Rituximab In Lupus Nephritis Research Articles

Clinical efficacy and safety of rituximab in lupus nephritis.

BackgroundLong-term treatment programs with low toxicity represent a therapeutic challenge in lupus nephritis (LN). Although a therapeutic benefit of rituximab (RTX) has been reported in LN patients who have failed conventional treatment, the results are controversial. We aimed to assess the clinical efficacy and safety of RTX as a new immunosuppressive medicine in the treatment of LN with a meta-analysis.MethodsBased on predetermined criteria, PubMed, Embase, and Cochrane Library were used to identify the eligible studies. Cochrane Review Manager version 5.3 was applied to pool the data extracted from individual investigations and provide summary effect estimates.ResultsTwenty-four studies with 940 patients were analyzed. In case series trials with specific LN assessment, the complete remission (CR) rate at 12 months was 35.9% (95% CI: 24.2%–49.5%), and total remission (TR: CR plus partial remission) was 73.4% (95% CI: 66.0%–79.7%). In controlled trials, RTX was associated with a higher probability of TR (OR =2.02, 95% CI: 1.23–3.32, P<0.01). The CR in the RTX group was higher than that in the control group, although there was no significant difference between the two groups (OR =1.98, 95% CI: 0.90–4.39, P>0.05). Additionally, RTX treatment significantly decreased proteinuria (mean difference: −2.79, 95% CI: −3.95 to −1.62, P<0.01) as well as the renal activity index in patients with LN (mean difference: −3.46, 95% CI: −4.43 to −2.50, P<0.01). In controlled trials, the relative risks of the adverse events of infection and infusion reaction were not notably different between the two groups.ConclusionRTX is a promising therapy for the treatment of LN due to significant clinical efficacy and a favorable safety profile. In future studies, larger study populations and longer-term time points may identify additional important patient-centered outcomes.

Peripheral Blood B Cell Depletion after Rituximab and Complete Response in Lupus Nephritis.

Incomplete peripheral blood B cell depletion after rituximab in lupus nephritis might correlate with inability to reduce tubulointerstitial lymphoid aggregates in the kidney, which together could be responsible for inadequate response to treatment. We utilized data from the Lupus Nephritis Assessment with Rituximab (LUNAR) study to characterize the variability of peripheral blood B cell depletion after rituximab and assess its association with complete response in patients with lupus nephritis. We analyzed 68 participants treated with rituximab. Peripheral blood B cell depletion was defined as 0 cells/µl, termed "complete peripheral depletion," assessed over 78 weeks. Logistic regression was used to estimate the association between characteristics of complete peripheral depletion and complete response (defined as urine protein-to-creatinine ratio <0.5 mg/mg, and normal serum creatinine or an increase in creatinine <15%, if normal at baseline), assessed at week 78. A total of 53 (78%) participants achieved complete peripheral depletion (0 cells/µl) in a median time of 182 days (interquartile range, 80-339).The median duration of complete peripheral depletion was 71 days (interquartile range, 14-158). Twenty-five (47%) participants with complete peripheral depletion achieved complete response, compared with two (13%) without. Complete peripheral depletion was associated with complete response (unadjusted odds ratio [OR], 5.8; 95% confidence interval [95% CI], 1.2 to 28; P=0.03). Longer time to achieving complete peripheral depletion was associated with a lower likelihood of complete response (unadjusted OR, 0.89; 95% CI, 0.81 to 0.98; P=0.02). Complete peripheral depletion lasting >71 days (the median) was associated with complete response (unadjusted OR, 4.1; 95% CI, 1.5 to 11; P=0.008). There was substantial variability in peripheral blood B cell depletion in patients with lupus nephritis treated with rituximab from the LUNAR trial. Achievement of complete peripheral depletion, as well as the rapidity and duration of complete peripheral depletion, were associated with complete response at week 78. This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2018_09_06_CJASNPodcast_18_10_.mp3.

Single-dose rituximab in refractory lupus nephritis.

Off-label use of rituximab in lupus nephritis is reported to be beneficial. While the optimal dose is unknown, the regimen of four intravenous doses of 375 mg/m(2) is commonly employed, despite expense and potential side-effects. To investigate the response to single-dose rituximab, added to standard corticosteroids plus additional immunosuppressive agent, in refractory lupus nephritis. Consecutive consenting patients with refractory lupus nephritis despite steroids plus either cyclophosphamide, mycophenolate or azathioprine were enrolled in this ethics-approved, open-label, prospective study. After baseline assessment, patients received one intravenous infusion of 375 mg/m(2) rituximab. Clinical, biochemical and serological (DsDNA, complement) responses to this dose were analysed. Complete renal response (CR) was defined as normalisation of creatinine, albumin, proteinuria and urinary RBCs and partial response (PR) as ≥50% improvement in at least one parameter, without deterioration in others. B-cell depletion was defined as peripheral CD19 lymphocyte count ≤0.05 × 10(9) /L. Fourteen patients were enrolled in the study. All were B-cell-depleted until 8 months post-dose. Eleven patients (79%) responded (2CR, 9PR) at a median time of 5 months, with a 6-month probability of renal response of 43%. Five patients (45%) relapsed at a median time of 17 months. DsDNA titres decreased in 69%. Side-effects were minimal. Single-dose rituximab is effective in relapsed/refractory lupus nephritis. Longevity of B-cell depletion with single-dose rituximab is similar to that of four doses with potentially fewer side-effects.

Rituximab in Lupus Nephritis: A Non-systematic Review

Lupus nephritis (LN) is a common and severe complication in patients with lupus. Current therapy is based on immunosuppressive drugs and glucocorticoids. Recently, rituximab has been proposed as an alternative treatment for LN. Rituximab is a monoclonal antibody directed against the CD20 antigen receptor on B cells. The aim of this review is to summarize all the available information about rituximab in LN. Eleven studies were found; three of them were observational studies (2 prospective and 1 retrospective) and eight were clinical trials (7 open-label studies and only 1 randomized controlled trial [RCT]). The evidence is insufficient to establish the role of rituximab in the treatment of LN. Results from the only RCT, which were negative, suggest a clinical benefit in black people. Further studies must confirm this hypothesis. Controlled clinical trials involving adaptive randomization are required to establish the real benefit of rituximab in LN.

Rituximab en nefritis lúpica: una revisión no sistemática

Lupus nephritis (LN) is a common and severe complication in patients with lupus. Current therapy is based on immunosuppressive drugs and glucocorticoids. Recently, rituximab has been proposed as an alternative treatment for LN. Rituximab is a monoclonal antibody directed against the CD20 antigen receptor on B cells. The aim of this review is to summarize all the available information about rituximab in LN. Eleven studies were found; three of them were observational studies (2 prospective and 1 retrospective) and eight were clinical trials (7 open-label studies and only 1 randomized controlled trial [RCT]). The evidence is insufficient to establish the role of rituximab in the treatment of LN. Results from the only RCT, which were negative, suggest a clinical benefit in black people. Further studies must confirm this hypothesis. Controlled clinical trials involving adaptive randomization are required to establish the real benefit of rituximab in LN.

Is rituximab effective for induction of remission in lupus nephritis?

The combination of cyclophosphamide and steroids constitutes the standard treatment in lupus nephritis requiring immunosuppressive therapy. However, it is associated with important adverse effects, so there is interest in alternative immunosuppressors such as rituximab. Searching in Epistemonikos database, which is maintained by screening 19 databases, we identified 5 systematic reviews including 24 studies. We combined the evidence using summary of findings tables following the GRADE approach and concluded there is uncertainty about the effects of rituximab in lupus nephritis because the certainty of the evidence is very low, probably leads to important adverse effects, and has high cost. Rituximab should not be used outside the context of a clinical trial, or only in cases where other treatments have failed and there are no resource constraints.

Minimising steroids in lupus nephritis – will B cell depletion pave the way?

The aim of this review is to briefly explore how steroids came to be a presumed adjunct to all treatment regimens for lupus nephritis, despite being the main cause of long term damage among patients with lupus and despite increasingly effective alternative agents. I then go on to compare and contrast how differently immunosuppression regimens have developed in the world of solid organ transplantation. Almost from the start of transplantation a clear goal was to develop steroid sparing regimens - and now units such as our own routinely use induction with a biological, a single week of steroids and then monotherapy with tacrolimus. There has been a clear trend of using biologicals as induction agents and less immunosuppression in the long run but with improved outcomes. The drive has not been the same in lupus nephritis despite there being almost no evidence to support the use of steroids and certainly nothing to suggest correct dosage and timing. Rituximab, a B cell depleting antibody, offers great promise as a treatment agent despite the negative randomised control LUNAR trial. I briefly review our own data, demonstrating that early use of rituximab in lupus nephritis allows omission of oral steroids with excellent rates of remission (complete and partial). I review why the LUNAR trial should not discourage the use of rituximab. Finally, I introduce the RITUXILUP trial, a multicentre randomised controlled trial we are developing to formally evaluate our oral steroid avoiding regimen against a standard treatment regimen of mycophenolate mofetil and steroids. We have to follow the lead of our transplant colleagues and challenge the assumption that the future for lupus nephritis cannot be steroid free.

Updates on B-cell immunotherapies for systemic lupus erythematosus and Sjogren's syndrome

Last year was marked by important clinical and mechanistic studies that improved our understanding of B-cell immunotherapy for systemic lupus erythematosus (SLE) and Sjogren's syndrome. Here, we will highlight the most relevant studies published in the last 18 months. The highlight of the year was the approval of belimumab on the basis of two major trials. On the flip side, the disappointing results of rituximab in lupus nephritis provided a clinical and mechanistic counterpoint in SLE. Still, major limitations in the LUpus Nephritis Assessment with Rituximab (LUNAR) trial, positive subset analysis and new open studies and registries continue to provide hope for and major insights into the use of B-cell depletion. In Sjogren's syndrome, the role of B-cell depletion has been further investigated, both for glandular and extraglandular manifestations of the disease with mixed results in a disease in which outcomes are notoriously hard to measure. The approval of anti-B cell activating factor therapy and an increasing body of open studies with rituximab as well as subset studies and secondary analysis of the Efficacy and Safety of Rituximab in Moderately-to-Severely Active Systemic Lupus Erythematosus (EXPLORER) and LUNAR trials provide hope for B-cell immunotherapy and significant insight into its mechanisms of action and utilization in a selected subset of patients. Ongoing clinical trials of other B-cell targeting agents are eagerly anticipated.

Rituximab in Severe Lupus Nephritis

Standard treatment for lupus nephritis, including corticosteroids and cyclophosphamide, is efficient but is still associated with refractory or relapsing disease, or severe deleterious effects. Rituximab, a monoclonal chimeric anti-B cell antibody, is increasingly used in patients with lupus nephritis, but reported series were small and had a short follow-up. The authors analyzed clinical and histologic data of 20 patients who were treated with rituximab for lupus nephritis and followed up for at least 12 mo. Nineteen women and one man received rituximab as induction treatment for an active class IV (15 cases) or class V (5 cases) lupus nephritis. Rituximab was given for lupus nephritis refractory to standard treatment (12 cases), for relapsing disease (6 cases), or as first-line treatment (2 cases). Three patients received cyclophosphamide concomitantly with rituximab. Ten received new injections of rituximab as maintenance therapy. Side effects included mainly five infections and four moderate neutropenias. After a median follow-up of 22 mo, complete or partial renal remission was obtained in 12 patients (60%). Lupus nephritis relapsed in one patient, who responded to a new course of rituximab. The achievement of B cell depletion 1 mo after rituximab, which negatively correlated with black ethnicity and hypoalbuminemia, was strongly associated with renal response. Rapidly progressive glomerulonephritis did not respond to rituximab. Rituximab is an interesting therapeutic option in relapsing or refractory lupus nephritis when early B cell depletion is obtained.