PMID- 38178250 OWN - NLM STAT- MEDLINE DCOM- 20240108 LR - 20240226 IS - 1478-6362 (Electronic) IS - 1478-6354 (Print) IS - 1478-6354 (Linking) VI - 26 IP - 1 DP - 2024 Jan 4 TI - The effects of suppressing inflammation by tofacitinib may simultaneously improve glycaemic parameters and inflammatory markers in rheumatoid arthritis patients with comorbid type 2 diabetes: a proof-of-concept, open, prospective, clinical study. PG - 14 LID - 10.1186/s13075-023-03249-7 [doi] LID - 14 AB - BACKGROUND: A consistent connection has been increasingly reported between rheumatoid arthritis (RA), insulin resistance (IR), and type 2 diabetes (T2D). The beta-cell apoptosis induced by pro-inflammatory cytokines, which could be exaggerated in the context of RA, is associated with increased expression pro-apoptotic proteins, which is dependent on JAnus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) activation. On these bases, we aimed to evaluate if the administration of tofacitinib, a potent and selective JAK inhibitor, could simultaneously improve glycaemic parameters and inflammatory markers in patients with RA and comorbid T2D. METHODS: The primary endpoint was the change in the 1998-updated homeostatic model assessment of IR (HOMA2-IR) after 6 months of treatment with tofacitinib in RA patients with T2D. Consecutive RA patients with T2D diagnosis were included in this proof-of-concept, open, prospective, clinical study, which was planned before the recent emergence of safety signals about tofacitinib. Additional endpoints were also assessed regarding RA disease activity and metabolic parameters. RESULTS: Forty consecutive RA patients with T2D were included (female sex 68.9%, mean age of 63.4 +/- 9.9 years). During 6-month follow-up, a progressive reduction of HOMA2-IR was observed in RA patients with T2D treated with tofacitinib. Specifically, a significant effect of tofacitinib was shown on the overall reduction of HOMA2-IR (beta = - 1.1, p = 0.019, 95%CI - 1.5 to - 0.76). Also, HOMA2-beta enhanced in these patients highlighting an improvement of insulin sensitivity. Furthermore, although a longer follow-up is required, a trend in glycated haemoglobin reduction was also recorded. The administration of tofacitinib induced an improvement in RA disease activity, and a significant reduction of DAS28-CRP and SDAI was observed; 76.8% of patients achieved a good clinical response. In this study, no major adverse events (AEs) were retrieved without the identification of new safety signals. Specifically, no life-threatening AEs and cardiovascular and/or thromboembolic events were recorded. CONCLUSIONS: The administration of tofacitinib in RA with T2D led to a simultaneous improvement of IR and inflammatory disease activity, inducing a "bidirectional" benefit in these patients. However, further specific designed and powered studies are warranted to entirely evaluate the metabolic effects of tofacitinib in RA patients with T2D. CI - (c) 2024. The Author(s). FAU - Di Muzio, Claudia AU - Di Muzio C AD - Rheumatology Unit, Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, Delta 6 Building, PO box 67100, L'Aquila, Italy. FAU - Di Cola, Ilenia AU - Di Cola I AD - Rheumatology Unit, Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, Delta 6 Building, PO box 67100, L'Aquila, Italy. FAU - Shariat Panahi, Azadeh AU - Shariat Panahi A AD - Rheumatology Unit, Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, Delta 6 Building, PO box 67100, L'Aquila, Italy. FAU - Ursini, Francesco AU - Ursini F AD - Medicine and Rheumatology Unit, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy. AD - Department of Biomedical and Neuromotor Sciences (DIBINEM), Alma Mater Studiorum University of Bologna, Bologna, Italy. FAU - Iagnocco, Annamaria AU - Iagnocco A AD - Academic Rheumatology Centre, Dipartimento di Scienze Cliniche e Biologiche Universita di Torino - AO Mauriziano di Torino, Turin, Italy. FAU - Giacomelli, Roberto AU - Giacomelli R AD - Clinical and Research Section of Rheumatology and Clinical Immunology, Fondazione Policlinico Campus Bio-Medico, Via Alvaro del Portillo 200, 00128, Rome, Italy. AD - Rheumatology and Clinical Immunology, Department of Medicine, University of Rome "Campus Biomedico", School of Medicine, Rome, Italy. FAU - Cipriani, Paola AU - Cipriani P AD - Rheumatology Unit, Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, Delta 6 Building, PO box 67100, L'Aquila, Italy. FAU - Ruscitti, Piero AU - Ruscitti P AD - Rheumatology Unit, Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, Delta 6 Building, PO box 67100, L'Aquila, Italy. piero.ruscitti@univaq.it. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20240104 PL - England TA - Arthritis Res Ther JT - Arthritis research & therapy JID - 101154438 RN - 87LA6FU830 (tofacitinib) RN - 0 (Pyrroles) RN - 0 (Antirheumatic Agents) SB - IM MH - Humans MH - Female MH - Middle Aged MH - Aged MH - *Diabetes Mellitus, Type 2/complications/drug therapy MH - Prospective Studies MH - *Arthritis, Rheumatoid/complications/drug therapy MH - Inflammation/drug therapy/chemically induced MH - Pyrroles/therapeutic use MH - Treatment Outcome MH - *Antirheumatic Agents/therapeutic use PMC - PMC10765862 OTO - NOTNLM OT - Precision medicine OT - Rheumatoid arthritis OT - Therapy OT - Tofacitinib OT - Type 2 diabetes COIS- The authors declare no competing interests. EDAT- 2024/01/05 00:42 MHDA- 2024/01/08 06:42 PMCR- 2024/01/04 CRDT- 2024/01/04 23:53 PHST- 2023/11/04 00:00 [received] PHST- 2023/12/21 00:00 [accepted] PHST- 2024/01/08 06:42 [medline] PHST- 2024/01/05 00:42 [pubmed] PHST- 2024/01/04 23:53 [entrez] PHST- 2024/01/04 00:00 [pmc-release] AID - 10.1186/s13075-023-03249-7 [pii] AID - 3249 [pii] AID - 10.1186/s13075-023-03249-7 [doi] PST - epublish SO - Arthritis Res Ther. 2024 Jan 4;26(1):14. doi: 10.1186/s13075-023-03249-7.