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Granulomatosis with polyangiitis (GPA), previously called as Wegener's disease, is a systemic vasculitis of unknown etiology affecting medium and small vessels. Classically, it affects upper and lower airways, kidneys, skin, and joints. Granulomatous inflammation combined with positive antineutrophilic cytoplasmic antibodies (ANCA) are characteristic of this disease. Gastrointestinal involvement is extremely rare, and so far, only 3 cases have been reported with stomach involvement. Here, the authors described the 1st case of GPA presenting as gastric ulcer, which was successfully treated with rituximab.
A 48-year-old woman presented to the gastroenterology clinic with a 6-month history of abdominal pain, nausea, heartburn, and unintentional 10-pound weight loss. She denied dysphagia, odynophagia, diarrhea, hematemesis, hematochezia, and melena. Physical examination was remarkable only for epigastric tenderness. Esophagogastroduodenoscopy (EGD) revealed a solitary 14-mm deep cratering ulcer in the gastric fundus with congestion and erythema throughout the stomach. Esophageal and duodenal mucosa appeared endoscopically normal. Directed biopsy showed marked active chronic gastritis with deep ulceration associated with scattered lymphoid aggregates and nonnecrotizing granulomatous inflammation with multinucleated giant cells (Figure 1). No Helicobacter species, viral inclusion bodies, acid-fast bacilli, or fungi were identified (corresponding cytochemical and immunohistochemical stains were all negative). Omeprazole was initiated at 40 mg twice daily empirically.
The patient presented 2 months later with cough, pleuritic chest pain, and hemoptysis. Chest x-ray showed 2.6-cm lobulated mass in right upper lobe and chest computed tomography (CT) with contrast revealed 2 large necrotic masses: 1 in the right upper lobe, the other is in the mediastinum. Bronchoscopy combined with transbronchial biopsies were negative for malignancy and the bronchoalveolar lavage negative for any bacterial, fungal, and mycobacterial infection. Purified protein derivative (PPD) and Gold quantiferon tests were also negative. Liver chemistries showed alkaline phosphatase 390 (34–104 U/L), AST 44 (13–40 U/L), and ALT 139 (7–52 U/L). Histoplasma serum antibody was positive, but histoplasma urine antigen was negative. Pulmonary service believed that patient has histoplasmosis and started her on empirical oral itraconazole. However, her health status continued to decline. She developed spiking fever, and hemoptysis worsened. She was admitted to the inpatient service, and intravenous (IV) amphotericin-B was initiated after the recommendation of infectious disease service. Repeat EGD showed persistence of the ulcer with further development of a sinus tract expressing exudate and necrotic debris. Biopsies showed mild active chronic gastritis. Again, no microorganisms or viral inclusion bodies were identified. Endoscopic ultrasound was then performed with fine needle aspiration of subcarinal and right paratracheal lymph nodes. No evidence of infection or malignancy was identified. One week into the hospitalization, the patient developed respiratory failure requiring intubation, severe migratory arthralgias, and pruritic skin lesions on the right flank and on both legs. Complete blood count, serum chemistries, urinalysis, hepatitis screen, and human immunodeficiency virus screen were all unremarkable. Antinuclear antibody (ANA) was positive, but specific antibodies were negative and complements were normal. C-ANCA was also positive, and Pbb0020 antibody level was 7.21 (0.8–1.19 AU/mL). Anti-MPO antibody was negative (0.14 [0.0–0.79 AU/mL]). Skin biopsy showed leukocytoclastic vasculitis. At this point, a diagnosis of GPA was established, and the patient was given pulse methylprednisolone 1 g IV daily for 3 days and IV cyclophosphamide 750 mg/m2. She had an excellent clinical response and was promptly extubated and discharged. She was continued on prednisone orally 1 mg·kg−1·d−1, IV cyclophosphamide 750 mg/m2 monthly for 6 months. At 3-month posthospitalization, the patient appeared to be in remission with dramatic improvement in symptoms, low anti-Pbb0020 titers, near-complete resolution of pulmonary masses on CT, and complete healing of the ulcer on EGD. Prednisone was slowly tapered to 10 mg/d over 6 months while she received IV cyclophosphamide therapy. After the completion of IV cyclophosphamide therapy, methotrexate PO 15 mg/wk was initiated. Although she was on maintenance therapy, follow-up CT chest showed relapse of the necrotic lung lesions although she was completely asymptomatic. She had follow-up bronchoscopy, and Bronchoalveolar lavage (BAL) was negative for mycobacterial and fungal infection. She was treated with rituximab 375 mg/m2 every week for 4 weeks and was started on azathioprine. Approximately 2 years after her initial diagnosis, she is completely asymptomatic and has complete resolution of the lung mass. She is being maintained on azathioprine 150 mg/d.
GPA is characterized by necrotizing granulomatous inflammation and vasculitis. It may affect any organ system during its initial presentation but typically involve upper airways, lungs, and/or kidneys. This case is unusual because the sentinel event was a gastric ulcer with granulomatous inflammation, initially unrecognized as a presentation of GPA. It was not until the later part of the disease that the patient developed classic GPA findings and then the original gastric biopsy were attributed to GPA. Interestingly, this patient also had transiently elevated liver enzymes, which improved with cyclophosphamide raising the possibility that she may have had hepatic involvement, but this was not histologically documented as no liver biopsy was performed.
Gastrointestinal involvement is extremely rare with stomach involvement as the least often described.
and none had gastric ulcer as the initial presentation. Interestingly, none of them had biopsy-proven granulomatous inflammation when compared with this patient.
Prednisone combined with cyclophosphamide has been the standard of care to treat GPA for decades. Lately, rituximab has been found to be useful in the treatment of GPA and has been approved by FDA for treatment of ANCA-associated vasculitis.
Based on that information, the authors treated their patient with rituximab when she relapsed. She responded well to rituximab, and now, she is being maintained on azathioprine.
From a purely histologic standpoint, granulomatous inflammation in the stomach, with or without ulceration, may be seen in a variety of settings including Crohn's disease, infection (Helicobacter species, fungi, and acid-fast bacilli), foreign body reaction, drug reaction, and sarcoidosis. Although obscure, it is proposed that GPA should be considered in the differential diagnosis of granulomatous ulceration of stomach when a more common explanation cannot be found.
Rituximab can be successfully used to treat relapsing form of GPA and has emerged as an effective and safer alternative to cyclophosphamide in the remission induction of GPA.
Relapsing esophageal and gastric ulcers revealing Wegener's granulomatosis.