Real-world experience with tofacitinib in ulcerative colitis - a systematic review and meta-analysis

BACKGROUND AND AIMS: Tofacitinib is a Janus kinase inhibitor (JAKi) recently approved for the treatment of moderate to severe ulcerative colitis (UC) based on robust efficacy and safety data derived from OCTAVE clinical trials. Evidence on the outcomes of tofacitinib therapy in real-world UC patients is needed, as a number of these patients would be deemed ineligible for clinical trials. We have therefore summarised data derived from observational, real-world evidence (RWE) studies on the effectiveness and safety of tofacitinib in moderate to severe UC patients. METHODS: We searched the PubMed, EMBASE, Scopus, Web of Science and Cochrane databases for observational studies on the use of tofacitinib in UC patients, published between 30 May 2018 and 24 January 2021. Pooled induction (8–14 weeks) and maintenance (16–26 weeks) clinical response and remission rates were calculated, as well as the proportion of reported adverse events using random effects models. RESULTS: Nine studies were included, comprising 830 patients, of which 81% were previously treated with anti-tumour necrosis factor (TNF) and 57% with vedolizumab. Induction of clinical response and remission were achieved in 51% (95% confidence interval, 41–60%) and 37% (26–45%) of patients, after a median follow-up of 8 weeks. At the end of a median follow-up of 24 weeks, maintenance of clinical response and remission were met in 40% (31–50%) and 29% (23–36%) of patients, respectively. Thirty-two percent of the patients had at least one adverse event, the most commonly reported being mild infection (13%) and worsening of UC, requiring colectomy (13%). A third of the patients (35%) discontinued tofacitinib, most frequently due to primary non-response (51%). CONCLUSION: Tofacitinib is a safe and effective therapy in real-world UC patients, as previously reported by clinical trials

Atypical Mycobacterial Infection Presenting as Persistent Skin Lesion in a Patient with Ulcerative Colitis

Immunosuppressive drugs are commonly used for the treatment of inflammatory bowel disease. Patients receiving immunosuppressants are susceptible to a variety of infections with opportunistic pathogens. We present a case of skin infection with Mycobacterium chelonae in a 60-year-old Caucasian woman with ulcerative colitis who had been treated with corticosteroids and azathioprine. The disease manifested with fever and rash involving the right leg. Infliximab was administered due to a presumptive diagnosis of pyoderma gangrenosum, leading to worsening of the clinical syndrome and admission to our hospital. Routine cultures from various sites were all negative. However, Ziehl-Neelsen staining of pus from the lesions revealed acid-fast bacilli, and culture yielded a rapidly growing mycobacterium further identified as M. chelonae. The patient responded to a clarithromycin-based regimen. Clinicians should be aware of skin lesions caused by atypical mycobacteria in immunocompromised patients with inflammatory bowel disease. Furthermore, they should be able to thoroughly investigate and promptly treat these conditions

Rates, predictive factors and effectiveness of ustekinumab intensification to 4- or 6-weekly intervals in Crohn's disease

Background: The UNITI trial reports efficacy of ustekinumab (UST) dose intensification in Crohn's disease (CD) from 12- to 8-weekly, but not 4-weekly. We aimed 1) to assess the cumulative incidence of UST dose intensification to 4- or 6-weekly, 2) to identify factors associated with dose intensification, and 3) to assess the effectiveness of this strategy. Methods: We performed a retrospective, observational cohort study in NHS Lothian including all UST treated CD patients (2015–2020). Results: 163 CD patients were treated with UST (median follow-up: 20.3 months [13.4–38.4]), of whom 55 (33.7%) underwent dose intensification to 4-weekly (n = 50, 30.7%) or 6-weekly (n = 5, 3.1%). After 1 year 29.9% were dose intensified. Prior exposure to both anti-TNF and vedolizumab (HR 9.5; 1.3–70.9), and concomitant steroid use at UST start (HR 1.8; 1.0–3.1) were associated with dose intensification. Following dose intensification, 62.6% patients (29/55) remained on UST beyond 1 year. Corticosteroid-free clinical remission was achieved in 27% at week 16 and 29.6% at last follow-up. Conclusion: One third of CD patients treated with UST underwent dose intensification to a 4- or 6-weekly interval within the first year. Patients who failed both anti-TNF and vedolizumab, or required steroids at initiation were more likely to dose intensify.</p

Effectiveness and Safety of Adalimumab Biosimilar SB5 in IBD:Outcomes in Originator to SB5 Switch, Double Biosimilar Switch and Bio-Naieve SB5 Observational Cohorts

BACKGROUND AND AIMS: Multiple adalimumab [ADA] biosimilars are now approved for use in inflammatory bowel disease [IBD]; however, effectiveness and safety data remain scarce. We aimed to investigate long-term outcomes of the ADA biosimilar SB5 in IBD patients following a switch from the ADA originator [SB5-switch cohort] or after start of SB5 [SB5-start cohort]. METHODS: We performed an observational cohort study in a tertiary IBD referral centre. All IBD patients treated with Humira underwent an elective switch to SB5. We identified all these patients in a biological prescription database that prospectively registered all ADA start and stop dates including brand names. Data on IBD phenotype, C-reactive protein [CRP], drug persistence, ADA drug and antibody levels, and faecal calprotectin were collected. RESULTS: In total, 481 patients were treated with SB5, 256 in the SB5-switch cohort (median follow-up: 13.7 months [IQR 8.6–15.2]) and 225 in the SB5-start cohort [median follow-up: 8.3 months [4.2–12.8]). Of the SB5-switch cohort, 70.8% remained on SB5 beyond 1 year; 90/256 discontinued SB5, mainly due to adverse events [46/90] or secondary loss of response [37/90]. In the SB5-start cohort, 81/225 discontinued SB5, resulting in SB5-drug persistence of 60.3% beyond 1 year. No differences in clinical remission [p = 0.53], CRP [p = 0.80], faecal calprotectin [p = 0.40] and ADA trough levels [p = 0.55] were found between baseline, week 26 and week 52 following switch. Injection site pain was the most frequently reported adverse event. CONCLUSION: Switching from ADA originator to SB5 appeared effective and safe in this study with over 12 months of follow-up

Systematic Review with Network Meta-Analysis: Efficacy of Induction Therapy with a Second Biological Agent in Anti-TNF-Experienced Crohn’s Disease Patients

Background and Aim. Crohn’s disease (CD) is a chronic inflammatory condition of the gastrointestinal tract with the potential to progress to a severe debilitating state. Treatment with biological agents is highly efficient, improving both short-term outcomes and long-term prognosis. Nonetheless, up to 60% of patients receiving biological therapy will exhibit nonresponse at some point. The optimal management of such patients is not clearly defined. Besides traditional anti-TNF agents (infliximab, adalimumab, and certolizumab), alternative biological therapies (natalizumab, vedolizumab, and ustekinumab) are currently available for the treatment of CD. Our aim was to analyze all available evidence regarding efficacy of a second biological in “biological-treatment-experienced” patients. Methods. A systematic review of the literature was conducted using specific criteria for selecting relevant randomized clinical trials evaluating response to administration of secondary biological therapy in “anti-TNF-experienced” CD patients. Data from these studies was used to perform (a) traditional meta-analysis to ascertain the effect of secondary treatment versus placebo and (b) network meta-analysis to compare indirectly the efficacy of available biological agents. Results. Out of initially 977 studies, only eight were included for analysis, providing a total of 1281 treated and 733 placebo-receiving CD patients. Treatment with a second biological was found to be superior to placebo for both induction of remission (OR 2.2, 95% CI 1.7 to 3) and response (OR 1.9, 95% CI 1.5 to 2.5), with global rates of 24% and 42%, respectively (placebo rate: 11% and 27%, p<0.0001 for both). Indirect comparisons performed with network meta-analysis suggest no specific agent is clearly superior to others, with relatively better results observed for adalimumab in inducing disease remission. Conclusion. In anti-TNF-experienced CD patients, secondary biological administration may be efficient, while no specific agent seems to outperform the others. Further research is needed to identify optimal management strategies for this challenging subset of patients

Systematic Review with Network Meta-Analysis: Efficacy of Induction Therapy with a Second Biological Agent in Anti-TNF-Experienced Crohn&apos;s Disease Patients

Background and Aim. Crohn’s disease (CD) is a chronic inflammatory condition of the gastrointestinal tract with the potential to progress to a severe debilitating state. Treatment with biological agents is highly efficient, improving both short-term outcomes and long-term prognosis. Nonetheless, up to 60% of patients receiving biological therapy will exhibit nonresponse at some point. The optimal management of such patients is not clearly defined. Besides traditional anti-TNF agents (infliximab, adalimumab, and certolizumab), alternative biological therapies (natalizumab, vedolizumab, and ustekinumab) are currently available for the treatment of CD. Our aim was to analyze all available evidence regarding efficacy of a second biological in “biological-treatment-experienced” patients. Methods. A systematic review of the literature was conducted using specific criteria for selecting relevant randomized clinical trials evaluating response to administration of secondary biological therapy in “anti-TNF-experienced” CD patients. Data from these studies was used to perform (a) traditional meta-analysis to ascertain the effect of secondary treatment versus placebo and (b) network meta-analysis to compare indirectly the efficacy of available biological agents. Results. Out of initially 977 studies, only eight were included for analysis, providing a total of 1281 treated and 733 placebo-receiving CD patients. Treatment with a second biological was found to be superior to placebo for both induction of remission (OR 2.2, 95% CI 1.7 to 3) and response (OR 1.9, 95% CI 1.5 to 2.5), with global rates of 24% and 42%, respectively (placebo rate: 11% and 27%, p &lt; 0 0001 for both). Indirect comparisons performed with network meta-analysis suggest no specific agent is clearly superior to others, with relatively better results observed for adalimumab in inducing disease remission. Conclusion. In anti-TNF-experienced CD patients, secondary biological administration may be efficient, while no specific agent seems to outperform the others. Further research is needed to identify optimal management strategies for this challenging subset of patients

High intestinal and systemic levels of decoy receptor 3 (DcR3) and its ligand TL1A in active ulcerative colitis

Decoy receptor-3 (DcR3) is a member of the TNF receptor superfamily of proteins, which has been implicated in anti-apoptotic and anti-inflammatory pathways, via binding to TL1A, LIGHT and Fas-L. The role of the TL1A/DcR3 ligand/receptor pair in ulcerative colitis (UC) has not been studied. We investigated the systemic (peripheral blood) and local (large intestine) expression of DcR3 and TL1A in 64 patients with UC and 56 healthy controls. DcR3 serum concentrations were highly elevated in patients with active UC (P &lt; 0.0001 vs. healthy controls). This elevation was clearly related to the presence of intestinal inflammation as it was less frequently observed in patients in remission (P=0.003 vs. active UC) whereas effective treatment resulted in disappearance or significant decrease of serum DcR3 (P=0.006 vs. pre-treatment). Furthermore, DcR3 mRNA transcripts were significantly elevated in inflamed areas of the colon (P=0.002 vs. non-affected of the same patient). In addition to DcR3 elevation, we found increased circulating levels of TL1A in patients with either active or inactive UC in comparison to healthy controls (P &lt; 0.001 for both). We conclude that elevated serum DcR3 may serve as an indicator of active colonic inflammation in patients with UC. TL1A/DcR3-mediated pathways may participate in the pathogenesis of UC. (C) 2010 Elsevier Inc. All rights reserved

Circulating levels of TNF-like cytokine 1A (TL1A) and its decoy receptor 3 (DcR3) in rheumatoid arthritis

TL1A is a novel TNF-tike cytokine, which provides co-stimulatory and Th1-polarizing signals to activated lymphocytes, via binding to death-domain receptor 3 (DR3). These functions are inhibited when TL1A associates to decoy receptor 3 (DcR3). We investigated the serum expression of TL1A and DcR3 in 81 patients with RA and 51 healthy controls. TL1A concentrations were elevated in patients by 5-fold (P&lt;0.00001). This increase was more prominent in RFactor-positive patients and correlated with clinical activity in this subgroup. DcR3 was detected more frequently and in significantly higher values in RA-derived sera, correlated strongly with TL1A, and was present in inflammatory synovial fluid. Severe RA stage was associated with highly elevated TL1A and DcR3 serum levels. Treatment with an anti-TNF agent significantly decreased TL1A serum levels. We conclude that TL1A may serve as an inflammatory marker in RA. Interactions between TL1A and its receptors may be important in the pathogenesis of RA. (C) 2008 Elsevier Inc. All rights reserved