The primary objectives of the study were to evaluate the efficacy and safety of tofacitinib and baricitinib up to 24 months of follow-up in patients with rheumatoid arthritis (RA) treated in Southern Italy. Patients' data, activity index, and clinimetric scores were collected at baseline (T0), six (T6), twelve (T12), and twenty-four (T24) months following treatment initiation. At six, twelve, and twenty-four months, adverse events and treatment cessation were also recorded. Sixty-eight patients (mean age: 62.2±10.9 years; mean RA duration: 15±9.6 years) were enrolled over a period of 12 weeks. At baseline, twenty-four patients (35.3%) were treated with tofacitinib, and forty-four patients (64.7%) were treated with baricitinib. The baseline mean disease activity was moderate as measured by DAS28- ESR (5.0±1.0), DAS 28 CRP (4.69±0.94), and SDAI (26.87±10.73) score. Before beginning JAKinhibs therapy, thirty-two patients (61.8%) were taking bDMARDs, while the remaining thirty-six (38.2%) were bDMARDs-naïve. The 24-month retention rate for JAKinhibs was 91.1%. Six months after beginning treatment with JAKinhibs, a statistically significant improvement was observed in all evaluated activity indices and clinimetric scores. Improvement was confirmed during the 12- and 24-month follow-up evaluations. The positive correlation between baseline-T6 SDAI delta and discontinuation of JAKinhibs (p=0.02) suggests that RA worsening in the first six months may be a predictor of therapy withdrawal. Patients with RA responded favorably to tofacitinib and baricitinib in this prospective, real-world study from a single center in Southern Italy. Efficacy was observed despite an underlying persistent and treatment-resistant disease.