B cell depletion therapy in systemic lupus erythaematosus: relationships among serum B lymphocyte stimulator levels, autoantibody profile and clinical response

Cambridge, G; Isenberg, David; Edwards, Jcw; Leandro, Maria; Migone, Thi‐Sau; Teodorescu, Marius; Stohl, William

doi:10.1136/ard.2007.079418

Cited by 166 publications

(123 citation statements)

References 19 publications

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“…Differences in patterns of fluctuations in anti‐dsDNA antibodies between patients implied a variable contribution from anti‐dsDNA committed B cell clones (CD20+) sensitive to B cell depletion, as well as from long‐lived (IgG) plasma cells (CD20−) 53. Autoantibody‐committed B cells are often preferentially removed by rituximab, as has also been shown in patients with RA 39, 54.…”

Section: Discussionmentioning

confidence: 79%

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: 79%

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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“…Unfortunately, clinical efficacy of belimumab is rather modest, perhaps because of other B cell survival factors that affect persistence of autoreactive B cells. Indeed, experience with rituximab suggests that clinical response and B cell depletion are linked; for example, reappearance of B cells in the peripheral blood of rituximab-treated patients can foretell disease flare (50,51). Thus, clinical efficacy of B cell-targeted therapies may require functional suppression of autoreactive B cells, whereas clinical safety may require survival of protective nonautoreactive B cells.…”

Section: Discussionmentioning

confidence: 99%

Antibody-Mediated Coengagement of FcγRIIb and B Cell Receptor Complex Suppresses Humoral Immunity in Systemic Lupus Erythematosus

Horton

Chu

Ortiz

et al. 2011

The Journal of Immunology

124

111

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Engagement of the low-affinity Ab receptor FcγRIIb downregulates B cell activation, and its dysfunction is associated with autoimmunity in mice and humans. We engineered the Fc domain of an anti-human CD19 Ab to bind FcγRIIb with high affinity, promoting the coengagement of FcγRIIb with the BCR complex. This Ab (XmAb5871) stimulated phosphorylation of the ITIM of FcγRIIb and suppressed BCR-induced calcium mobilization, proliferation, and costimulatory molecule expression of human B cells from healthy volunteers and systemic lupus erythematosus (SLE) patients, as well as B cell proliferation induced by LPS, IL-4, or BAFF. XmAb5871 suppressed humoral immunity against tetanus toxoid and reduced serum IgM, IgG, and IgE levels in SCID mice engrafted with SLE or healthy human PBMC. XmAb5871 treatment also increased survival of mice engrafted with PBMC from a unique SLE patient. Unlike anti-CD20 Ab, coengagement of FcγRIIb and BCR complex did not promote B cell depletion in human PBMC cultures or in mice. Thus, amplification of the FcγRIIb inhibitory pathway in activated B cells may represent a novel B cell-targeted immunosuppressive therapeutic approach for SLE and other autoimmune diseases that should avoid the complications associated with B cell depletion.

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“…In particular, why in a small subgroup of patients rituximab therapy failed to achieve remission and to reduce circulating anti-PLA 2 R autoantibodies despite full B cell depletion remains elusive. In rheumatoid arthritis and systemic lupus erythematosus, 24 rituximab administration reduces circulating autoantibodies much more than total immunoglobulins or antimicrobial antibodies. These data have been taken to suggest that in the aforementioned autoimmune diseases autoantibodies are predominantly produced by shortlived B cells that express the CD20 antigen, whereas other immunoglobulins emerge from differentiated plasmablasts or plasmacells that do not express the antigen.…”

Section: Discussionmentioning

confidence: 99%

Anti-Phospholipase A2 Receptor Antibody Titer Predicts Post-Rituximab Outcome of Membranous Nephropathy

Ruggenenti

Dębiec

Ruggiero

et al. 2015

Journal of the American Society of Nephrology

309

255

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Rituximab induces nephrotic syndrome (NS) remission in two-thirds of patients with primary membranous nephropathy (MN), even after other treatments have failed. To assess the relationships among treatment effect, circulating nephritogenic anti-phospholipase A 2 receptor (anti-PLA 2 R) autoantibodies and genetic polymorphisms predisposing to antibody production we serially monitored 24-hour proteinuria and antibody titer in patients with primary MN and long-lasting NS consenting to rituximab (375 mg/m 2 ) therapy and genetic analyses. Over a median (range) follow-up of 30.8 (6.0-145.4) months, 84 of 132 rituximabtreated patients achieved complete or partial NS remission (primary end point), and 25 relapsed after remission. Outcomes of patients with or without detectable anti-PLA 2 R antibodies at baseline were similar. Among the 81 patients with antibodies, lower anti-PLA 2 R antibody titer at baseline (P=0.001) and full antibody depletion 6 months post-rituximab (hazard ratio [HR], 7.90; 95% confidence interval [95% CI], 2.54 to 24.60; P,0.001) strongly predicted remission. All 25 complete remissions were preceded by complete anti-PLA 2 R antibody depletion. On average, 50% anti-PLA 2 R titer reduction preceded equivalent proteinuria reduction by 10 months. Re-emergence of circulating antibodies predicted disease relapse (HR, 6.54; 95% CI, 1.57 to 27.40; P=0.01), whereas initial complete remission protected from the event (HR, 6.63; 95% CI, 2.37 to 18.53; P,0.001). Eighteen patients achieved persistent antibody depletion and complete remission and never relapsed. Outcome was independent of PLA2R1 and HLA-DQA1 polymorphisms and of previous immunosuppressive treatment. Therefore, assessing circulating anti-PLA 2 R autoantibodies and proteinuria may help in monitoring disease activity and guiding personalized rituximab therapy in nephrotic patients with primary MN.

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B cell depletion therapy in systemic lupus erythaematosus: relationships among serum B lymphocyte stimulator levels, autoantibody profile and clinical response

Cited by 166 publications

References 19 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

Antibody-Mediated Coengagement of FcγRIIb and B Cell Receptor Complex Suppresses Humoral Immunity in Systemic Lupus Erythematosus

Anti-Phospholipase A2 Receptor Antibody Titer Predicts Post-Rituximab Outcome of Membranous Nephropathy

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