Background: A consistent connection has been increasingly reported between rheumatoid arthritis (RA), insulin resistance, and type 2 diabetes (T2D) [1]. The β-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 by JAnus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) activation [2]. Considering that JAK inhibitors (JAKis) are successfully used in RA, it could be theoretically hypothesized that these drugs could bidirectionally improve inflammatory signs and associated glucose abnormalities in patients with T2D. In fact, according to previous findings [3-5], the administration of some RA-specific therapies could target the mechanisms of the concomitant cardiometabolic comorbidity providing a study model to be applied in this context.

Objectives: 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 in a proof-of-concept, open, prospective, clinical study.

Methods: The primary endpoint was the change in homeostatic model assessment 2 of insulin resistance (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 [6]. 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). All included patients had a moderate-to-high RA disease activity at the study inclusion. Among them, 60.5% of patients had high blood pressure, 41.9% showed a current or previous smoking habit, 27.9% were obese, and 18.6% had dyslipidaemia, and 4.2% had clinical atherosclerosis.

During the 6-month follow-up, a progressive reduction of HOMA2-IR was observed in RA patients with T2D treated with tofacitinib (p=0.025). Specifically, a significant effect of tofacitinib was shown on the overall reduction of HOMA2-IR (β: −1.1, p=0.019, 95%CI −1.5 to −0.76) in age- and male-sex adjusted linear mixed model. Paralleling with HOMA2-IR, also HOMA2-β-cell function enhanced highlighting an improvement of insulin sensitivity in these patients treated with tofacitinib (p=0.035). Furthermore, although a longer follow-up is required on this metabolic outcome, a non-significant trend in glycated hemoglobin reduction was also recorded in our cohort (p=0.077). Fasting plasma glucose and lipid profile did not significantly change during the follow-up. Moreover, BMI did not modify, thus excluding a possible anorexigenic effect of tofacitinib in these patients. Also, the administration of tofacitinib induced an improvement of RA disease activity, a significant reduction of DAS28-CRP (p<0.001) and SDAI (p=0.011) was observed; 76.8% of patients achieved a good clinical response after 6 months of follow-up. In addition, CRP (p=0.035), patient global disease assessment (p=0.018), and VAS pain (p=0.024) significantly reduced.

In this study, no major adverse events (AEs) were retrieved without the identification of new safety signals. Specifically, no life-threatening AEs, cardiovascular and/or thromboembolic events were recorded.

Conclusion: 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.

REFERENCES: [1] Giacomelli R, et al. Expert Rev Clin Immunol. 2016;12:849-55.

[2] Gurzov EN, et al. FEBS J. 2016;283:3002-15.

[3] Di Muzio C, et al. BioDrugs. 2022;36:673-685.

[4] Ruscitti P, et al. PLoS Med. 2019;16:e1002901.

[5] Genovese MC, et al. Arthritis Res Ther. 2020;22:206.

[6] Ytterberg SR, et al. N Engl J Med. 2022;386:316-326.

Acknowledgements: NIL.

Disclosure of Interests: Piero Ruscitti Pfizer, Claudia Di Muzio: None declared, Ilenia Di Cola: None declared, Azadeh Shariat Panahi: None declared, Federica Sensini: None declared, Francesco Ursini: None declared, Annamaria Iagnocco: None declared, Roberto Giacomelli: None declared, Paola Cipriani: None declared.