-Associated Vasculitis (AAV)”. Curr Rheumatol Rep.. vol. 18. 2016 Dec. pp. 70(This review discusses the genetic, histologic and clinical factors associated with poor outcome as well as possible future biomarkers that may be more effective in predicting disease outcome.)
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