Objectives <p>Subcutaneous methotrexate (SC MTX) provides more reliable bioavailability than oral MTX; however, longitudinal real-world data incorporating musculoskeletal ultrasound (MSUS) remain limited. We aimed to evaluate longitudinal changes in clinical disease activity and ultrasound-detected synovitis, particularly power Doppler (PD) activity, after switching from oral to SC MTX in patients with rheumatoid arthritis (RA).</p> Methods <p>This two-center retrospective cohort study included 57 patients with RA who switched from oral to SC MTX in routine clinical practice. Clinical disease activity measures (DAS28-CRP, SDAI, and CDAI) were assessed at baseline and at 1, 3, and 6 months. In patients with available longitudinal MSUS follow-up, semiquantitative gray-scale (GS) and PD scores of the representative joint were evaluated at the same time points. Longitudinal changes were analyzed using linear mixed-effects models with Dunnett-adjusted comparisons versus baseline. Baseline characteristics of patients with and without 6-month ultrasound follow-up were compared using standardized mean differences.</p> Results <p>Clinical disease activity improved over time following the switch to SC MTX. Significant reductions from baseline were observed for SDAI, CDAI, and DAS28-CRP at all follow-up visits. Representative-joint PD scores showed a significant overall longitudinal reduction, with adjusted mean decreases of 0.64 points at 1 month and 0.95 points at 3 months compared with baseline. Although representative-joint PD scores also showed a numerical reduction at 6 months, statistical significance was not maintained after adjustment for multiple comparisons. In contrast, representative-joint GS scores showed numerical improvement but no statistically significant overall longitudinal change. DAS28-CRP remission (&lt;2.6) was achieved in 30/56 (53.6%) patients at 1 month, 38/55 (69.1%) at 3 months, and 34/52 (65.4%) at 6 months. MSUS follow-up was available in 40 patients at baseline, 29 at 1 month, 20 at 3 months, and 17 at 6 months. Most missing 6-month ultrasound assessments were attributable to clinical remission or low disease activity.</p> Conclusions <p>In this real-world observational study, switching from oral to SC MTX was associated with early reductions in representative-joint PD-detected synovitis, with statistically significant improvement observed at 1 and 3 months, together with improvements in clinical disease activity over six months. Because of the retrospective design, absence of a comparator group, and incomplete ultrasound follow-up, residual confounding and selection bias cannot be excluded. These findings should therefore be considered hypothesis-generating but suggest that MSUS, particularly PD assessment, may provide a useful objective tool for monitoring inflammatory activity after switching to SC MTX in routine clinical practice.</p> Clinical trial number <p>Not applicable.</p>