PMID- 31984480 OWN - NLM STAT- MEDLINE DCOM- 20200522 LR - 20220913 IS - 1469-493X (Electronic) IS - 1361-6137 (Linking) VI - 1 IP - 1 DP - 2020 Jan 27 TI - Oral Janus kinase inhibitors for maintenance of remission in ulcerative colitis. PG - CD012381 LID - 10.1002/14651858.CD012381.pub2 [doi] LID - CD012381 AB - BACKGROUND: Tofacitinib is an oral Janus kinase (JAK) inhibitor which blocks cytokine signaling involved in the pathogenesis of autoimmune diseases including ulcerative colitis (UC). The etiology of UC is poorly understood, however research suggests the development and progression of the disease is due to a dysregulated immune response leading to inflammation of the colonic mucosa in genetically predisposed individuals. Additional medications are currently required since some patients do not respond to the available medications and some medications are associated with serious adverse events (SAEs). JAK inhibitors have been widely studied in diseases including rheumatoid arthritis and Crohn's disease and may represent a promising and novel therapeutic option for the treatment of UC. OBJECTIVES: The primary objective was to assess the efficacy and safety of oral JAK inhibitors for the maintenance of remission in participants with quiescent UC. SEARCH METHODS: We searched the following databases from inception to 20 September 2019: MEDLINE, Embase, CENTRAL, and the Cochrane IBD Group Specialized Register, WHO trials registry and clinicaltrials.gov. References and conference abstracts were searched to identify additional studies. SELECTION CRITERIA: Randomized control trial (RCTs) in which an oral JAK inhibitor was compared with placebo or active comparator in the treatment of quiescent UC were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Two review authors independently screened studies for inclusion and extraction. Bias was assessed using the Cochrane 'Risk of bias' tool. The primary outcome was the proportion of participants who failed to maintain remission as defined by any included studies. Secondary outcomes included failure to maintain clinical response, failure to maintain endoscopic remission, failure to maintain endoscopic response, disease-specific quality of life, adverse events (AEs), withdrawal due to AEs and SAEs. We calculated the risk ratio (RR) and 95% confidence intervals (95% CI) for each dichotomous outcome. Data were analyzed on an intention-to-treat basis. The overall certainty of the evidence supporting the outcomes was evaluated using the GRADE criteria. MAIN RESULTS: One RCT (593 participants) including patients with moderately to severely active UC met the inclusion criteria. Patients were randomly assigned in a 1:1:1 ratio to receive maintenance therapy with tofacitinib at 5 mg twice daily, 10 mg twice daily or placebo for 52 weeks. The primary endpoint was remission at 52 weeks and the secondary endpoints included mucosal healing at 52 weeks, sustained remission at 24 and 52 weeks and glucocorticosteroid-free remission. This study was rated as low risk of bias. The study reported on most of the pre-specified primary and secondary outcomes for this review including clinical remission, clinical response, endoscopic remission, AEs, SAEs and withdrawal due to AEs. However, the included study did not report on endoscopic response or disease-specific quality of life. Sixty-three per cent (247/395) of tofacitinib participants failed to maintain clinical remission at 52 weeks compared to 89% (176/198) of placebo participants (RR 0.70, 95% CI 0.64 to 0.77; high-certainty evidence). Forty-three per cent (171/395) of tofacitinib participants failed to maintain clinical response at 52 weeks compared to 80% (158/198) of placebo participants (RR 0.54, 95% CI 0.48 to 0.62; high-certainty evidence). Eighty-four per cent (333/395) of tofacitinib participants failed to maintain endoscopic remission at 52 weeks compared to 96% (190/198) of placebo participants (RR 0.88, 95% CI 0.83 to 0.92; high-certainty evidence). AEs were reported in 76% (299/394) of tofacitinib participants compared with 75% (149/198) of placebo participants (RR 1.01, 95% CI 0.92 to 1.11; high-certainty evidence). Commonly reported AEs included worsening UC, nasopharyngitis, arthralgia (joint pain)and headache. SAEs were reported in 5% (21/394) of tofacitinib participants compared with 7% (13/198) of placebo participants (RR 0.81, 95% CI 0.42 to 1.59; low-certainty evidence). SAEs included non-melanoma skin cancers, cardiovascular events, cancer other than non-melanoma skin cancer, Bowen's disease, skin papilloma and uterine leiomyoma (a tumour in the uterus). There was a higher proportion of participants who withdrew due to an AE in the placebo group compared to the tofacitinib group. Nine per cent (37/394) of participants taking tofacitinib withdrew due to an AE compared to 19% (37/198) of participants taking placebo (RR 0.50, 95% CI 0.33 to 0.77; moderate-certainty evidence). The most common reason for withdrawal due to an AE was worsening UC. The included study did not report on endoscopic response or on mean disease-specific quality of life scores. AUTHORS' CONCLUSIONS: High-certainty evidence suggests that tofacitinib is superior to placebo for maintenance of clinical and endoscopic remission at 52 weeks in participants with moderate-to-severe UC in remission. The optimal dose of tofacitinib for maintenance therapy is unknown. High-certainty evidence suggests that there is no increased risk of AEs with tofacitinib compared to placebo. However, we are uncertain about the effect of tofacitinib on SAEs due to the low number of events. Further studies are required to look at the long-term effectiveness and safety of using tofacitinib and other oral JAK inhibitors as maintenance therapy in participants with moderate-to-severe UC in remission. CI - Copyright (c) 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. FAU - Davies, Sarah C AU - Davies SC AD - University of Western Ontario, Schulich School of Medicine & Dentistry, London, ON, Canada. FAU - Hussein, Isra M AU - Hussein IM AD - University of Toronto, Faculty of Medicine, 1 King's College Circle, Toronto, ON, Canada, M5S 1A8. FAU - Nguyen, Tran M AU - Nguyen TM AD - Robarts Clinical Trials, 100 Dundas Street, Suite 200, London, ON, Canada. FAU - Parker, Claire E AU - Parker CE AD - Robarts Clinical Trials, 100 Dundas Street, Suite 200, London, ON, Canada. FAU - Khanna, Reena AU - Khanna R AD - University of Western Ontario, Department of Medicine, London, ON, Canada. FAU - Jairath, Vipul AU - Jairath V AD - University of Western Ontario, Department of Medicine, London, ON, Canada. LA - eng PT - Journal Article PT - Meta-Analysis PT - Systematic Review DEP - 20200127 PL - England TA - Cochrane Database Syst Rev JT - The Cochrane database of systematic reviews JID - 100909747 RN - 0 (Janus Kinase Inhibitors) RN - 0 (Piperidines) RN - 0 (Protein Kinase Inhibitors) RN - 0 (Pyrimidines) RN - 0 (Pyrroles) RN - 87LA6FU830 (tofacitinib) SB - IM UOF - doi: 10.1002/14651858.CD012381 MH - Colitis, Ulcerative/*drug therapy MH - Humans MH - Janus Kinase Inhibitors/*therapeutic use MH - Maintenance Chemotherapy MH - Piperidines/*therapeutic use MH - Protein Kinase Inhibitors MH - Pyrimidines/*therapeutic use MH - Pyrroles/*therapeutic use MH - Quality of Life MH - Randomized Controlled Trials as Topic PMC - PMC6984444 COIS- IMH, CEP, SD and TMN have no known conflicts of interest. RK has received consulting fees from AbbVie, Janssen, Pfizer, Shire, Takeda, Genetec/Roche, Robarts Clinical Trials, Pendopharm, Innomar, Encycle, Merck. VJ has received has received consulting fees from AbbVie, Eli Lilly, GlaxoSmithKline, Arena pharmaceuticals, Genetech, Pendopharm, Sandoz, Merck, Takeda, Janssen, Robarts Clinical Trials, Topivert, and Celltrion; and speaker's fees from Takeda, Janssen, Shire, Ferring, Abbvie, and Pfizer EDAT- 2020/01/28 06:00 MHDA- 2020/05/23 06:00 PMCR- 2021/01/27 CRDT- 2020/01/28 06:00 PHST- 2020/01/28 06:00 [entrez] PHST- 2020/01/28 06:00 [pubmed] PHST- 2020/05/23 06:00 [medline] PHST- 2021/01/27 00:00 [pmc-release] AID - CD012381.pub2 [pii] AID - 10.1002/14651858.CD012381.pub2 [doi] PST - epublish SO - Cochrane Database Syst Rev. 2020 Jan 27;1(1):CD012381. doi: 10.1002/14651858.CD012381.pub2.