B cell reconstitution and T helper cell balance after rituximab treatment of active primary Sjögren's syndrome: A double‐blind, placebo‐controlled study

Abdulahad, Wayel H.; Meijer, Jiska; Kroese, Franciscus; Meiners, Petra M.; Vissink, Arjan; Spijkervet, Frederik; Kallenberg, Cornelis; Bootsma, Hendrika

doi:10.1002/art.30236

Cited by 55 publications

(54 citation statements)

References 31 publications

(31 reference statements)

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“…Total memory B cells and IgM memory and switched memory B cell subsets also started to reconstitute around 6 months after RTX infusion in most patients. However, although total CD19 + and mature B cells reached baseline levels at 12 months, the memory B cell compartment still appeared significantly decreased at this time point, which was already observed after RTX treatment in other B cell-mediated autoimmune diseases [29][30][31][32][33] and is in agreement with the physiologic B cell ontogeny, in which memory B cells are the last emerging B cell subset. 14 Interestingly, RTX administration did not alter levels of total CD3 We then analyzed the clinical response in the cohort of 28 patients with FRNS/SDNS subjected to RTX treatment.…”

Section: Discussionsupporting

confidence: 80%

B Cell Reconstitution after Rituximab Treatment in Idiopathic Nephrotic Syndrome

Colucci¹,

Carsetti²,

Cascioli

et al. 2015

JASN

175

165

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The pathogenesis of nephrotic syndrome is unclear. However, the efficacy of rituximab, a B cell-depleting antibody, in nephrotic syndrome suggests a pathogenic role of B cells. In this retrospective study, we determined by flow cytometry levels of B and T cell subpopulations before and after rituximab infusion in 28 pediatric patients with frequently relapsing or steroid-dependent nephrotic syndrome. At baseline, patients had lower median percentages of transitional and mature B cells than age-matched healthy controls (P,0.001). Rituximab induced full depletion of B cells (,1% of lymphocytes). At 1 year, most patients exhibited complete total and mature B cell recovery, whereas memory B cell subsets remained significantly depleted. Total T cell concentration did not change with rituximab, whereas the CD4 + /CD8 + T cell ratio tended to increase. Fourteen patients relapsed within 24 months, with a median follow-up of 11.2 months (interquartile range, 8-17.7 months). We observed no difference at baseline between nonrelapsing and relapsing patients in several clinical parameters and cell subset concentrations. Reconstitution of all memory B cell subpopulations, number of immunosuppressive drugs, and dose of tacrolimus during the last 4 months of follow-up were predictive of relapse in univariate Cox regression analysis. However, only delayed reconstitution of switched memory B cells, independent of immunosuppressive treatment, was protective against relapse in multivariate (P,0.01) and receiver operator characteristic (P,0.01 for percentage of lymphocytes; P=0.02 for absolute count) analyses. Evaluation of switched memory B cell recovery after rituximab may be useful for predicting relapse in patients with nephrotic syndrome.

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Section: Discussionsupporting

confidence: 80%

B Cell Reconstitution after Rituximab Treatment in Idiopathic Nephrotic Syndrome

Colucci¹,

Carsetti²,

Cascioli

et al. 2015

JASN

175

165

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“…Very few data are available regarding the role of RTX on the T cell arm of the immune system in pSS. A recent study failed to detect a reduction of total circulating T cells in RTX-treated pSS patients [20]. However, it has been reported that RTX is able to affect IL-17 in this disease by reducing its mRNA in MSGs [21].…”

Section: Discussionmentioning

confidence: 96%

“…However, it has been observed that RTX is also able to deplete circulating total CD3 1 T cells [17] as well as circulating and synovial Th17 cells in rheumatoid arthritis (RA) [18,19]. With regard to pSS, although a previous study reported that the overall percentage of circulating effector T cells did not change significantly after RTX treatment [20], the observation that RTX reduces glandular IL-17 and IL-22 expression [21,22] raised the hypothesis that at least some pathogenic T cell subpopulations may be targeted.…”

Section: Introductionmentioning

confidence: 99%

Interleukin (IL)-17-producing pathogenic T lymphocytes co-express CD20 and are depleted by rituximab in primary Sjögren's syndrome: a pilot study

Alunno

Carubbi

Bistoni

et al. 2016

Clinical and Experimental Immunology

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1These authors contributed equally to the study. SummaryCompelling evidence suggests that interleukin (IL)-17 and IL-17-producing cells play a pivotal role in the pathogenesis of primary Sj€ ogren's syndrome (pSS). We investigated phenotypical and functional effects of the anti-CD20 antibody rituximab (RTX) on circulating and glandular IL-17-producing T cells in pSS. RTX is able to deplete glandular IL-

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“…Furthermore, therapeutic B cell depletion strategies targeting CD20 provide clinical relief from pSS symptoms (6,7). However, symptoms usually return 6-9 mo after treatment, and disease relapse apparently coincides with the reappearance of peripheral B cell subpopulations in the blood (7,8). All of the above observations strongly suggest that B cells and/or plasma cells play a significant role in the disease mechanisms underlying pSS, although their exact role in pSS pathogenesis is still undefined.…”

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confidence: 99%

Ig Gene Analysis Reveals Altered Selective Pressures on Ig-Producing Cells in Parotid Glands of Primary Sjögren’s Syndrome Patients

Hamza

Hershberg

Kallenberg

et al. 2015

The Journal of Immunology

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In this study, we sought to understand the selective pressures shaping the Ig-producing cell repertoire in the parotid glands of primary Sjögren’s syndrome (pSS) patients before and after rituximab treatment (RTX). In particular, we evaluated the role of potential N-glycosylation motifs acquired by somatic hypermutation (ac-Nglycs) within Ig H chain V region (IGHV) genes as alternative selective pressures for B cells in pSS. Five pSS patients received RTX. Sequential parotid salivary gland biopsies were taken before RTX, at 12 wk and at 36–52 wk after treatment. Parotid biopsies from four non-pSS patients served as controls. Sequence analysis was carried out on the IgA and IgG RNA transcripts expressing IGHV3 genes in all parotid biopsies. Both IgG and IgA sequences from pSS patients exhibited no evidence for positive Ag-driven selection pressure in their CDRs in contrast to non-pSS controls. The prevalence of IgG sequences with ac-Nglycs was significantly higher in pSS patients than in non-pSS controls. Selection pressures shaping the IgG and IgA repertoire within pSS patients’ parotid glands are distinct from those in non-pSS controls, with very little evidence for positive (auto)antigen selection. The higher prevalence of ac-Nglycs on pSS-IgG compared with non-pSS IgG indicates that ac-Nglycs could be an alternative form of selection pressure. We speculate that B cell hyperproliferation within parotid glands of pSS patients may result from Ag-independent interactions such as that between glycosylated B cell receptors and lectins within the microenvironment rather than (auto)antigen-specific stimulation. Our study brings a new perspective into research on pSS.

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B cell reconstitution and T helper cell balance after rituximab treatment of active primary Sjögren's syndrome: A double‐blind, placebo‐controlled study

Cited by 55 publications

References 31 publications

B Cell Reconstitution after Rituximab Treatment in Idiopathic Nephrotic Syndrome

B Cell Reconstitution after Rituximab Treatment in Idiopathic Nephrotic Syndrome

Interleukin (IL)-17-producing pathogenic T lymphocytes co-express CD20 and are depleted by rituximab in primary Sjögren's syndrome: a pilot study

Ig Gene Analysis Reveals Altered Selective Pressures on Ig-Producing Cells in Parotid Glands of Primary Sjögren’s Syndrome Patients

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