Abstract
Background and Aims
Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis. We present primary completion analysis from RIVETING, an ongoing, ...double-blind, randomised, parallel-group trial evaluating efficacy and safety of tofacitinib dose reduction to 5 mg twice daily BID versus remaining on 10 mg BID in patients in stable remission on tofacitinib 10 mg BID maintenance therapy.
Methods
Patients had received tofacitinib 10 mg BID for ≥ 2 consecutive years and been in stable remission for ≥ 6 months before enrolment. The primary endpoint was modified Mayo score remission at Month 6. Safety was assessed up to February 20, 2020 data cut-off.
Results
In all, 140 patients were randomised 1:1 to tofacitinib 5 or 10 mg BID; 77.1% and 90.0% of patients in the 5 and 10 mg BID groups, respectively, were in modified Mayo score remission at Month 6 (adjusted difference 12.9%; 95% confidence interval CI 0.5–25.0). Smaller differences between treatment groups were seen in patients with baseline endoscopic subscore of 0 versus 1 9.8%; –3.0–22.6, and 21.1%; –6.1–48.2, respectively, and in patients without versus with prior tumour necrosis factor inhibitor TNFi failure 9.5%; –6.6–25.6, and 17.4%; –1.6–36.3, respectively. Adverse events AE and serious AE rates were similar across treatment groups; no deaths were reported.
Conclusions
Most patients in stable remission on 10 mg BID maintenance therapy maintained remission following dose de-escalation. For patients who dose de-escalated, those in deep endoscopic remission and those without prior TNFi failure were more likely to maintain remission. Efficacy data were limited to the first 6 months; a longer duration of follow-up during RIVETING will further characterise the impact of dose reduction on maintenance of remission. Safety findings were consistent with the established safety profile of tofacitinib.
Summary
Background
Identifying predictors of therapeutic response is the cornerstone of personalised medicine.
Aim
To identify predictors of long‐term healing of severe inflammatory lesions based on ...magnetic resonance enterography (MRE) findings in patients with Crohn’s disease (CD) treated with tumour necrosis factor alpha (TNF‐α) inhibitors.
Methods
This prospective longitudinal single‐centre study included patients with clinically active CD requiring treatment with TNF‐α inhibitors with at least one intestinal segment with a severe inflammatory lesion detected by MRE (segmental MaRIA ≥11). MRE data were obtained at baseline, and at weeks 14 and 46. The primary endpoint was healing of severe inflammatory lesions (MaRIA <11) in each segment. The secondary endpoint was healing of all severe inflammatory lesions on a per‐patient analysis.
Results
We included 58 patients with 86 intestinal segments with severe inflammatory lesions. At week 46, healing of severe lesions was found in 51/86 (59.3%) segments, and complete healing of inflammatory lesions in all segments was found in 28/58 (48.6%) patients. Multivariable analysis found baseline‐negative predictors of long‐term healing of severe inflammation were ileal (as opposed to colonic) location (OR 0.00, 0.00‐0.56 P = 0.002) and presence of creeping fat on MRE (OR 0.00 0.00‐0.57; P = 0.001). Persistence of segmental MaRIA score >10.6 at week 14 was a negative predictor of healing at week 46 (OR 0.3 0.04‐‐0.38; P < 0.001).
Conclusion
In patients with CD, the absence of creeping fat detected at baseline MRE and location of severe inflammatory lesions are clinically relevant predictors of long‐term healing of severe inflammation under treatment with TNF‐α inhibitors.
Background & Aims Crohn’s disease (CD) has been associated with an altered immune response to commensal microbiota, mostly based on increased seroreactivity to microbial proteins. Although T cells ...are believed to contribute to the development of CD, little is known about the antigens involved. We investigated the antigen-specificity of T cells isolated from patients with CD. Methods We isolated peripheral blood mononuclear cells from 65 patients with CD and 45 healthy individuals (controls). We investigated T-cell reactivity to commensal microbial antigens using proliferation assays (based on thymidine incorporation and carboxyfluorescein succinimidyl ester dilution). Gene expression patterns were determined using microarray and real-time polymerase chain reaction analyses. Cytokines, chemokines, and antibodies were measured by enzyme-linked immunosorbent assay, flow cytometry, or multiplex cytokine assays. Intestinal crypts were obtained from surgical resection specimens of 7 individuals without inflammatory bowel disease. We examined the effects of commensal-specific CD4+ T cells on primary intestinal epithelial cells from these samples. Results The bacterial proteins FlaX, A4-fla2, and YidX increased proliferation of CD4+ T cells isolated from peripheral blood of patients with CD compared with controls. In blood samples from controls, CD4+ T cells specific for FlaX, A4-fla2, or YidX had a T-helper (Th)1 phenotype; a larger proportion of CD4+ T cells specific for these proteins in patients with CD had a Th17 phenotype or produced Th1 and Th17 cytokines. When supernatants collected from commensal-specific CD4+ T cells from patients with CD were applied to healthy intestinal epithelial cells, the epithelial cells increased the expression of the chemokines CXCL1, CXCL8, and CCL20. Conclusions A larger proportion of commensal-specific CD4+ T cells from patients with CD have a Th17 phenotype or produce Th1 and Th17 cytokines, compared with T cells from controls; this might contribute to intestinal inflammation in patients with CD. These cells might be targeted for treatment of CD. The transcriptional data of commensal-specific CD4+ T cells from healthy individuals and CD patients have been deposited in the Gene Expression Omnibus at the National Center for Biotechnology Information (accession no: GSE70469 ).
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