Predicting and managing primary and secondary non-response to rituximab using B-cell biomarkers in systemic lupus erythematosus

Yusof, Yuzaiful Md; Shaw, Daniel J; El-Sherbiny, Yasser M.; Dunn, Emma; Rawstron, Andy; Emery, Paul; Vital, Edward M

doi:10.1136/annrheumdis-2017-211191

Cited by 98 publications

(114 citation statements)

References 29 publications

(29 reference statements)

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“…Patients with low C4 levels, those who had received fewer previous immunosuppressive drugs, and those with severe disease were more likely to respond favorably to RTX. This finding suggests that the ideal candidates for RTX may be those with more active disease and without a clear refractory course, which is consistent with the results of other studies .…”

Section: Discussionsupporting

confidence: 91%

“…Clinical predictors of response to RTX in SLE have been investigated, with heterogeneous results across different cohorts . Severe disease, lack of hematologic involvement, or previous treatment with high‐dose steroids were associated with a good response in 116 patients ; younger age and achievement of B cell depletion 6 weeks after treatment with RTX were other favorable characteristics in a different population of 117 patients . Among biomarkers, the proportion of plasmablasts 6 months after RTX treatment and a single‐nucleotide polymorphism in the IL2/IL21 area have been associated with response .…”

Section: Introductionmentioning

confidence: 99%

“…Severe disease, lack of hematologic involvement, or previous treatment with high‐dose steroids were associated with a good response in 116 patients ; younger age and achievement of B cell depletion 6 weeks after treatment with RTX were other favorable characteristics in a different population of 117 patients . Among biomarkers, the proportion of plasmablasts 6 months after RTX treatment and a single‐nucleotide polymorphism in the IL2/IL21 area have been associated with response . The former has been replicated in 2 different cohorts, while the latter, although it has a strong biologic rationale , has so far been replicated only in a cohort of patients with microscopic polyangiitis .…”

Section: Introductionmentioning

confidence: 99%

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Rituximab as Maintenance Treatment for Systemic Lupus Erythematosus: A Multicenter Observational Study of 147 Patients

Cassia

Alberici

Jones

et al. 2019

Arthritis & Rheumatology

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Objective. The efficacy of rituximab (RTX) in systemic lupus erythematosus (SLE) is a subject of debate. This study was undertaken to investigate the outcomes of RTX treatment in a European SLE cohort, with an emphasis on the role of RTX as a maintenance agent.Methods. All patients with SLE who were receiving RTX as induction therapy in 4 centers were included. Patients who received a single course of RTX and those who received RTX maintenance treatment (RMT) were followed up after treatment. Disease flares during the follow-up period were defined as an increase in disease activity and the number or dose of immunosuppressive drugs.Results. Of 147 patients, 27% experienced treatment failure at 6 months. In a multivariate analysis, a low number of previous immunosuppressive therapies (P = 0.034) and low C4 levels (P = 0.008) reduced the risk of treatment failure. Eighty patients received RMT over a median of 24.5 months during which 85 relapses, mainly musculoskeletal, were recorded (1.06 per patient). At the time of the last RTX course, 84% of the patients were in remission. Twentyeight (35%) of 80 patients never experienced a flare during RMT and had low damage accrual. Active articular disease at the time of the first RTX administration was associated with a risk of flare during RMT (P = 0.011). After RMT, relapse-free survival was similar to that in patients receiving a single RTX course (P = 0.72).Conclusion. RMT is a potential treatment option for patients with difficult-to-treat disease. Relapses occur during RMT and are more likely in those with active articular disease at the time of the first RTX administration. Relapse risk after RMT remains high and apparently comparable to that seen after a single RTX course.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Rituximab as Maintenance Treatment for Systemic Lupus Erythematosus: A Multicenter Observational Study of 147 Patients

Cassia

Alberici

Jones

et al. 2019

Arthritis & Rheumatology

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“…Our finding that circulating ASCs are persistent is consistent with a large body of evidence showing that ASCs, particularly those expressing lower levels of CD20, resist depletion owing to their CD20 expression and tissue localization (22,24,25,48). ASC frequency post-RTX is also known to be a reliable predictor of treatment response in SLE and RA patients treated with RTX (11,(49)(50)(51). By using the repertoire to directly trace and quantify the frequency of these ASCs, we show that many ASCs that reconstitute the B cell compartment after therapy come from preexisting, circulating B cell populations detectable prior to depletion.…”

Section: Discussionsupporting

confidence: 88%

Single-cell repertoire tracing identifies rituximab refractory B cells during myasthenia gravis relapses

Jiang

Fichtner

Hoehn

et al. 2019

Preprint

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One Sentence Summary: Disease relevant B cells during post-rituximab (RTX) relapse emerge from the unsuccessful depletion of pre-existing B cell clones; single-cell transcriptomic phenotyping combined with lineage tracing using paired B cell receptor repertoires identified both persistent antibody-secreting cell as well as memory B cell subsets.Abstract: Rituximab, an anti-CD20 B cell-depleting therapy, is indicated to treat a growing number of autoimmune disorders. However, disease relapses can occur when the B cell compartment is re-established after treatment. To explore the mechanism of relapse, we studied patients with muscle-specific kinase (MuSK) myasthenia gravis (MG), a paradigm for B cellmediated autoimmune diseases in which pathology is directly associated with autoantibody production. Whether the failed depletion of specific clones leads to the persistence of autoantibody producing B cell subsets has yet to be elucidated. Here we show that rituximab (RTX) therapy is not fully effective at eliminating disease-associated B cells and provide a mechanistic understanding of relapse. We carried out single-cell transcriptional and B cell receptor (BCR) profiling on longitudinal B cell samples from the peripheral blood of MuSK MG patients who relapsed after rituximab therapy. Computational analysis of these data identified individual B cells that were refractory to rituximab depletion by linking them to clones that were present prior to therapy and continued to persist after therapy. These persistent B cell clones were present at high frequency, and included both antibody-secreting cells and memory B cells. They were disproportionately isotype switched with elevated somatic hypermutation frequencies and a gene expression signature associated with antigen-experience and B cell clonal expansion. We further identified both antibody-secreting cells and memory B cells with specificity for MuSK autoantigen that were clonally expanded during relapse and persistent. Our results provide evidence that post-rituximab relapse in MuSK MG is associated with the failed depletion of autoantigen-specific B cell subsets. This work provides insight into the durability of human B cells during treatment with therapeutic CD20-specific monoclonal antibodies. The transcriptional signatures associated with B cell resistance may represent new therapeutic avenues for treatment and biomarkers of depletion efficacy.

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“…Following an initial response, the majority of RMD patients treated with RTX ultimately experience a relapse, requiring repeat cycles to recapture response. Repeat cycles of RTX are effective . However, attrition of immunoglobulin levels may occur .…”

Section: Introductionmentioning

confidence: 99%

Predicting Severe Infection and Effects of Hypogammaglobulinemia During Therapy With Rituximab in Rheumatic and Musculoskeletal Diseases

Yusof

Vital

McElvenny

et al. 2019

Arthritis & Rheumatology

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Objective To evaluate predictors of serious infection events (SIEs) during rituximab (RTX) therapy and effects of hypogammaglobulinemia on SIE rates, and humoral response and its persistence after discontinuation of RTX in the treatment of rheumatic and musculoskeletal diseases (RMDs). Methods A retrospective longitudinal study of 700 RMD patients treated with RTX in a single center was conducted. Immunoglobulin levels were measured at baseline and at 4–6 months after each treatment cycle. Baseline predictors of SIEs were assessed using multivariable logistic regression; for RTX cycles 2–4, a mixed‐effects logistic regression model was used. Results A total of 507 patients (72%) had rheumatoid arthritis, 94 (13%) had systemic lupus erythematosus, 49 (7%) had antineutrophil cytoplasmic antibody–associated vasculitis, and 50 (7%) had other RMDs. The number of SIEs recorded was 281 in 176 patients (9.8 per 100 person‐years). Predictors of SIEs included non–RTX‐specific comorbidities (previous history of SIE, cancer, chronic lung disease, diabetes mellitus, and heart failure), higher corticosteroid dose, and RTX‐specific factors, including low IgG (<6 gm/liter) both at baseline and during treatment, RTX‐associated neutropenia, higher IgM, and longer time to RTX re‐treatment, but not B cell count or depletion status. Of 110 patients with low IgG, SIE rates were higher in those with low IgG at baseline (16.4 per 100 person‐years) and in those who acquired low IgG during or after RTX treatment (21.3 per 100 person‐years) versus those with normal IgG (9.7 per 100 person‐years). Five of 8 patients (63%) had impaired humoral response to pneumococcus and hemophilus following vaccination challenge, and only 4 of 11 patients (36%) had IgG normalized after switching biologic disease‐modifying antirheumatic drugs. Conclusion Immunoglobulin levels should be monitored at baseline and before each RTX cycle to identify patients at risk of SIEs. Individualized risk–benefit assessment should be undertaken in those with lower IgG as this is a consistent SIE predictor and may increase infection profiles when RTX is switched to different therapies.

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Predicting and managing primary and secondary non-response to rituximab using B-cell biomarkers in systemic lupus erythematosus

Cited by 98 publications

References 29 publications

Rituximab as Maintenance Treatment for Systemic Lupus Erythematosus: A Multicenter Observational Study of 147 Patients

Rituximab as Maintenance Treatment for Systemic Lupus Erythematosus: A Multicenter Observational Study of 147 Patients

Single-cell repertoire tracing identifies rituximab refractory B cells during myasthenia gravis relapses

Predicting Severe Infection and Effects of Hypogammaglobulinemia During Therapy With Rituximab in Rheumatic and Musculoskeletal Diseases

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