Extraintestinal manifestations at baseline, and the effect of tofacitinib, in patients with moderate to severe ulcerative colitis

David T Rubin, Walter Reinisch, Thomas Greuter, Paulo G Kotze, Marcia Pinheiro, Rajiv Mundayat, Eric Maller, Marc Fellmann, Nervin Lawendy, Irene Modesto, Stephan R Vavricka, Gary R Lichtenstein, David T Rubin, Walter Reinisch, Thomas Greuter, Paulo G Kotze, Marcia Pinheiro, Rajiv Mundayat, Eric Maller, Marc Fellmann, Nervin Lawendy, Irene Modesto, Stephan R Vavricka, Gary R Lichtenstein

Abstract

Introduction: Extraintestinal manifestations (EIMs) in patients with ulcerative colitis (UC) are common. Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of UC. We evaluated the efficacy of tofacitinib in patients with EIMs, and the impact of tofacitinib on EIMs in patients with UC in the OCTAVE clinical program.

Methods: Data from two 8-week induction studies (OCTAVE Induction 1 and 2) and a 52-week maintenance study (OCTAVE Sustain) were analyzed. The effect of tofacitinib on efficacy outcomes stratified by EIM status, proportion of predefined prior and active EIMs at baseline, and change from baseline in EIMs were determined at the end of the treatment period (weeks 8 or 52), or at early termination.

Results: At baseline of OCTAVE Induction 1 and 2, and OCTAVE Sustain, 27.0% and 9.0% of patients had a history of EIMs (prior or active), respectively. Patients treated with tofacitinib 10 mg twice daily (BID) achieved remission and had endoscopic improvement in all studies, irrespective of any history of EIMs. A greater proportion of patients had active peripheral arthritis at baseline of OCTAVE Induction 1 and 2 versus OCTAVE Sustain. In OCTAVE Induction 1 and 2, similar proportions of tofacitinib and placebo-treated patients with active peripheral arthritis experienced either no change (81.3% and 85.7%, respectively) or an improvement (15.6% and 14.3%, respectively). By week 52 of OCTAVE Sustain, improvements in active peripheral arthritis were only observed in tofacitinib-treated patients (16.7% and 33.3% with tofacitinib 5 and 10 mg BID, respectively).

Conclusion: Any history of EIMs did not influence the efficacy of tofacitinib 10 mg BID for induction or maintenance of UC. The most common active EIM was peripheral arthritis, for which many patients in OCTAVE Induction 1 and 2, and OCTAVE Sustain, reported improvement or no change from baseline with tofacitinib treatment.Clinicaltrials.gov:NCT01465763; NCT01458951; NCT01458574.

Keywords: extraintestinal manifestations; tofacitinib; ulcerative colitis.

Conflict of interest statement

Conflict of interest statement: DTR has received consulting fees from AbbVie, AbGenomics, Allergan, Biomica, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Check-Cap Ltd., Dizal Pharma, Galen Pharma, Genentech, Gilead Sciences, GlaxoSmithKline, Ichnos Sciences, InDex Pharmaceuticals, Janssen, Lilly, Narrow River Management, Pfizer Inc., Prometheus Laboratories, Reistone Biopharma, Shire, Takeda, and Techlab Inc.; and grant support from Takeda. WR has received research support from Abbott, AbbVie, AESCA, Centocor, Dr. Falk Pharma, Immundiagnostik, and MSD; lecture fees from Abbott, AbbVie, AESCA, Aptalis, Celltrion, Centocor, Danone, Dr. Falk Pharma, Elan, Ferring Pharmaceuticals, Immundiagnostik, Mitsubishi Tanabe Pharma, MSD, Otsuka, PDL, Pharmacosmos, Schering-Plough, Shire, Takeda, Therakos, Vifor, and Yakult; and consulting fees from Abbott, AbbVie, AESCA, Amgen, AM Pharma, Astellas, AstraZeneca, Avaxia Biologics, Bioclinica, Biogen Idec, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Cellerix, Celltrion, Centocor, ChemoCentryx, Covance, Danone, Dr. Falk Pharma, Elan, Ferring Pharmaceuticals, Galapagos, Genentech, Gilead Sciences, Grünenthal, ICON, Index Pharma, Inova, Janssen, Johnson and Johnson, Kyowa Hakko Kirin Pharma, Lipid Therapeutics, MedImmune, Millennium, Mitsubishi Tanabe Pharma, MSD, Nestlé, Novartis, Ocera, Otsuka, PDL, Pfizer Inc., Pharmacosmos, Procter & Gamble, Prometheus Laboratories, Robarts Clinical Trials, Schering-Plough, Second Genome, SetPoint Medical, Takeda, Therakos, TiGenix, UCB, Vifor, Zyngenia, and 4SC. TG has a consultancy contract with Sanofi-Aventis; received a travel grant from Falk Pharma GmbH and Vifor; and an unrestricted research grant from Novartis. PGK has received consulting and speaker fees from AbbVie, Janssen, Pfizer Inc., and Takeda; and speaker fees from UCB. MP, RM, MF, NL, and IM are employees and stockholders of Pfizer Inc. EM was an employee of Pfizer Inc. at the time this research was conducted. SRV has received consulting fees and unrestricted research grants from Abbott, Ferring Pharmaceuticals, MSD, Pfizer Inc., Takeda, Tillotts, UCB, Vifor, and Falk Pharma GmbH. GRL has received research support and/or funding from Celgene, Janssen Orthobiotech, Pfizer Inc, Takeda, and UCB; consulting fees from AbbVie, American Regent, Cellceutix, Celgene, Eli Lilly, Endo Pharmaceuticals, Ferring Pharmaceuticals, Gilead Sciences, Janssen Orthobiotech, Merck, Morphic Therapeutics, Pfizer Inc., Prometheus Laboratories, Romark, Salix/Valeant, Shire, Takeda, and UCB; honoraria from the American College of Gastroenterology, American Regent, Gastroenterology and Hepatology, Merck, Romark, Springer Science and Business Media, and Up-To-Date; and royalties from Professional Communications Inc. and SLACK Inc.

© The Author(s), 2021.

Figures

Figure 1.
Figure 1.
EIMs experienced by patients at baseline by treatment group in OCTAVE Induction 1 and 2. Percentages represent the proportion of patients with prior or active EIMs at OCTAVE Induction baseline in placebo (N1 = 233) or tofacitinib 10 mg BID (N1 = 902) groups. BID, twice daily; BL, baseline; EIM, extraintestinal manifestation; N1, number of patients with non-missing data.
Figure 2.
Figure 2.
Proportion of patients in remission (A), and with endoscopic improvement (B) at week 8 in OCTAVE Induction 1 and 2, by EIM status at baseline (FAS, NRI, central read). Δ, difference from placebo; BID, twice daily; CI, confidence interval; EIM, extraintestinal manifestation; FAS, full analysis set; n, number of patients with efficacy response; N, number of evaluable patients; NRI, non-responder imputation.
Figure 3.
Figure 3.
Peripheral arthritis: change from OCTAVE Induction baseline at week 8 or early termination (A) and change from OCTAVE Sustain baseline at week 52 or early termination (B), by EIM status. BID, twice daily; BL, baseline; EIM, extraintestinal manifestation; n, number of patients in the specified category with non-missing values at week 8/early termination or week 52/early termination.
Figure 4.
Figure 4.
Proportion of patients in remission (A), with endoscopic improvement (B), and sustained steroid-free remission (C), at week 52 in OCTAVE Sustain, by EIM status at baseline (FAS, NRI, central read). Δ, difference from placebo; BID, twice daily; CI, confidence interval; EIM, extraintestinal manifestation; FAS, full analysis set; N, number of evaluable patients; n, number of patients with efficacy response; NRI, non-responder imputation.

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