0290: Evaluation of Treatment Discontinuation Due to Adverse Events, and the Effect of Cardiovascular Risk Factors or Type of JAK-inhibitors: An International Collaboration of Registries of Rheumatoid Arthritis Patients (the "JAK-pot" Study)

Kim Lauper¹, Romain Aymon², Denis Mongin², Sytske Anne Bergstra³, Denis Choquette⁴, Catalin Codreanu⁵, Ori Elkayam⁶, Kimme Hyrich⁷, Florenzo Iannone⁸, Nevsun Inanc⁹, Lianne Kearsley-Fleet¹⁰, Tore K. kvien¹¹, Eirik Kristianslund¹², Burkhard Leeb¹³, Galina Lukina¹⁴, Dan Nordstrom¹⁵, Karel Pavelka¹⁶, Manuel Pombo-Suarez¹⁷, Ziga Rotar¹⁸, Maria José Santos¹⁹, Delphine Courvoisier²⁰ and Axel Finckh²¹, ¹Geneva University Hospitals, Genéve, Switzerland, ²Geneva University Hospitals, Geneva, Switzerland, ³LUMC, Leiden, Netherlands, ⁴Centre Hospitalier de l'Université de Montréal, Montréal, QC, Canada, ⁵Center for Rheumatic Diseases, Bucharest, Romania, ⁶Tel Aviv Sourasky Medical Center, Tel Aviv, Israel, ⁷The University of Manchester, Manchester, United Kingdom, ⁸School of Medicine University of Bari, Bari, Italy, ⁹Marmara University School of Medicine, Division of Rheumatology, Istanbul, Turkey, ¹⁰Centre for Epidemiology Versus Arthritis, University of Manchester, Manchester, United Kingdom, ¹¹Diakonhjemmet Hospital, Oslo, Norway, ¹²Diakonhjemmet Hospital, Division of Rheumatology and Research, Oslo, Norway, ¹³Bioreg, Stockerau, Austria, ¹⁴Federal state budgetary scientific institution �Research Institute of rheumatology named after V. A. Nasonova�, Moscow, Russia, ¹⁵Helsinki University Hospital, Helsinki, Finland, ¹⁶Institute of Rheumatology, Department of Rheumatology, 1st Faculty of Medicine, Charles University, Prague, Czech Republic, Praha, Czech Republic, ¹⁷Hospital Clinico Universitario, Santiago de Compostela, Spain, ¹⁸University Medical Centre Ljubljana, Ljubljana, Slovenia, ¹⁹Hospital Garcia de Orta, Almada, Charneca da Caparica, Portugal, ²⁰University Hospitals of Geneva, Geneva, Switzerland, ²¹Geneva University Hospital, Geneve - Vesenaz, Switzerland

Background/Purpose: The "ORAL Surveillance" study¹ suggests an increased risk of serious adverse events (AEs) with tofacitinib, a JAK-inhibitor (JAKi), compared to TNF-inhibitors (TNFi). Currently, there is limited real-world evidence for the tolerability and safety of JAKi. This study aims to assess the safety of JAKi compared to other biologics in a real-world population, evaluating treatment discontinuation for AEs and the effect of cardiovascular risk factors and type of JAKi on this outcome.

Methods: We pooled the data from 16 national RA registries from across Europe, Québec (Canada), Turkey, and Israel. We compared treatment discontinuation due to AEs by treatment groups, JAKi vs TNFi, and JAKi vs bDMARDs with other modes of action (OMA), as an overall measure of tolerability and safety of JAKi. We included only treatment courses initiated during a period when all treatment options were available, to limit potential selection biases. We used standard descriptive statistics for baseline characteristics. We plotted unadjusted cumulative incidence, then we used a cause-specific Cox model accounting for competing risks of stopping for ineffectiveness or other reasons, to obtain association between covariates and the instantaneous hazard rate for AEs. Variables listed in Table 1 were used for adjustment in the fully-adjusted cause-specific Cox model. A subgroup analysis examined only patients with age >50 years and at least one cardiovascular risk factor, as in ORAL-surveillance (RCT-duplicate cohort). We also investigated whether results differed by type of JAKi (tofacitinib vs others).

Results: 43,748 treatment courses were included in the analysis (Table 1). In the JAKi group, 50% of patients were treated with tofacitinib, and 44% with baricitinib, with only a few patients treated with upadacitinib or filgotinib. We observed higher treatment discontinuation due to AEs with OMA compared to JAKi, and similar rates between JAKi and TNFi (Figure 1). The fully adjusted hazard rate of treatment discontinuation for AEs was also similar for TNFi vs JAKi (aHR 1.11, 95%CI 0.98 to 1.25), but higher for OMA vs JAKi (aHR 1.23, 95% CI 1.09 to 1.40, Figure 2). The rate of treatment discontinuation for AEs was higher in women than men (aHR 1.36, 95%CI 1.22 to 1.51). The results in the RCT-duplicate subpopulation cohort (35% of all treatment, N=15,541) were similar than in the full cohort, with higher treatment discontinuation for OMA vs JAKi (aHR 1.38, 95%CI 1.14-1.66) and similar for TNFi vs JAKi (aHR 1.12, 95%CI 0.94 to 1.34) although there was overall more treatment discontinuation for AEs. These ratios were also similar for OMA and TNFi vs tofacitinib or vs other JAKis.

Conclusion: After adjusting for potential confounders, the rate of treatment discontinuation for AEs was comparable between JAKi and TNFi, but higher for OMA vs JAKi. We found no differences in these ratios by type of JAKi (tofacitinib or others, mostly baricitinib) or in the RCT-duplicate cohort compared to the overall population, although treatment discontinuation for AEs was higher overall in this subgroup.

^{Ref: 1. Ytterberg SR et al. N Engl J Med. 2022 Jan 27;386(4):316-326. doi: 10.1056/NEJMoa2109927}

Table 1: Baseline characteristics of the population by treatment groups: Janus kinase inhibitors (JAKi), TNF inhibitors (TNFi), and biologics with other modes of action (OMA)

Figure 1: Comparison of the crude cumulative incidence of treatment discontinuation for adverse events among the Janus kinase inhibitors (JAKi), TNF inhibitors (TNFi), and biologics with other modes of action (OMA) groups.

Figure 2: Adjusted hazards ratios of discontinuation for adverse events for TNFi-inhibitors (TNFi) vs Janus kinase inhibitors (JAK) and biologics with other modes of action (OMA) vs JAKi
Disclosures: K. Lauper, Pfizer, Viatris, Celltrion; R. Aymon, None; D. Mongin, None; S. Bergstra, None; D. Choquette, AbbVie/Abbott, Amgen, Eli Lilly, Fresenius Kabi, Novartis, Pfizer, Sandoz, Tavapharm; C. Codreanu, AbbVie/Abbott, Amgen, AstraZeneca, Boehringer-Ingelheim, Ewopharma, Eli Lilly, Novartis, Pfizer; O. Elkayam, Pfizer, Eli Lilly, AbbVie/Abbott, Novartis, Janssen, Boehringer-Ingelheim; K. Hyrich, AbbVie/Abbott, Pfizer, Bristol-Myers Squibb(BMS); F. Iannone, None; N. Inanc, AbbVie/Abbott, Eli Lilly, Merck/MSD, novartis, Pfizer, Roche, Amgen, Celltrion, UCB; L. Kearsley-Fleet, None; T. kvien, Pfizer, AbbVie/Abbott, Eli Lilly, galapagos; E. Kristianslund, None; B. Leeb, Sandoz, AbbVie/Abbott, Eli Lilly, Roche, Grunenthal, Biogen, Celgene; G. Lukina, AbbVie/Abbott, Eli Lilly, Merck/MSD, Roche, Pfizer; D. Nordstrom, AbbVie/Abbott, Bristol-Myers Squibb(BMS), Merck/MSD, Eli Lilly, Novartis, Pfizer, Roche, UCB; K. Pavelka, MSD, Pfizer, Roche, Eli Lilly, Medac, UCB, SOBI, Biogen, Sandoz, Viatris; M. Pombo-Suarez, Janssen, Eli Lilly, Merck/MSD, Novartis, sanofi; Z. Rotar, Pfizer, AbbVie/Abbott, Eli Lilly; M. Santos, AbbVie/Abbott, AstraZeneca, pfizer, Novartis, Eli Lilly; D. Courvoisier, None; A. Finckh, Pfizer, Bristol-Myers Squibb(BMS), Merck/MSD, Eli Lilly, AbbVie/Abbott, galapagos, mylan, UCB, Viatris.