A 48 -year-old Indian woman presented to the gastroenterology clinic with complaints of upper abdominal pain, heartburn, and unintentional 10-pound weight loss over a period of 6 months. Review of the system was negative for headache, nasal discharge, cough, chest pain, shortness of breath, sinusitis, joint pain, or skin rash. Past medical history is notable for hypothyroidism only. Family history and personal history is otherwise unremarkable. Her medications include levothyroxine 50 mcg daily. She underwent EGD, which revealed a solitary 1.4 cm ulcer in the gastric fundus. Biopsy of the ulcer revealed active chronic gastritis with lymphoid aggregates and nonnecrotizing granulomatous inflammation with multinucleated giant cells (Figure 1).
Histochemical staining and culture results were negative for any bacterial, viral, and fungal infections. The biopsy was negative for gastric carcinoma. She was then empirically treated with proton pump inhibitors. Two months later, the patient presented to emergency room with cough, pleuritic chest pain, and hemoptysis. The CT chest showed two large necrotic masses (Figure 2): one in the right upper lobe with a cavitary lesion and the other in the mediastinum.
She eventually underwent elective bronchoscopy with transbronchial biopsies and bronchoalveolar lavage (BAL). Right upper lobe transbronchial biopsy showed bronchial mucosa with acute and chronic inflammation (lymphocytes, neutrophils, eosinophils, and rare histiocytes) and small submucosal microabscess. Lung alveolar parenchyma was without significant histopathological changes. The biopsy was negative for any form of lung malignancy. The BAL was negative for pulmonary hemorrhage. No fungi, pneumocystis, or viral inclusion bodies were identified in BAL. Bacterial and fungal and mycobacterial cultures of BAL were negative as well. Infectious disease workup showed positive histoplasma serum antibody but histoplasma urine antigen was negative. Presumed diagnosis of histoplasmosis was made, and she was started on oral itraconazole as outpatient therapy. The patient did not respond well, and her clinical status continued to decline. She then presented to the emergency room with spiking fevers and recurrence of hemoptysis. She was admitted to the inpatient service and started on IV amphotericin-B per infectious disease service recommendations. During hospitalization, she complained of epigastric discomfort. CT abdomen showed opacity around the previously found gastric ulcer and fluid collection adjacent to the stomach and pancreatic bed. Repeat EGD showed further development of a sinus tract in the ulcer, leaking exudate, and necrotic debris. Biopsies of the ulcer again showed mild active chronic gastritis. No evidence of infection or malignancy was identified. During the hospital course, she developed arthralgia and maculopapular pruritic skin lesions on the right flank and both legs. After a week into the hospitalization, the patient developed severe shortness of breath and acute respiratory failure that required intubation and mechanical ventilation. CT chest revealed worsening of the previous right upper lobe cavitary lesion with pleural effusion. Skin biopsy showed leukocytoclastic vasculitis. Further workup showed positive ANA in the low titer (1 : 40, homogenous pattern). Specific antibodies, e.g., anti-dsDNA, anti-Smith ab, anti-SSA and SS-B, were negative. Complements, C3: 113 (90-180 mg/dl) and C4: 12 (10-40 mg/dl), were within normal limits. The C-reactive protein level was 86 mg/dl (normal < 0.5 mg/dl). Serum protein electrophoresis showed polyclonal acute phase reactant pattern. C-ANCA was positive with positive PR3: 7.21 (0.8-1.19 AU/mL). Anti-MPO antibody was negative. At this point, the diagnosis of GPA was established.
She was treated with pulse methylprednisolone 1 g IV daily for 3 days and IV cyclophosphamide 750 mg/m2. During hospitalization, she received a course of sulfamethoxazole-trimethoprim (800-160 mg DS) tab PO twice daily for 5 days for urinary tract infection. She responded very well and was promptly extubated and discharged in two weeks. She was maintained on PO prednisone 1 mg/kg/day and IV cyclophosphamide 750 mg/m2 monthly for the next 6 months. At 3 months post-hospital discharge follow-up, she was completely asymptomatic. Repeat anti-PR3 titer was 3.6 (normal 0.8-1.19 AU/mL). There was a near-complete resolution of pulmonary masses on repeat CT (Figure 3) and complete healing of the ulcer on follow-up EGD.
Prednisone was tapered to 10 mg/d over 6 months while she received monthly IV cyclophosphamide induction therapy. The PR3 antibody level was 1.0 and within normal limits. She was eventually started on PO methotrexate 15 mg/week as maintenance therapy for GPA. While she was on methotrexate, 6 months follow-up CT chest showed relapse of the necrotic lung lesions at the same place as before in the right upper lobe. The ANCA (PR-3) antibody level was 2.8 (normal 0.8-1.19 AU/mL). Clinically, she was asymptomatic. Again, she underwent extensive workup with bronchoscopy, and bronchoalveolar lavage was negative for any infection or malignancy. She was diagnosed with GPA relapse and treated with rituximab 375 mg/m2 every week for 4 weeks and was started on azathioprine 50 mg/day for maintenance therapy. Gradually, the azathioprine dose was increased to 150 mg/day over next 2 months. She was followed up as outpatient closely with repeat CT chest every 6 months, which showed regression of the lung lesion. Approximately, 2 years since her initial presentation, she was in complete remission with resolution of the lung lesion. Interestingly, about a year later, routine follow-up labs in the clinic revealed hematuria with 6 RBCs per high-power field (normal 0-4 per high-power field) and urine protein creatine ratio of 0.67 equivalent to 24 hours urinary protein of 670 mg. Follow-up 24-hour urine collection showed proteinuria of 1.3 gm. Physical examination was unremarkable. Her repeat antibody profile showed positive ANA: 206 (normal <100 au/ml), anti-dsDNA Ab:135 (normal <100 au/ml), anti-Smith Ab: 14 (normal < 100 au/ml), anti-RNP Ab: 36 (normal < 100 au/ml), SS-A Ab: 6 (normal < 100 au/ml), SS-B Ab: 7 (normal < 100 au/ml), antihistone Ab: 9 (normal < 100 au/ml), rheumatoid factor: 10 (normal < 14 au/ml), and anti-CCP Ab level: 1 (normal < 5 unit/ml). Follow-up complement levels were normal: C3, 152 (normal: 87-200 mg/dl), and C4, 25 (normal: 19-25 mg/dl). Repeat C-reactive protein levels were 0.6 and 0.7 (normal: < 5 mg/dl). Viral hepatitis screen and cryoglobulin screen were negative. Repeat ANCA and anti-PR3 as well as anti MPO antibodies were negative. Her antibody profile and proteinuria were concerning for new-onset SLE with renal involvement. She was then referred to nephrology and underwent renal biopsy.
Renal biopsy showed diffuse thickening of the glomerular basement membrane (GBM) with normal cellularity on light microscopy (Figure 4). Mesangial and endocapillary proliferation were negligible. No cellular crescents, pseudocrescents, or acute necrotizing lesions or vasculitis are seen. Immunofluorescent microscopy showed diffuse, granular immunoglobulin deposition along GBM (Figure 5). Immunostaining was positive for IgG, C3. Electron micrograph (Figure 6) showed subepithelial granular deposits but no subendothelial deposits. Congo red stain for amyloidosis was negative. Staining for anti-phospholipase A2 receptor (PLA2R) and anti-thrombospondin (THSD7a) antibodies were negative, which makes primary membranous nephropathy less likely. Considering the + ANA and double-stranded DNA Ab, the renal biopsy diagnosis was consistent with secondary pure membranous (type V) lupus nephritis. Ultimately, she was diagnosed with SLE/AAV overlap syndrome with class V membranous lupus nephropathy. She was started on lisinopril and was titrated to 20 mg/day. Azathioprine was slowly tapered and discontinued because she has finished 3 years of treatment for GPA. She declined high-dose steroid and mycophenolate mofetil for treatment of lupus nephritis. On follow-up CT scan, she had minor relapse of GPA in the form of enlargement of pulmonary nodule even though she was asymptomatic. The ANCA (PR-3) antibody titer was 1.7 (normal 0.8-1.19 AU/mL). She was given another round of rituximab 375 mg/m2 without induction corticosteroid dose. Follow-up 6 months CT chest showed resolution of the mass. Urinalysis and urine protein/creatinine ratio are negative for proteinuria and hematuria. She is completely asymptomatic and back to her normal activities. The patient has been in full remission for lupus nephritis for 1 year and for 9 months after the last relapse of GPA.