Efficacy and Safety of Ocrelizumab in Active Proliferative Lupus Nephritis: Results From a Randomized, Double‐Blind, Phase III Study

Mysler, Eduardo; Spindler, Alberto; Guzmán, Renato; Bijl, Marc; Jayne, David; Furie, Richard; Houssiau, Frédéric; Drappa, Jörn; Close, David; Maciuca, Romeo; Rao, K Tushara; Shahdad, Saba; Brunetta, Paul

doi:10.1002/art.38037

Cited by 314 publications

(174 citation statements)

References 30 publications

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“…Together with the potential removal of activated naive and memory cells by MMF, this may explain the profound effect of using a combination of rituximab and MMF on serum IgM levels. Co‐therapy with MMF has been associated with a higher rate of infections in clinical trial studies using ocrelizumab 50, and low Ig was noted in patients treated with a combination of MMF and atacicept 51. In the later study, low IgM levels in SLE patients treated with MMF alone in the placebo arm did not recover over the course of the study.…”

Section: Discussionmentioning

confidence: 92%

Pragmatic Treatment of Patients With Systemic Lupus Erythematosus With Rituximab: Long‐Term Effects on Serum Immunoglobulins

Reddy

Martinez

Isenberg

et al. 2017

Arthritis Care & Research

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ObjectiveB cell–depletion therapy based on rituximab is a therapeutic option for refractory disease in patients with systemic lupus erythematosus (SLE). The aim of this observational study was to document long‐term effects on B cell function by following serum immunoglobulin levels in patients with SLE treated with rituximab in routine clinical practice.MethodsWe included 57 consecutive patients with SLE treated with rituximab and concomitant/sequential immunosuppressants and measured serum total IgG, IgM, and IgA and IgG anti‐dsDNA antibodies, over a median of 48 months most recent followup. Flow cytometry was used prospectively to assess B cell phenotypes in 17 of 57 patients.ResultsTwelve patients (21%) had persistent IgM hypogammaglobulinemia (<0.4 gm/liter), and 4 of 57 (5%) had low IgG (<7 gm/liter) at the most recent followup (range 12–144 months). This was not associated with serious adverse events or high anti–double‐stranded DNA (anti‐dsDNA) antibodies (>1,000 IU/ml; normal <50 IU/ml). Factors predictive of low serum IgM included baseline serum IgM ≤0.8 gm/liter (receiver operator curve analysis) and subsequent therapy with mycophenolate mofetil (MMF; odds ratio 6.8, compared with other immunosuppressants). In patients maintaining normal IgM levels (9 of 17), the frequency of circulating IgD+CD27+ B cells was significantly higher (P = 0.05). At 12 months after rituximab, 7 of 30 SLE patients with baseline anti‐dsDNA ≤1,000 IU/ml had lost seropositivity.ConclusionLower baseline serum IgM levels and sequential therapy with MMF were predictive of IgM hypogammaglobulinemia after rituximab in SLE, but this was not associated with higher levels of anti‐dsDNA antibodies or an increased risk of infections. This provides useful directions for clinicians regarding rituximab and sequential immunosuppressive treatment for patients with SLE.

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Section: Discussionmentioning

confidence: 92%

Pragmatic Treatment of Patients With Systemic Lupus Erythematosus With Rituximab: Long‐Term Effects on Serum Immunoglobulins

Reddy

Martinez

Isenberg

et al. 2017

Arthritis Care & Research

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“…A controlled clinical trial of rituximab in anti-AChR MG is currently ongoing (NCT02110706). Second-generation anti-CD20 monoclonal antibodies that are fully humanized and with enhanced effector functions will also likely be tried in MG in the future [101,102]. Targeting B cells may provide benefit in MG not only by reducing the numbers of antibodyproducing cells (the likely mechanism in anti-MuSK MG), but also by modulating other B-cell functions, including antigen presentation and cytokine production.…”

Section: B Cells B-cell Trophic Factors and Plasma Cellsmentioning

confidence: 99%

Current Treatment, Emerging Translational Therapies, and New Therapeutic Targets for Autoimmune Myasthenia Gravis

2016

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Myasthenia gravis (MG) is an autoimmune disease associated with the production of autoantibodies against 1) the skeletal muscle acetylcholine receptor; 2) muscle-specific kinase, a receptor tyrosine kinase critical for the maintenance of neuromuscular synapses; 3) low-density lipoprotein receptor-related protein 4, an important molecular binding partner for muscle-specific kinase; and 4) other muscle endplate proteins. In addition to the profile of autoantibodies, MG may be classified according the location of the affected muscles (ocular vs generalized), the age of symptom onset, and the nature of thymic pathology. Immunopathologic events leading to the production of autoantibodies differ in the various disease subtypes. Advances in our knowledge of the immunopathogenesis of the subtypes of MG will allow for directed utilization of the ever-growing repertoire of therapeutic agents that target distinct nodes in the immune pathway relevant to the initiation and maintenance of autoimmune disease. In this review, we examine the pathogenesis of MG subtypes, current treatment options, and emerging new treatments and therapeutic targets.

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“…Several agents have been investigated as add-on therapies for LN. In the Lupus Nephritis Assessment with Rituximab (LUNAR) study (ClinicalTrials.gov identifier NCT00282347), rituximab failed to demonstrate additional efficacy, and the ocrelizumab and atacicept programs were prematurely terminated because of toxicity (30)(31)(32).…”

Section: Discussionmentioning

confidence: 99%

Efficacy and Safety of Abatacept in Lupus Nephritis: A Twelve‐Month, Randomized, Double‐Blind Study

Furie

Nicholls

Cheng

et al. 2014

Arthritis & Rheumatology

305

186

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Objective. To compare the efficacy and safety of intravenous (IV) abatacept, a selective T cell costimulation modulator, versus placebo for the treatment of active class III or IV lupus nephritis, when used on a background of mycophenolate mofetil and glucocorticoids.Methods. This was a 12-month, randomized, phase II/III, multicenter, international, double-blind study. A total of 298 patients were treated in 1 of 3 IV treatment arms: placebo, abatacept at the standard weight-tiered dose (approximating 10 mg/kg), or abatacept at 30 mg/kg for 3 months, followed by the standard weight-tiered dose (abatacept 30/10). The primary end point, time to confirmed complete response, was a composite measure that required maintenance of glomerular filtration rate, minimal proteinuria, and inactive urinary sediment over the 52-week treatment period.Results. There were no differences among treatment arms in the time to confirmed complete response or in the proportion of subjects with confirmed complete response following 52 weeks of treatment. Treatment with abatacept was associated with greater improvements from baseline in anti-double-stranded DNA antibody, C3, and C4 levels. Among 122 patients with nephrotic-range proteinuria, treatment with abatacept resulted in an ϳ20-30% greater reduction in mean urinary protein-to-creatinine ratio compared with placebo. Abatacept was well tolerated; rates of deaths, serious adverse events, and serious infections were similar across treatment arms. Gastroenteritis and herpes zoster occurred more frequently with abatacept treatment.Conclusion. Although the primary end point was not met, abatacept showed evidence of biologic activity and was well tolerated in patients with active class III or IV lupus nephritis.Lupus nephritis (LN) is characterized by the activation and persistence of autoreactive T and B cells and the presence of potentially pathogenic autoantibodies (1). Abatacept is a fusion protein comprising ClinicalTrials.gov identifier: NCT00430677.

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Efficacy and Safety of Ocrelizumab in Active Proliferative Lupus Nephritis: Results From a Randomized, Double‐Blind, Phase III Study

Cited by 314 publications

References 30 publications

Pragmatic Treatment of Patients With Systemic Lupus Erythematosus With Rituximab: Long‐Term Effects on Serum Immunoglobulins

Pragmatic Treatment of Patients With Systemic Lupus Erythematosus With Rituximab: Long‐Term Effects on Serum Immunoglobulins

Current Treatment, Emerging Translational Therapies, and New Therapeutic Targets for Autoimmune Myasthenia Gravis

Efficacy and Safety of Abatacept in Lupus Nephritis: A Twelve‐Month, Randomized, Double‐Blind Study

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