A Case of Palpable Purpura, Swollen Legs, and Joint Pains: Wegener's Granulomatosis ?
Wegener's granulomatosis is a rare form of vasculitis that usually affects the respiratory tract and kidneys, but the musculoskeletal system, eyes, skin, and central nervous system may also be involved. The diagnosis is not always obvious, because initial symptoms may be vague. We present a case of a 57-year-old man who was hospitalized after being diagnosed with congestive heart failure. His complaints included dyspnea, leg swelling, joint pain, and skin rashes. Computed tomography, echocardiography, laboratory testing, and, finally, biopsy of the skin lesions and lung and sinus tissue led to the diagnosis of Wegener's granulomatosis. The patient responded to long-term treatment with immunosuppressive therapy.
A 57-year-old man was admitted to the general medicine floor with decompensated congestive heart failure (CHF). His medical history was significant only for CHF, which was recently diagnosed based on symmetrical lower extremity edema, dyspnea, and moderate weight gain. He was referred for hospital-based management when he did not improve with outpatient treatment and developed a rash and joint pains. On admission, he complained of shortness of breath, leg swelling, and multiple joint pains.
Physical examination was significant for mild proptosis and scleral injection (Figure 1). He was febrile, 101.1?F, and dyspneic at rest with bloody nasal discharge. He also had pruritic lesions on his hands and feet (Figures 2 and 3), large bilateral knee effusions, and synovitis of the hands and wrists
Complete blood cell count and basic metabolic profile were essentially normal. Urinalysis showed microscopic hematuria with more than 20 red blood cells per high-power field with no casts. Laboratory testing showed that antinuclear antibody, C-reactive protein, rheumatoid factor, and erythrocyte sedimentation rate were all within normal limits. Multiple blood cultures done during his hospital stay were negative.
A chest radiograph demonstrated signs of early heart failure and chronic obstructive pulmonary disease changes only. A subsequent computed tomography (CT) scan of the thorax revealed small peripheral cavitating lung granulomas. A CT scan of the sinuses showed left maxillary sinus fluid accumulation. Knee radiographs were normal. Analysis of synovial fluid from the knee joints revealed a noninflammatory pattern.
Transthoracic echocardiography showed normal left ventricular systolic function with an overall ejection fraction of approximately 70%. Because of his constitutional symptoms and palpable purpuric lesions, a transesophageal echocardiogram was performed to evaluate for subacute endocarditis. The study was negative for vegetations but revealed moderate-to-severe pulmonary hypertension. Biopsy of the skin lesions showed leukocytoclastic vasculitis consistent with a generalized small-vessel vasculitic process (Figure 4).?
The cytoplasmic antineutrophil cytoplasmic autoantibody (cANCA) test came back positive at a titer of 1:640 (normal, <1:40). A lung wedge biopsy showed hemosiderin deposition within intraalveolar macrophages, suggesting chronic alveolar hemorrhage.
To confirm the now-suspected diagnosis of Wegener's granulomatosis, a sinus biopsy was done, which showed characteristic granulomatous inflammation and vasculitis (Figure 5).
The patient improved rapidly with intravenous methylprednisolone acetate (A-Methapred, Solu-Medrol), 1 g/d, followed by oral prednisone (Deltasone, Meticorten, Orasone, etc.), with a fall in cANCA (<1:16). However, 2 months later, the patient relapsed clinically while tapering prednisone, with a rising titer of cANCA (1:64). Longterm immunosuppressive treatment, including daily oral cyclophosphamide (Cytoxan) and prednisone, was started along with daily trimethoprim/sulfamethoxazole (TMP/SMX [Bactrim, Cotrim, Septra]) therapy for Pneumocystis carinii pneumonia prophylaxis. A year later, he remained symptom free with no laboratory evidence of Wegener's granulomatosis activity. The patient was switched from cyclophosphamide to weekly oral methotrexate (Rheumatrex) to avoid cyclophosphamide toxicity.
Wegener's granulomatosis is a necrotizing granulomatous vasculitis of unclear etiology that has a clinical predilection for the upper airways, lungs, and kidneys.1 Virtually any organ, however, can be affected. Ocular manifestations include scleritis, uveitis, and, rarely, orbital pseudotumor causing proptosis. Joints, skin, and the central nervous system are other commonly involved sites. For classification purposes, the American College of Rheumatology requires the presence of 2 of 4 criteria for diagnosis (Table).2
The diagnosis is most appropriately made by the histologic demonstration of necrosis, granulomas, and vasculitis in a clinically compatible setting. The important differential diagnoses to exclude are fungal or bacterial infections, neoplastic or lymphoproliferative disorders, and other vasculitides.3 Serum inflammatory markers can be normal; however, the presence of cANCA against serine protease 3 (PR3) is strongly indicative of Wegener's granulomatosis. Of patients with a positive cANCA test, 80%-98% will have Wegener's granulomatosis.4
The recommended treatment is daily combined glucocorticosteroid and oral cyclophosphamide therapy. Coadministration of TMP/SMX is used for P carinii pneumonia prophylaxis. Data from the 1950s suggested that before the availability of effective therapy, severe Wegener's granulomatosis was generally fatal in the absence of appropriate treatment. In 1958, a mean survival of only 5 months (and an 82% mortality at 1 year) in patients with Wegener's granulomatosis was reported.5 In a National Institutes of Health follow-up study, 93% of patients receiving the recommended treatment achieved complete remission.6 Relapses are common, occasionally with rising titers of cANCA. By itself, cANCA is not an indication for resumption of therapy, especially in the absence of clinical deterioration.3 The cumulative toxicity of cyclophosphamide limits long-term use. Several clinical trials involving plasma exchange, methotrexate, or tumor necrosis factor inhibitors, such as etanercept (Enbrel), are in progress.7,8
1. Hoffman GS, Kerr GS, Leavitt RY, et al. Wegener's granulomatosis: an analysis of 158 patients. Ann Intern Med. 1992;116:488-498.
2. Leavitt RY, Fauci AS, Bloch DA, et al. The American College of Rheumatology 1990 criteria for the classification of Wegener's granulomatosis. Arthritis Rheum. 1990;33:1101-1107.
3. Langford CA, Sneller MC. Update on the diagnosis and treatment of Wegener's granulomatosis. Adv Intern Med. 2001;46:177-206.
4. Esper GJ, Johnson JS. Update on the treatment of Wegener's granulomatosis. Bull Rheum Dis. 1999;48:1-4.
5. Stone JH, Hoffman GS. Wegener's granulomatosis and lymphomatoid granulomatosis. In: Hochberg MC, Smolen JS, Silman AJ, et al. (eds.) Rheumatology. 3rd ed. Mosby;2003:1635-1648.
6. Fauci AS, Haynes BF, Katz P, et al. Wegener's granulomatosis: prospective clinical and therapeutic experience with 85 patients for 21 years.Ann Intern Med. 1983;98:76-85.
7. Jayne DR. Conventional treatment and outcome of Wegener's granulomatosis and microscopic polyangiitis. Cleve Clin J Med. 2002;69(suppl 2):SII110-SII115.
8. Stone JH. Targeted therapies in systemic vasculitis. Cleve Clin J Med. 2002;69(suppl 2):SII124-SII128.