Background: JAK inhibitors are effective in autoimmune rheumatic diseases treatment but may promote weight gain. Beyond immune regulation, the JAK/STAT pathway plays important role in glucose and lipid metabolism, leptin and insulin signaling, and energy homeostasis. However, the precise molecular mechanisms, including effects on neuroendocrine regulation, remain unclear.

Objectives: The aim of the study is to comprehensively analyze obesity-related genes and their expression, particularly in patients with rheumatoid arthritis (RA) undergoing therapy with JAK kinase inhibitors, including upadacitinib and tofacitinib. Comparison of weight and body mass index (BMI) changes during treatment and identification of differences in the expression of obesity-related genes between groups of patients. Analysis of genes included in the Obesity Panel associated with JAK- kinase signaling pathways.

Methods: A total of 23 patients enrolled at the National Institute of Geriatrics, Rheumatology and Rehabilitation, Warsaw, Poland (18 with rheumatoid arthritis (RA), 3 with psoriatic arthritis (PsA), and 2 with ankylosing spondylitis (AS)) were included. Most were female (87,5%), mean age 45.35 ± 10.33 years, disease duration 8 years. The majority of patients enrolled in the study were of normal weight (65%), but 53% had excess body fat before starting the medication (93% had normal muscle mass). Gene expression analysis in peripheral blood mononuclear cells (PBMCs) was performed using the Obesity panel from NanoString nCounter (NanoString Technologies, Seattle, WA, USA) at two time points: before treatment and after 6 months of therapy).

Results: We observed a significant decrease in disease activity after 6 months of therapy, reflected by a reduction in DAS28. No significant increase in BMI was observed in our cohort, which may be related to the small sample size or compensatory behavioral changes. Gene expression analysis demonstrated a downregulation of inflammation-related genes, including STAT3 and LDHA, accompanied by neuro-metabolic alterations, such as decreased expression of GLP1R and NTSR1 , and increased expression of NMB . Baseline GLP1R expression was significantly lower in patients without elevated NT-proBNP compared to those with elevated NT-proBNP; however, this difference was no longer observed after treatment.Significant correlations were identified between NTSR1 expression and BMI (r ² = 0.41), phase angle (r ² = 0.47), and STAT3 expression (r ² = 0.38). Independent of timepoint, comparison between normal-weight and overweight/obese patients revealed significant differences in genes involved in neuroendocrine regulation of appetite and satiety ( NMUR1 , NTSR1, CCK ), lipid metabolism and adipogenesis (PPARG, ABCA1), and inflammatory signaling ( IKBKG ). Additionally, PPARG expression correlated with resting metabolic rate (r ² = 0.51).

Conclusions: The study highlights gene expression differences between overweight and normal weight patients, particularly in neuro-metabolic pathways. Our findings also confirm that JAK inhibitor therapy effectively reduces inflammatory activity, accompanied by corresponding changes in the expression of immune and metabolic genes, as well as improvements in the patients’ clinical picture. The observed transcriptomic alterations may reflect molecular adaptations in appetite regulation, emotional processing, and metabolic homeostasis induced by JAK inhibitor therapy; however long-term studies are needed to confirmed these effects.

REFERENCES: [1] Dodington DW, Desai HR, Woo M. JAK/STAT – emerging players in metabolism. Trends in Endocrinology & Metabolism . 2018;29(1):55–65.

[2] Venkatachalam S, Mir N, Naina N, et al. Do Janus kinase inhibitors lead to weight gain in rheumatoid arthritis patients? Annals of the Rheumatic Diseases . 2024;83(Suppl 1):1602.

Acknowledgments: NIL.

Disclosure of Interests: None declared.