Concurrent treatment with rituximab and plasma exchange for severe refractory granulomatosis with polyangiitis: A case report

Abstract

Rationale: Rituximab is recommended to induce remission of severe granulomatosis with polyangiitis (GPA). Plasma exchange (PE) may be considered in the setting of rapidly progressive glomerulonephritis (RPGN) with a serum creatinine increase of more than 5.6 mg/dl or diffuse alveolar hemorrhage (DAH). However, there are no sufficient studies on combination therapy with rituximab and PE in GPA.

Patient concerns: A 23-year-old woman was admitted with fever, abdominal pain, and diarrhea on suspicion of infectious colitis. Colonoscopy showed hemorrhagic colitis and antibiotic treatment was ineffective. Physical examination revealed episcleritis and skin lesions similar to Janeway lesions or Osler nodes on her palms and soles. Transesophageal echocardiogram (TEE) revealed mitral valve vegetation mimicking infective endocarditis. However, no pathogen was grown in the blood culture. Ten days after admission, blood-tinged sputum and respiratory distress developed. Imaging studies of lung, bronchoscopy, and bronchoalveolar lavage indicated DAH. Moreover, serum creatinine levels rapidly increased from 0.8 mg/dl to 6.1 mg/dl with proteinuria.

Diagnosis: The patient was diagnosed with GPA and non-infectious endocarditis, DAH, and RPGN, based on a biopsy which revealed pauci-immune crescentic glomerulonephritis with granuloma and leukocytoclastic vasculitis and antineutrophil cytoplasmic antibodies against proteinase 3- positivity.

Interventions: Initial methylprednisolone pulse therapy (1 g daily for 3 days) proved unsuccessful. After initiating PE, creatinine levels began to slowly decline, but DAH continued to deteriorate. Rituximab combined with PE therapy was considered. We performed PE every 2 to 3 days for 5 total treatments combined with rituximab (375 mg/m, once weekly for 4 weeks).

Outcomes: After the combination treatment of rituximab and PE, alveolar hemorrhage stopped. Chest X-ray and laboratory data, including serum creatinine and hemoglobin, notably improved. Mitral valve vegetation was no longer observed in follow-up TEE. GPA remained stable with low dose prednisolone and immunosuppressants over a follow-up period of 5 years.

Lessons: This case suggests that the use of rituximab and concurrent PE may represent a promising combination for severe and refractory GPA.

Figure 1

Clinical manifestations and pathologic findings. A. Colonoscopy showing a 1 cm aphthous ulcer at the terminal ileum and multiple reddish spots on the entire colon. B. Erythematous macules on fingers. C. Violaceous subcutaneous nodules on the palm. D. Erythematous papules and violaceous subcutaneous nodules on the sole. E. Vegetation of the mitral valve (white asterisk) with transesophageal echocardiogram. F. Skin biopsy showing diffuse perivascular chronic inflammatory cell infiltration. (H&E stain, original magnification, ×400).

Figure 2

Imaging findings during deterioration and improvement of diffuse alveolar hemorrhage. A. Chest X-ray showing reticular opacity in the whole lung field following the development of respiratory distress. B. Chest X-ray showing no significant changes with plasma exchange alone. C. Chest X-ray showing marked improvement in diffuse lung infiltration after combination therapy with rituximab and plasma exchange. D. Chest CT revealing diffuse ground-glass opacity in both lung fields. E. Chest CT showing improvement in diffuse ground-glass opacity with interlobular septal thickening.

Figure 3

Pathologic findings of renal biopsy. A. Light microscopy (hematoxylin and eosin (H&E) stain, original magnification, ×400) showing glomerulitis with the crescent formation (arrow) and periglomerular granuloma (asterisk). Mononuclear cell infiltration and interstitial fibrosis with tubular atrophy were observed in the tubulointerstitium. B. Electron microscopic (original magnification, ×400) finding showing focal foot process effacement and increased mesangial matrix and cells.

Figure 4

Clinical course during the first admission (A) and changes in kidney function during the long-term follow-up period (B). A. Dosing schedules of rituximab and plasma exchange and changes in creatinine and hemoglobin levels. Plasma exchanges were performed every 2 to 3 days for a total of 5 treatments (days 16, 18, 20, 23, and 25), combined with rituximab (once weekly for 4 weeks). B. Changes in creatinine and UPC levels during the 6-year follow-up period. Aza = azathioprine, Cr = creatinine, CYC = cyclosporine, Hb = hemoglobin, MMF = mycophenolate mofetil, MPD = methylprednisolone, Pd = prednisolone, pRBC = packed red blood cell, Tac = tacrolimus, UPC = urine protein to creatinine ratio.