Can Baseline Features Predict Progression to Defined CTD? Insights from a Minimum 5-Year Follow-Up Study of 504 Patients with UCTD

Objectives Undifferentiated connective tissue disease (UCTD) represents a systemic autoimmune condition characterized by clinical and serological features suggestive of defined connective tissue diseases (CTDs), yet insufficient to fulfill existing classification criteria. Despite increasing interest, long-term outcomes—particularly progression to defined CTDs—remain incompletely understood. This study aimed to evaluate the clinical outcomes of a UCTD cohort followed for at least 5 years and to identify baseline clinical and serological factors associated with an increased risk of evolution to a defined CTD. Methods A total of 658 patients were screened for this retrospective cohort study. After applying predefined eligibility criteria, 504 patients who met established UCTD definitions were included. Baseline clinical, laboratory, and serological characteristics were analyzed. Two patient outcome groups were defined at 5-year follow-up: those who evolved to a defined CTD and those who remained stable. Given the limited number of cases evolving to defined CTDs, group comparisons were performed using Student’s t-test or Mann-Whitney U test rather than logistic regression. Autoantibodies were assessed using indirect immunofluorescence for ANA and validated immunoassays for anti-dsDNA, anti-Sm, anti-Ro/SS-A, anti-La/SS-B, anti-Scl-70, anti-centromere, anti-U1RNP, anti-Jo1, rheumatoid factor, anti-cyclic citrullinated peptide antibodies (ACPA), antiphospholipid antibodies (anti-β2 glycoprotein I IgM/IgG, anti-cardiolipin IgM/IgG), and lupus anticoagulant. Results After a mean follow-up of 82 months, 102 of the 504 UCTD patients (20.2%) developed a defined CTD (37 Sjögren’s disease (SjD), 35 systemic lupus erythematosus (SLE), 12 systemic sclerosis (SSc), 14 rheumatoid arthritis, and 4 mixed connective tissue disease) within a follow-up period of at least 5 years. The most common clinical manifestations of UCTD included arthralgias, sicca symptoms, photosensitivity, oral aphthae, and Raynaud’s phenomenon. Differentiation was significantly associated with features such as a Schirmer test <5 mm (p=0.007), anti-dsDNA (p=0.001), anti-Ro/SS-A (p<0.001), and hypocomplementemia (p=0.004). Multivariate analysis identified several disease-specific predictors, including anti-Ro/SS-A for SjD and anti-dsDNA and hypocomplementemia for SLE. Conclusions Approximately one-fifth of UCTD patients progressed to a defined connective tissue disease during long-term follow-up, most frequently to SjD or SLE. Anti-Ro/SS-A, anti-dsDNA, and a Schirmer test <5 mm were significant predictors of progression.