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B-Cell Dysregulation in Crohn's Disease Is Partially Restored with Infliximab Therapy.

ABSTRACT: B-cell depletion can improve a variety of chronic inflammatory diseases, but does not appear beneficial for patients with Crohn's disease.To elucidate the involvement of B cells in Crohn's disease, we here performed an 'in depth' analysis of intestinal and blood B-cells in this chronic inflammatory disease.Patients with Crohn's disease were recruited to study B-cell infiltrates in intestinal biopsies (n = 5), serum immunoglobulin levels and the phenotype and molecular characteristics of blood B-cell subsets (n = 21). The effects of infliximab treatment were studied in 9 patients.Granulomatous tissue showed infiltrates of B lymphocytes rather than Ig-secreting plasma cells. Circulating transitional B cells and CD21low B cells were elevated. IgM memory B cells were reduced and natural effector cells showed decreased replication histories and somatic hypermutation (SHM) levels. In contrast, IgG and IgA memory B cells were normally present and their Ig gene transcripts carried increased SHM levels. The numbers of transitional and natural effector cells were normal in patients who responded clinically well to infliximab.B cells in patients with Crohn's disease showed signs of chronic stimulation with localization to granulomatous tissue and increased molecular maturation of IgA and IgG. Therapy with TNF?-blockers restored the defect in IgM memory B-cell generation and normalized transitional B-cell levels, making these subsets candidate markers for treatment monitoring. Together, these results suggest a chronic, aberrant B-cell response in patients with Crohn's disease, which could be targeted with new therapeutics that specifically regulate B-cell function.

SUBMITTER: Timmermans WM

PROVIDER: S-EPMC4965034 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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B-Cell Dysregulation in Crohn's Disease Is Partially Restored with Infliximab Therapy.

Timmermans Wilhelmina M C WM van Laar Jan A M JA van der Houwen Tim B TB Kamphuis Lieke S J LS Bartol Sophinus J W SJ Lam King H KH Ouwendijk Rob J RJ Sparrow Miles P MP Gibson Peter R PR van Hagen P Martin PM van Zelm Menno C MC

PloS one 20160728 7

<h4>Background</h4>B-cell depletion can improve a variety of chronic inflammatory diseases, but does not appear beneficial for patients with Crohn's disease.<h4>Objective</h4>To elucidate the involvement of B cells in Crohn's disease, we here performed an 'in depth' analysis of intestinal and blood B-cells in this chronic inflammatory disease.<h4>Methods</h4>Patients with Crohn's disease were recruited to study B-cell infiltrates in intestinal biopsies (n = 5), serum immunoglobulin levels and th ...[more]

PMID: 27468085

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Project description:BackgroundEpisodic infliximab (IFX) treatment is associated with the formation of antibodies to IFX (ATIs) in the majority of patients, which can lead to infusion reactions and a shorter duration of response. Concomitant use of immunosuppressives (IS) reduces the risk of ATI formation.Aims and methodsTo investigate which of the IS-that is, methotrexate (MTX) or azathioprine (AZA)-is most effective at reducing the risk of ATI formation, a multicentre cohort of 174 patients with Crohn's disease, treated with IFX in an on-demand schedule, was prospectively studied. Three groups were studied: no IS (n = 59), concomitant MTX (n = 50) and concomitant AZA (n = 65). ATI and IFX concentrations were measured in a blinded manner at Prometheus Laboratories before and 4 weeks after each infusion.ResultsATIs were detected in 55% (96/174) of the patients. The concomitant use of IS therapy (AZA or MTX) was associated with a lower incidence of ATIs (53/115; 46%) compared with patients not taking concomitant IS therapy (43/59; 73%; p<0.001). The incidence of ATIs was not different for the MTX group (44%) compared with the AZA group (48%). Patients not taking IS therapy had lower IFX levels (median 2.42 microg/ml (interquartile range (IQR) 1-10.8), maximum 21 microg/ml) 4 weeks after any follow-up infusion than patients taking concomitant IS therapy (median 6.45 microg/ml (IQR 3-11.6), maximum 21 microg/ml; p = 0.065), but there was no difference between MTX or AZA. In patients who developed significant ATIs >8 microg/ml during follow-up, the IFX levels 4 weeks after the first infusion were retrospectively found to be significantly lower than in patients who did not develop ATIs on follow-up or had inconclusive ATIs.ConclusionConcomitant IS therapy reduces ATI formation associated with IFX treatment and improves the pharmacokinetics of IFX. There is no difference between MTX and AZA in reducing these risks. ATI profoundly influences the pharmacokinetics of IFX. The formation of ATIs >8 microg/ml is associated with lower serum levels of IFX already at 4 weeks after its first administration.

Dataset Information

B-Cell Dysregulation in Crohn's Disease Is Partially Restored with Infliximab Therapy.

Publications

B-Cell Dysregulation in Crohn's Disease Is Partially Restored with Infliximab Therapy.

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