Induction of remission by B lymphocyte depletion in eleven patients with refractory antineutrophil cytoplasmic antibody–associated vasculitis

Keogh, Karina A.; Wylam, Mark E.; Stone, John H.; Specks, Ulrich

doi:10.1002/art.20718

Cited by 395 publications

(257 citation statements)

References 15 publications

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“…Multiple courses of rituximab effectively induced further remissions following relapses, and re-treatment on a preemptive basis resulted in sustained remissions. These results are consistent with those of previous studies (9,(12)(13)(14)(15)(16)(17)(18)(19)(20). This is the largest series reported to date, and it pools the results from 4 UK centers.…”

Section: Discussionsupporting

confidence: 92%

“…In studies of small numbers of patients, rituximab has been associated with high rates of remission, often Ͼ80%, in patients with vasculitis that had been refractory to standard therapies (9,(12)(13)(14)(15)(16)(17)(18)(19). Relapses of vasculitis following rituximab therapy have occurred, although efficacy with second and subsequent courses of rituximab has been reported (9,13,14).…”

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confidence: 99%

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A multicenter survey of rituximab therapy for refractory antineutrophil cytoplasmic antibody–associated vasculitis

Jones¹,

Ferraro²,

Chaudhry³

et al. 2009

Arthritis & Rheumatism

323

214

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Objective. B cell depletion with rituximab has allowed remissions in relapsing or refractory antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis in small studies. The aim of this study was to determine the efficacy and safety of rituximab for ANCA-associated vasculitis in a larger multicenter cohort. This permitted comparison of rituximab dosing regimens, the value of continuing immunosuppression, and investigation of ANCA and B cell levels as retreatment biomarkers.Methods. Retrospective, standardized data collection from 65 sequential patients receiving rituximab for refractory ANCA-associated vasculitis at 4 centers in the UK was used.Results. All patients achieved B cell depletion. Complete remission occurred in 49 of the 65 patients (75%), partial remission in 15 (23%), and no response in 1 (2%). The prednisolone dosage was reduced from 12.5 mg/day (median) to 9.0 mg/day at 6 months (P ‫؍‬ 0.0006). Immunosuppressive therapy was withdrawn in 37 of 60 patients (62%). Twenty-eight of 49 patients who achieved full remission (57%) experienced relapse (median 11.5 months). B cell return preceded relapse in 14 of 27 patients (52%). Although ANCA levels fell after rituximab therapy, relapse was not associated with ANCA positivity or a rise in ANCA levels. Neither the initial rituximab regimen (4 infusions of 375 mg/m 2 each given 1 week apart or 2 infusions of 1 gm each given 2 weeks apart) nor withdrawal of immunosuppressive therapy (37 of 60 patients [62%]) influenced the timing of relapse. Thirty-eight patients received >2 courses of rituximab, and complete remission was induced or maintained in 32 of them (84%). IgM levels fell, although IgG levels remained stable. Forty-six serious adverse events occurred, including 2 episodes of lateonset neutropenia, which were attributed to rituximab.Conclusion. Rituximab was effective remission induction therapy for refractory ANCA-associated vasculitis in this study. There was no difference in efficacy between the 2 main treatment regimens. Continuing immunosuppression did not reduce relapses. Relapses occurred, but re-treatment was effective and safe. There was no clear influence of rituximab on the frequency of serious adverse events. ANCA and B cell levels lacked sufficient sensitivity to guide the timing of re-treatment.

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Section: Discussionsupporting

confidence: 92%

mentioning

confidence: 99%

A multicenter survey of rituximab therapy for refractory antineutrophil cytoplasmic antibody–associated vasculitis

Jones¹,

Ferraro²,

Chaudhry³

et al. 2009

Arthritis & Rheumatism

323

214

View full text Add to dashboard Cite

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“…Treatment with rituximab could potentially spare the adverse effects of prednisone and other traditional immunosuppressive agents. Recent data from uncontrolled trials indicated that rituximab is effective in the treatment of idiopathic membranous glomerulopathy, 13 systemic lupus erythematosus, 14,15 ANCA vasculitis, 16 type II cryoglobulinemic glomerulonephritis, 17 and FGN. 18 Only four of our patients were treated with rituximab, given alone in two who achieved PR (Table 7) and in combination with other agents in two who had PRD.…”

Section: Discussionmentioning

confidence: 99%

Proliferative Glomerulonephritis with Monoclonal IgG Deposits

Nasr

Satoskar

Markowitz

et al. 2009

Journal of the American Society of Nephrology

335

434

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Dysproteinemias that result in monoclonal glomerular deposits of IgG are relatively uncommon. Here, we report the largest series of proliferative glomerulonephritis with monoclonal IgG deposits, a form of renal involvement by monoclonal gammopathy that mimics immune-complex glomerulonephritis. We retrospectively identified 37 patients, most of whom were white (81%), female (62%), or older than 50 yr (65%). At presentation, 49% had nephrotic syndrome, 68% had renal insufficiency, and 77% had hematuria. In 30% of the patients, we identified a monoclonal serum protein with the same heavy-and light-chain isotypes as the glomerular deposits (mostly IgG1 or IgG2), but only one patient had myeloma. Histologic patterns were predominantly membranoproliferative (57%) or endocapillary proliferative (35%) with membranous features. Electron microscopy revealed granular, nonorganized deposits, and immunofluorescence demonstrated glomerular deposits that stained for a single light-chain isotype and a single heavy-chain subtype, most commonly IgG3 (53%). During an average of 30.3 mo of follow-up for 32 patients with available data, 38% had complete or partial recovery, 38% had persistent renal dysfunction, and 22% progressed to ESRD. Correlates of ESRD on univariate analysis were higher creatinine at biopsy, percentage of glomerulosclerosis, and degree of interstitial fibrosis but not immunomodulatory treatment or presence of a monoclonal spike. On multivariate analysis, higher percentage of glomerulosclerosis was the only independent predictor of ESRD. Only one patient lacking a monoclonal spike at presentation subsequently developed a monoclonal spike and no patient with a monoclonal spike at presentation subsequently developed a hematologic malignancy. We conclude that proliferative glomerulonephritis with monoclonal IgG deposits does not seem to be a precursor of myeloma in the vast majority of patients.

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“…[3][4][5][6][7][8][9][10][11] A multicenter study of 65 patients with refractory AAV demonstrated peripheral B cell depletion in all patients after a first course of rituximab, and complete remission was achieved in 75% (n=49) of patients. 12 Of the 49 patients who experienced initial complete remission, 29 patients relapsed (57%) with a median time to relapse of approximately 11.5 months.…”

mentioning

confidence: 99%

Tubular Lesions Predict Renal Outcome in Antineutrophil Cytoplasmic Antibody–Associated Glomerulonephritis after Rituximab Therapy

Berden

Jones

Erasmus

et al. 2012

Journal of the American Society of Nephrology

105

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Histopathological features in renal biopsies of patients with antineutrophil cytoplasmic antibody-associated vasculitis have predictive value for renal outcome in patients who receive standard treatment with cyclophosphamide and corticosteroids; however, whether the same holds true for rituximab-treated patients is unknown. We describe associations between renal histopathology and outcomes among patients treated with a rituximab-based regimen in the Randomized Trial of Rituximab versus Cyclophosphamide in ANCAAssociated Vasculitis trial. Two pathologists, blinded to clinical data, reviewed biopsies from 30 patients according to a standardized protocol that included assessment of T cell, B cell, and plasma cell infiltration, as well as scoring for tubulitis, interstitial inflammation, and glomerulitis. We did not observe associations between immunohistology scores and age, sex, estimated GFR at entry, or requirement for dialysis. However, tubulointerstitial inflammation was more severe among patients who had a positive test for the myeloperoxidase antineutrophil cytoplasmic antibody. In a multiple linear regression model, both CD3 + T cell tubulitis and tubular atrophy independently associated with estimated GFR at 12 months. Tubular atrophy remained an independent predictor at 24 months (P,0.01). These results suggest that in addition to anti-B cell therapy, therapy directed at T cells may improve renal outcomes in antineutrophil cytoplasmic antibody-associated vasculitis. Established treatment regimens for systemic antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and GN, consisting of cyclophosphamide and high-dose glucocorticoids, target both T and B cells. Standard treatment is associated with serious adverse events and the accumulation of therapy-related adverse events is an important cause of early mortality. 1,2 Therefore, ongoing studies involve the search for treatments that improve rates of sustained remission while minimizing adverse events. Several small studies of off-label treatment with rituximab, an anti-CD20 mAb, suggest that it induces remission in patients with systemic AAV refractory to standard therapy. 3-11 A multicenter study of 65 patients with refractory AAV demonstrated peripheral B cell depletion in all patients after a first course of rituximab, and complete remission was achieved in 75% (n=49) of patients. 12 Of the 49 patients who experienced initial complete

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Induction of remission by B lymphocyte depletion in eleven patients with refractory antineutrophil cytoplasmic antibody–associated vasculitis

Cited by 395 publications

References 15 publications

A multicenter survey of rituximab therapy for refractory antineutrophil cytoplasmic antibody–associated vasculitis

A multicenter survey of rituximab therapy for refractory antineutrophil cytoplasmic antibody–associated vasculitis

Proliferative Glomerulonephritis with Monoclonal IgG Deposits

Tubular Lesions Predict Renal Outcome in Antineutrophil Cytoplasmic Antibody–Associated Glomerulonephritis after Rituximab Therapy

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