Distribution and Cytokine Profile of Peripheral B Cell Subsets Is Perturbed in Pediatric IBD and Partially Restored During a Successful IFX Therapy

Abstract

Background The role of B cells in inflammatory bowel disease (IBD) is ambiguous, as B cells may have both pathogenic and protective functions in IBD. We studied B cell subsets before and after initiation of an anti-tumor necrosis factor alpha (anti-TNFα) therapy in pediatric IBD. The aim of the study was to examine the behavior of B cells in pediatric IBD patients undergoing an anti-TNFα therapy and, more specifically, to clarify their association with a successful or an unsuccessful infliximab (IFX) treatment. Methods A total of N = 42 pediatric IBD patients (Crohn disease, n = 30; ulcerative colitis, n = 12) for whom an anti-TNFα therapy with and without a concomitant azathioprine (AZA) medication was administered were recruited. Fourteen healthy age-matched children served as control patients. Blood samples were collected before initiation of the anti-TNFα therapy, before the fourth infusion at the end of the induction phase, and after 6 and 12 months under therapy maintenance. Flow cytometry (CD20, CD27, CD38, CD138) and intracellular staining (interleukin 10 [IL10], TNFα, granzyme B) were performed. Responders to successful IFX therapy were classified exhibiting a fecal calprotectin level of below 100 µg/g or achieving levels of <10% of the baseline value at initiation than at the end of the 12-month follow-up period. Results Before initiation of anti-TNFα therapy, flow cytometry revealed increased percentages of naïve B cells whereas transitional B cells were reduced compared with those in the healthy control patients. The IL10-producing B cells of both ulcerative colitis and Crohn disease patients were reduced at the initiation of IFX therapy, whereas TNFα-producing transitional CD24hiCD38hi B cells in ulcerative colitis patients were increased compared with those in healthy control patients. After 12 months of therapy, we detected a significant increase of IL10-producing transitional B cells in responding patients. The IFX trough levels in the responding patients showed a significant increase until 6 months after IFX initiation, attaining mean values of 9.9 µg/mL, whereas the IFX dosage was significantly lower than that in the nonresponding patients. The IFX trough levels in AZA-treated patients reached earlier therapeutic levels than in patients without AZA comedication, whereas during the course of the IFX therapy, comedication with AZA had no significant effect on the outcome. Conclusions Attaining a normalization of IL10 production among CD24hiCD38hi B cells after 12 months of therapy may represent additional information about the reconstitution of a patient’s immune system in responding patients. The achievement of an IFX trough level of ~10 µg/mL at 6 months of treatment is associated with a successful anti-TNFα therapy. In addition, AZA comedication supports an earlier achievement of therapeutic IFX trough levels.

Significant advantages for first line treatment with TNF-alpha inhibitors in pediatric patients with inflammatory bowel disease – Data from the multicenter CEDATA-GPGE registry study

“…In particular, higher infliximab trough levels after induction have been shown to predict remission 1 year after the administration of infliximab in studies of pediatric patients with UC and CD ( 38 , 39 ). In addition, the dosage of the biological drug does not substitute for pharmacokinetics, as the amount of drug applied does not necessarily correspond to the determined drug trough level for several reasons ( 40 ).…”

Potential of B-cell-targeting therapy in overcoming multidrug resistance and tissue invasiveness associated with P-glycoprotein expressing-B cell compartments

“…On the other autoimmune diseases, the clinical response to TNF antagonists in patients with inflammatory bowel diseases (IBD) is reported to be obtained through the effects to B cells. The IL10producing B cells of both ulcerative colitis and Crohn disease patients were reduced compared with those in healthy control patients and detected a significant increase in responding patients after treatment with infliximab, a TNF antagonist [63]. IgD þ CD27 -B cell and activated B cell subsets in reported to be predominant in peripheral blood of sarcoidosis patients [64].…”

Current Role of Monoclonal Antibody Therapy in Pediatric IBD: A Special Focus on Therapeutic Drug Monitoring and Treat-to-Target Strategies

“…Proactive drug monitoring of adalimumab in the randomized PAILOT trial was associated with significantly higher rates of corticoid-free remission and lower inflammatory markers [ 69 ]. Infliximab trough levels greater than 10 mg/mL are generally associated with remission and higher rates of perianal fistula healing in pediatric IBD patients [ 54 , 92 ]. Yarur and colleagues recommend in adults a treat-to-target strategy until adequate infliximab levels are achieved [ 92 ].…”

“…For several of the above-mentioned reasons, the dose of the biological drug does not necessarily correspond to the determined drug trough levels [ 54 ]. Therefore, a Bayesian calculation model applied to drug concentrations represents a new approach to optimize treatment response to biologics in IBD by incorporating several individual parameters that affect drug clearance, such as sex, hypoalbuminemia, and fecal loss [ 54 ]. It predicts the treatment response to optimize dosing [ 98 ].…”

“…It predicts the treatment response to optimize dosing [ 98 ]. With the implementation of three trough-level measurements, the model was able to predict drug concentrations and thus be helpful for therapy adjustments [ 54 ]. Precision dosing showed better remission and response rates in adults compared to traditional dosing regimens [ 61 ].…”