4CPS-066 Influence of JAK1 gene polymorphisms on treatment response to JAK inhibitors in rheumatoid arthritis patients

<h3>Background and Importance</h3> JAK inhibitors(JAKi) block the JAK-STAT pathway, crucial in immune cell regulation. Genetic variations in JAK1 may influence treatment outcomes in rheumatoid arthritis, highlighting the importance of understanding individual genetic profiles to optimise therapeutic response to these drugs. <h3>Aim and Objectives</h3> To evaluate the influence of three single nucleotide polymorphisms(rs2230587,rs310241, rs2230588) in JAK1 gene involved in the JAK/STAT pathway on the response to treatment with JAKi drugs in patients diagnosed with rheumatoid arthritis(RA). <h3>Material and Methods</h3> Ambispective observational cohort study. Data and DNA from RA patients in Granada who had been treated with JAKi were obtained. Genotypes were determined by Taqman-PCR-Real-Time. Quantitative variables: age, body mass index (BMI), disease duration, previous therapies, treatment duration, and Disease activity measures (DAS28) at 0, 3, 6 and 12 months classified as remission, low, moderate and high activity. Qualitative variables: sex, first JAKi, treatment discontinuation and causes, dose changes. Data were collected from electronic prescriptions and medical records, and analysed with R Commander. <h3>Results</h3> Forty-one patients analysed,32 women median age 53.5 years(IQR 60.5–47.7). Median BMI 27.6(IQR 33.3–24.4). Median disease duration 11 years(IQR 20–6.7). Patients had received 2 prior biologic therapies(IQR 3.2–1) with median treatment duration 21 months(IQR 40–13).First JAKi received were tofacitinib(14),baricitinib(12),upadactinib(10),filgotinib (4). Sixteen patients discontinued treatment and 6 required dose changes. Causes for discontinuation were secondary failure(5),primary failure(3),adverse effects(4),lack of response(4). Analysis showed for rs2230587 polymorphism that the risk of having high disease activity at 6 months was observed to be 12-fold higher for patients with AG genotype vs GG(p-value=0.0315). For rs310241 GG genotype showed a 1.85-fold increased likelihood of remission at 6 months compared to AA(p=0.0364). Regarding rs2230588, the CC genotype carried a 9-fold higher risk of high disease activity versus CT, and 6-fold versus TT(p=0.0223). Additional analysis showed that patients‘ lower baseline DAS28 reduced the risk of unsatisfactory response(p-value=0.0006), fewer previous biological therapies increased the likelihood of success(p-value=0.01824) and longer treatment duration was associated with lower disease activity (p-value=0.02363). <h3>Conclusion and Relevance</h3> Response to JAKi drugs was associated with different single nucleotide allelic polymorphisms of the JAK1 gene. Nonetheless, further studies with large cohorts have to be performed to confirm these data in order to apply personalised medicine in clinical practice routine. <h3>References and/or Acknowledgements</h3> <h3>Conflict of Interest</h3> No conflict of interest