Introduction

Tofacitinib (TOFA) is a JAK inhibitor used for the treatment of rheumatologic diseases including rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. The efficacy of TOFA in rheumatology led to big expectations on a potential benefit on ulcerative colitis (UC)-associated spondyloarthropathy (SpA), but very few data are currently available.

Aims & Methods

Real-world Effectiveness of Tofacitinib on Ulcerative Colitis Associated Spondyloarthropathy (RETUCAS) is a prospective, multicentre, observational study designed to assess the effectiveness of TOFA on UC associated SpA and promoted by the Italian Group for the study of Inflammatory Bowel Disease (IG-IBD). Patients with UC and an established diagnosis of active axial or peripheral SpA at baseline were included. Active SpA at baseline was defined with an Ankylosing Spondylitis Disease Activity Score (ASDAS)-CRP ≥ 1.3 in case of axial SpA, and with a disease activity score (DAS)28-CRP ≥ 2.6 in case of peripheral SpA. The primary endpoint was the rate of patients achieving a steroid-free joint response (SFJR - defined by a decrease of ≥ 1.1 units of ASDAS-CRP for axial SpA, and a decrease of > 0.6 units of DAS28-CRP for peripheral SpA compared with baseline with no steroids use) at week 8 and 52. Secondary endpoints were the clinical intestinal response (CIR) and the steroid-free clinical intestinal remission (SFCIR) assessed with the partial Mayo score.

Results

44 patients were included (mean age: 43.8 ± 12.6 years; mean duration of disease: 14.2 ± 8.9 years; all but two were bio-experienced). Active axial Spa was reported in 4 patients (9.1%), active peripheral SpA in 31 cases (70.5%), and mixed (axial + peripheral) SpA in 9 cases (20.5%). At baseline, mean ASDAS-CRP was 2.4 ± 0.7, and DAS28-CRP was 3.5 ± 0.6. At 8 weeks, SFJR was reported in 52.3.% of patients, with a significant difference between patients with peripheral SpA only compared with the subgroup of patients with axial and mixed SpA (67.7% vs. 15.4%; p=0.001). At 52 weeks, SFJR was reported in 59.4.% of patients (peripheral SpA only: 66.7% vs. axial and mixed SpA: 37.5%; p=0.3). CIR was reported in 59.1% of patients at 8 weeks, and in 75.0% of patients at 52 weeks, with SFCIR achieved by 34.1% at 8 weeks, and 56.2% at 52 weeks. Three adverse events were reported: one case mild hypercholesterolemia, one case of mild elevation of transaminase levels, and one case of fever and malaise causing the withdrawal of TOFA after 3 days of administration.

Conclusion

This is the first prospective study designed specifically for the assessment of IBD-associated SpA and based on rheumatological scores. TOFA showed to be effective on UC-associated peripheral SpA, while more data are needed on axial SpA

Disclosure

The study was promoted by IG-IBD and received no funding

Introduction

Crohn’s disease (CD), as a type of inflammatory bowel disease (IBD), is characterized by chronic inflammation in the intestinal tract and its incidence is rising globally. The factors involved in causing or triggering Crohn’s disease (CD) have yet to be confirmed. We recently demonstrated that the intestinal microbiome composition is associated with the risk of CD development; however, its potential causal effect remains unknown. Our study investigated whether stool microbiome might contribute to or trigger dysregulated immune response by transplanting stool into germ-free mice (GFM).

Aims & Methods

Fecal samples were collected from 12 discordant pairs of siblings (one who did not develop CD referred to as Healthy Matched Control (HMC) and another who subsequently developed CD, referred to as pre-CD). These subjects were recruited as part of the Crohn's and Colitis Canada Genetic, Environmental, Microbial Project (CCC-GEM) project, a cohort of prospectively followed healthy first-degree relatives. The stool was transplanted into RAG1-/- GFM before T-cell transfer-induced colitis (3 transplanted mice per donor). Body weight was monitored for 6 weeks after T-cell transfer. Fecal Lipocalin-2 (LCN-2) was measured by ELISA to assess gut inflammation. Intestinal tissue damage was assessed by a validated histology scoring. Pro-inflammatory cytokine gene profiles of intestinal tissue were measured by qPCR. The feces of colitic mice were collected after 6 weeks of T-cell transfer and used to investigate metabolic profile measured by UHPLC-MS/MS.

Results

At week 2 after T-cell transfer, mouse recipients of pre-CD stool experienced greater weight loss than mice receiving stool from HMC (p=0.004). LCN-2 of pre-CD mice was significantly higher after T-cell transfer at week 3. Intriguingly, pre-CD stool recipient mice had a higher histological damage score in the ileum (p=0.031). Mice receiving pre-CD stool had increased expression of selected pro-inflammatory cytokine genes in the ileum including Tnfα, Il-1β, Ifnγ, Il-10 and Tgfβ compared to mice that received HMC stool. Colonic tissue showed significant increases in TNFα and Tgfβ in the mice recipient of the pre-CD stool. Moreover, pre-CD stool led to significant changes in 40 fecal metabolites compared to HMC microbiome (0.01<p≤0.05). Spearman correlation between certain metabolites and colitis markers in mouse was observed. Fecal metabolomics in humans revealed two shared metabolic pathways associated with future onset of CD and murine inflammatory markers. Notably, there was a positive correlation between sphingolipids in humans and mice that was associated with increased colitis in mice. Sphingolipid metabolites also demonstrated positive correlation with mouse colitis marker and human CD subclinical markers.

Conclusion

These results showed that transplanted pre-CD stool worsened T cell transfer colitis in mice compared to HMC stool. This suggests that stool microbiome of individuals with CD is functionally altered years before diagnosis, exhibiting greater inflammatory potential when transferred to susceptible mice. Modulating pre-CD microbiome composition and/or function could lead to novel methods of CD prevention.

Introduction

Ulcerative colitis (UC) and Crohn’s disease (CD), collectively inflammatory bowel disease (IBD), are characterized by chronic gastrointestinal tract inflammation. Recently, there has been interest in the use of selective oral tyrosine kinase 2 (TYK2) inhibitors for IBD treatment, which inhibit signalling downstream of multiple pro-inflammatory cytokines and may have an improved safety profile relative to non-specific Janus kinase (JAK) inhibition. Here, we use a transcriptomic approach to assess the involvement of TYK2-dependent signalling pathways in IBD, and how these are impacted by currently available treatments.

Aims & Methods

TYK2-dependent gene signatures were characterized using cytokine stimulation studies and co-expression analysis. Involvement of signature modules in IBD was assessed using disease model data generated from Takeda curated public datasets from 4059 biopsy samples from 2993 unique patients in 15 UC and 38 CD clinical studies, including assessments of golimumab, infliximab, ustekinumab, and vedolizumab. Pathway differential expression analysis was performed using Gene Set Enrichment Analysis (GSEA) and single-sample GSEA methods.^1,2

Results

Seven TYK2-dependent gene signature modules were defined, including two for type I interferon (IFN), three for IL-23, and two for IL-12. Type I IFN signatures were strongly enriched in both UC and CD, while enrichment of IL-23 was stronger in UC than CD, and enrichment of IL-12 was stronger in CD than UC. In each case, gene signature module enrichment was associated with greater disease severity. Pathway enrichment analysis of data from individual clinical studies demonstrated that specific type I IFN and IL-12 modules were significantly reduced, but not completely ameliorated, following treatment with golimumab, infliximab, ustekinumab, or vedolizumab. Further assessment of response to therapy in these studies showed that enrichment of type I IFN, IL-23, and IL-12 signature modules was associated with non-response to golimumab, infliximab, and vedolizumab.

Conclusion

Enrichment of TYK2-dependent gene signatures, including type I IFN, IL-23, and IL-12, is associated with both UC and CD. These TYK2-dependent enrichments are not fully mitigated through currently available treatments, and may be associated with non-response to treatment. It is important that all three signalling pathways are considered in the development of future treatment options.

References

1. Barbie DA, et al. Nature 2009;462:108–12.
2. Subramanian A, et al. Proc Natl Acad Sci U S A 2005;102:15545–50.

Disclosure

IP, NS, JT, PP, HW, PT, and VA are employees and shareholders of Takeda; AND was an employee and shareholder of Takeda at the time of the analysis. SSS-O is a consultant for and shareholder of CytoReason and AS-M, RS, ND, IW, and YC are employees and shareholders of CytoReason, which has received research funding from Takeda.