Rachel B. Jones

Rituximab versus Cyclophosphamide in ANCA-Associated Renal Vasculitis

BACKGROUND Cyclophosphamide induction regimens for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis are effective in 70 to 90% of patients, but they are associated with high rates of death and adverse events. Treatment with rituximab has led to remission rates of 80 to 90% among patients with refractory ANCA-associated vasculitis and may be safer than cyclophosphamide regimens. METHODS We compared rituximab with cyclophosphamide as induction therapy in ANCA-associated vasculitis. We randomly assigned, in a 3:1 ratio, 44 patients with newly diagnosed ANCA-associated vasculitis and renal involvement to a standard glucocorticoid regimen plus either rituximab at a dose of 375 mg per square meter of body-surface area per week for 4 weeks, with two intravenous cyclophosphamide pulses (33 patients, the rituximab group), or intravenous cyclophosphamide for 3 to 6 months followed by azathioprine (11 patients, the control group). Primary end points were sustained remission rates at 12 months and severe adverse events. RESULTS The median age was 68 years, and the glomerular filtration rate (GFR) was 18 ml per minute per 1.73 m(2) of body-surface area. A total of 25 patients in the rituximab group (76%) and 9 patients in the control group (82%) had a sustained remission (P=0.68). Severe adverse events occurred in 14 patients in the rituximab group (42%) and 4 patients in the control group (36%) (P=0.77). Six of the 33 patients in the rituximab group (18%) and 2 of the 11 patients in the control group (18%) died (P=1.00). The median increase in the GFR between 0 and 12 months was 19 ml per minute in the rituximab group and 15 ml per minute in the control group (P=0.14). CONCLUSIONS A rituximab-based regimen was not superior to standard intravenous cyclophosphamide for severe ANCA-associated vasculitis. Sustained-remission rates were high in both groups, and the rituximab-based regimen was not associated with reductions in early severe adverse events. (Funded by Cambridge University Hospitals National Health Service Foundation Trust and F. Hoffmann-La Roche; Current Controlled Trials number, ISRCTN28528813.)

Modification and validation of the Birmingham Vasculitis Activity Score (version 3)

Background: Comprehensive multisystem clinical assessment using the Birmingham Vasculitis Activity score (BVAS) is widely used in therapeutic studies of systemic vasculitis. Extensive use suggested a need to revise the instrument. The previous version of BVAS has been revised, according to usage and reviewed by an expert committee. Objective: To modify and validate version 3 of the BVAS in patients with systemic vasculitis. Methods: The new version of BVAS was tested in a prospective cross-sectional study of patients with vasculitis. Results: The number of items was reduced from 66 to 56. The subscores for new/worse disease and persistent disease were unified. In 313 patients with systemic vasculitis, BVAS(v.3) correlated with treatment decision (Spearman’s rs = 0.66, 95% CI 0.59 to 0.72), BVAS1 of version 2 (rs = 0.94, 95% CI 0.92 to 0.96), BVAS2 of version 2 in patients with persistent disease (rs = 0.60, 95% CI 0.21 to 0.83), C-reactive protein levels (rs = 0.43, 95% CI 0.31 to 0.54), physician’s global assessment (rs = 0.91, 95% CI 0.89 to 0.93) and vasculitis activity index (rs = 0.88, 95% CI 0.86 to 0.91). The intraclass correlation coefficients for reproducibility and repeatability were 0.96 (95% CI 0.95 to 0.97) and 0.96 (95% CI 0.92 to 0.97), respectively. In 39 patients assessed at diagnosis and again at 3 months, the BVAS(v.3) fell by 17 (95% CI 15 to 19) units (p<0.001, paired t test). Conclusion: BVAS(v.3) demonstrates convergence with BVAS(v.2), treatment decision, physician global assessment of disease activity, vasculitis activity index and C-reactive protein. It is repeatable, reproducible and sensitive to change. The new version of BVAS is validated for assessment of systemic vasculitis.

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

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 re-treatment 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 >or=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 late-onset 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.

Rituximab for remission maintenance in relapsing antineutrophil cytoplasmic antibody–associated vasculitis

OBJECTIVE Rituximab is effective induction therapy in refractory or relapsing antineutrophil cytoplasmic antibody-associated vasculitis (AAV). However, further relapse is common, and maintenance strategies are required. The aim of this study was to reduce relapse rates using a fixed-interval rituximab re-treatment protocol. METHODS Retrospective, standardized collection of data from sequential patients receiving rituximab for refractory or relapsing AAV at a single center was studied. Group A patients (n = 28) received rituximab induction therapy (4 infusions of 375 mg/m(2) or 2 infusions 1 gm) and further rituximab at the time of subsequent relapse. Group B patients (n = 45) received routine rituximab re-treatment for 2 years: 2 doses of 1 gm each for remission induction, then 1 gm every 6 months (total of 6 gm). Group C patients (n = 19) comprised patients in group A who subsequently relapsed and began routine re-treatment for 2 years. RESULTS Response (complete/partial remission) occurred in 26 of the 28 patients (93%) in group A, 43 of the 45 patients (96%) in group B, and 18 of the 19 patients (95%) in group C. At 2 years, relapses had occurred in 19 of 26 patients (73%) in group A, 5 of 43 (12%) in group B (P < 0.001), and 2 of 18 (11%) in group C (P < 0.001). At the last followup (median of 44 months), relapses had occurred in 85% of those in group A (22 of 26), 26% of those in group B (11 of 43; P < 0.001), and 56% of those in group C (10 of 18; P = 0.001). Glucocorticoid dosages were decreased and immunosuppression therapy was withdrawn in the majority of patients. Routine rituximab re-treatment was well tolerated, and no new safety issues were identified. CONCLUSION Two-year, fixed-interval rituximab re-treatment was associated with a reduction in relapse rates during the re-treatment period and a more prolonged period of remission during subsequent followup. In the absence of biomarkers that accurately predict relapse, routine rituximab re-treatment may be an effective strategy for remission maintenance in patients with refractory and relapsing AAV.

Rituximab-associated hypogammaglobulinemia: Incidence, predictors and outcomes in patients with multi-system autoimmune disease

Rituximab is a B cell depleting monoclonal antibody used to treat lymphoma and autoimmune disease. Hypogammaglobulinemia has occurred after rituximab for lymphoma and rheumatoid arthritis but data are scarce for other autoimmune indications. This study describes the incidence and severity of hypogammaglobulinemia in patients receiving rituximab for small vessel vasculitis and other multi-system autoimmune diseases. Predictors for and clinical outcomes of hypogammaglobulinemia were explored. We conducted a retrospective study in a tertiary referral specialist clinic. The severity of hypogammaglobulinemia was categorized by the nadir serum IgG concentration measured during clinical care. We identified 288 patients who received rituximab; 243 were eligible for inclusion with median follow up of 42 months. 26% were IgG hypogammaglobulinemic at the time that rituximab was initiated and 56% had IgG hypogammaglobulinemia during follow-up (5-6.9 g/L in 30%, 3-4.9 g/L in 22% and <3 g/L in 4%); IgM ≤0.3 g/L in 58%. The nadir IgG was non-sustained in 50% of cases with moderate/severe hypogammaglobulinemia. A weak association was noted between prior cyclophosphamide exposure and nadir IgG concentration, but not cumulative rituximab dose. IgG concentrations prior to and at the time of rituximab correlated with the nadir IgG post rituximab. IgG replacement was initiated because of recurrent infection in 12 (4.2%) patients and a lower IgG increased the odds ratio of receiving IgG replacement. Rituximab is associated with an increased risk of hypogammaglobulinemia but recovery of IgG level can occur. IgG monitoring may be useful for patients receiving rituximab.

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

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 ANCA-Associated 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.

Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis: 2-year results of a randomised trial

OBJECTIVES The RITUXVAS trial reported similar remission induction rates and safety between rituximab and cyclophosphamide based regimens for antineutrophil cytoplasm antibody (ANCA)-associated vasculitis at 12 months; however, immunosuppression maintenance requirements and longer-term outcomes after rituximab in ANCA-associated renal vasculitis are unknown. METHODS Forty-four patients with newly diagnosed ANCA-associated vasculitis and renal involvement were randomised, 3:1, to glucocorticoids plus either rituximab (375 mg/m(2)/week×4) with two intravenous cyclophosphamide pulses (n=33, rituximab group), or intravenous cyclophosphamide for 3-6 months followed by azathioprine (n=11, control group). RESULTS The primary end point at 24 months was a composite of death, end-stage renal disease and relapse, which occurred in 14/33 in the rituximab group (42%) and 4/11 in the control group (36%) (p=1.00). After remission induction treatment all patients in the rituximab group achieved complete B cell depletion and during subsequent follow-up, 23/33 (70%) had B cell return. Relapses occurred in seven in the rituximab group (21%) and two in the control group (18%) (p=1.00). All relapses in the rituximab group occurred after B cell return. CONCLUSIONS At 24 months, rates of the composite outcome of death, end-stage renal disease and relapse did not differ between groups. In the rituximab group, B cell return was associated with relapse. TRIAL REGISTRATION NUMBER ISRCTN28528813.

Long-term follow-up of patients who received repeat-dose rituximab as maintenance therapy for ANCA-associated vasculitis

OBJECTIVE ANCA-associated vasculitis (AAV) is characterized by a chronic relapsing course. Rituximab (RTX) is an effective maintenance treatment; however, the long-term outcomes after its discontinuation are unclear. The aim of this study was to explore the long-term outcomes of AAV patients treated with repeat-dose RTX maintenance therapy. METHODS AAV patients receiving a RTX treatment protocol consisting of an induction and maintenance phase were included. For initial remission induction, RTX was dosed at 1 g every 2 weeks or 375 mg/m(2) weekly for 4 consecutive weeks and for remission maintenance at 1 g every 6 months for 24 months. At the first RTX administration, ongoing immunosuppressives were withdrawn. RESULTS Sixty-nine patients were identified, 67 of whom were failing other therapies. Nine relapsed during the RTX treatment protocol; however, all 69 were in remission at the end of the maintenance phase on a median prednisolone dose of 2.5 mg/day and 9% were receiving additional immunosuppression. During subsequent observation, 28 patients relapsed a median of 34.4 months after the last RTX infusion. Risk factors for relapse were PR3-associated disease (P = 0.039), B cell return within 12 months of the last RTX infusion (P = 0.0038) and switch from ANCA negativity to positivity (P = 0.0046). Two patients died and two developed severe hypogammaglobulinaemia. CONCLUSION This study supports the efficacy and safety of a fixed-interval RTX maintenance regimen in relapsing/refractory AAV. Relapses after discontinuation of maintenance therapy did occur, but at a lower rate than after a single RTX induction course. PR3-associated disease, the switch from ANCA negative to positive and the return of B cells within 12 months of the last RTX administration were risk factors for further relapse.

Progress in treatment of ANCA-associated vasculitis

Autoantibodies to neutrophil cytoplasmic antigen-associated vasculitis (AAV) is characterised by inflammation of blood vessels. The introduction of immunosuppressive therapy with glucocorticoids and cyclophosphamide transformed AAV from a fatal condition to a largely treatable condition. Over the past 30 years, considerable progress has been made refining immunosuppressive regimens with a focus on minimising toxicity. There is, however, a high unmet need in the treatment of AAV. A proportion of patients are refractory to current therapies; 50% experience a relapse within 5 years and treatment toxicity contributes to mortality and chronic disability. As knowledge of the pathogenesis of vasculitis grows, it is mirrored by the availability of biological agents, which herald a revolution in the treatment of vasculitis. Lymphocyte-targeted and cytokine-targeted agents have been evaluated for the treatment of AAV and are entering the routine therapeutic arena with the potential to improve patient outcomes. As rare diseases, treatment advances in vasculitis depend on international collaborative research networks both to establish an evidence base for newer agents and to develop recommendations for patient management.

Should rituximab be used to treat antineutrophil cytoplasmic antibody associated vasculitis

It remains to be seen whether rituximab can live up to the high expectations and offer a more effective treatment for patients with AASV The antineutrophil cytoplasmic antibody (ANCA) associated systemic vasculitides (AASV) are a group of multisystem diseases characterised by a predominantly small vessel vasculitis and the occurrence of ANCA in most, but not all, cases. The two main forms of AASV are distinguished by the presence of granulomata and destructive lesions of the upper respiratory tract in Wegener’s granulomatosis (WG), which are absent in microscopic polyangiitis (MPA). Despite significant progress in the management of these diseases, there are still no fully satisfactory treatments for patients with either refractory or frequently relapsing disease. Current standard immunosuppressive treatment reduces mortality substantially, but a large proportion of patients, particularly those with WG, follow a frequently relapsing course.1 These patients are at high risk of cumulative toxicity from current treatments and also of increasing damage due to active disease.2 Cytotoxic drugs, especially cyclophosphamide, carry a substantial risk of severe side effects such as infertility and in the long term, malignancy (particularly bladder carcinoma), which makes them unappealing for the treatment of younger patients; additionally, there are problems of leucopenia and sepsis, which are of great concern, especially for the elderly.3,4 The advent of an effective and safe treatment for AASV would be a major advance in the management of these diseases. Rituximab, a chimeric, monoclonal IgG1 antibody directed against CD20, leads to destruction of B cells via complement mediated lysis and antibody dependent cellular cytotoxicity. It was originally developed as an agent for the treatment of non-Hodgkin’s lymphoma.5 CD20, which is a trans-membrane surface antigen of B cells of unknown biological role, is not expressed on pre-B cells and plasma cells so these cells are not affected …