UCTDs in the literature

The first description of undifferentiated diseases was made in 1969 by Sabo who described two illustrative cases of ‘undifferentiated or lanthanic collagen diseases’ and suggested three possible evolutions (i) the development of defined CTDs, (ii) the persistence as undifferentiated conditions and (iii) an intermittent undifferentiation. Interestingly, the cases described by Sabo were characterised by severe organ involvement and one patient died from the disease itself.

In 1980, LeRoy proposed the concept of undifferentiated connective tissue syndromes (UCTSs) to define early phases of CTDs mainly characterised by the presence of Raynaud’s phenomenon and puffy hands as opposed to mixed or overlapping syndromes. Like Sabo, he suggested that patients with an undifferentiated onset may evolve to definite conditions but could as well remain indefinitely undifferentiated or experience a remission of all pathologic features .

Subsequently, many authors have described UCTD; although the definitions used in the literature may slightly differ, in general, UCTDs have been defined as conditions characterised by the presence of signs and symptoms suggestive of a CTD but not fulfilling the existing classification criteria .

In 1991, Alarcon et al. reported that about 50% of patients with CTD of less than 1-year duration had an UCTD which subsequently could evolve to a defined CTD, resolve or remain undifferentiated . Similarly, we and others have reported that about 60% of patients with undifferentiated onset will remain as such during the disease course .

The evolution of UCTD to defined CTDs usually occurs within the first 5 years of disease . More commonly, UCTDs evolve into not only systemic lupus erythematosus (SLE), but also an evolution to systemic sclerosis (SSc), primary Sjögren’s syndrome (pSS), mixed connective tissue disease (MCTD), systemic vasculitis, polydermatomyositis (PM/DM) and rheumatoid arthritis (RA) has been described.

Differences in the literature data may be attributed to a number of reasons; among these the different assessment performed to exclude defined CTDs appears most important. For example, in spite of the fact that Raynaud’s phenomenon is a relatively frequent manifestation of UCTD, the evolution to SSc is not common; this could be attributed to the fact that, in some studies, patients with Raynaud’s phenomenon and other features suggestive of scleroderma (nailfold capillaroscopy and specific autoantibodies) have been considered as early scleroderma and have not been included among UCTD .

Clinical and serological variables that may predict an evolution of UCTD to SLE have been identified. While contrasting data are available regarding clinical manifestations (fever, discoid lupus, alopecia, serositis, photosensitivity), greater agreement exists on the predictive significance of anti-dsDNA antibodies, anti-Sm antibodies, anti-cardiolipin antibodies as well as the presence of multiple antibodies specificities .

Patients who do not develop a defined CTD (defined also as ‘stable’ UCTD) have a mild clinical picture characterised by the presence of arthralgias (37–80%), arthritis (14–70%), Raynaud’s phenomenon (45–60%), leucopenia (11–42%), anaemia, xerostomia (7–40%) and xerophtalmia (8–36%). Autoimmune thyroid disease is observed in 7–13% of patients. No major organ involvement (such as renal, neurological and pulmonary involvement) has been described .

Since the presence of anti-nuclear antibodies (ANAs) was not required by all authors to define UCTD, their positivity ranges from 58% up to 100% of the patients. When the presence of ANA was required for the definition of UCTD, usually patients present with a single antibody specificity with anti-Ro/SSA and anti-RNP antibodies being most frequently observed in 8–30% and 10–30% of patients respectively . Usually, UCTD patients do not present new autoantibody specificities even after long-term follow-up .

UCTDs are generally treated with low-dose corticosteroids and anti-malarials, and very rarely with immunosuppressive drugs. In our cohort, UCTD patients are treated with low-dose corticosteroids (36%) and/or antimalarial drugs (52%) and, at the time of their last observation, about 16% of UCTD patients were not receiving any therapy .

Anti-Ro/SSa positive UCTD

As previously reported, 8–30% of UCTD patients have anti-Ro/SSA antibodies and the characteristics of this subset of patients have been described. In 2001, Cavazzana et al. have described 148 UCTD patients with antibodies to Ro/SSA . The most common clinical manifestations of these patients were artralgias (86%), skin lesions (37%) (livedo, purpura, urticaria, acrocyanosis, sclerodactily and teleangectasias), Raynaud’s phenomenon (33%) and sicca symptoms (30%). Twenty-four percent developed a defined CTD during follow-up, mostly SLE and SS. In our cohort, 30% of UCTD patients presented anti-Ro/SSA antibodies alone; similarly to the data reported by Cavazzana, these patients presented mainly joint involvement, sicca symptoms and, less frequently, Raynaud’s phenomenon.

The analysis of the fine specificity of anti-Ro/SSA antibodies showed that most UCTD sera were reactive with Ro 52 kD, alone or in combination with Ro 60 kD (34% and 55%, respectively), while only 4% of the sera were reactive to isolated Ro 60 kD. No correlations were possible between anti-Ro/SSA specificity and the evolution of UCTD to SLE, or SS in view of the small number of patients with antibodies to isolated 60 Kd . Belfiore et al., on the contrary, observed that the presence of antibodies to isolated Ro60 kD was correlated with an evolution of UCTD to SLE, while the presence of antibodies to both 52 and 60 kD antigen was correlated with a progression to pSS. None of those patients with antibodies to the isolated 52 kD antigen evolved to defined CTD .

Anti-Ro/SSa positive UCTD

As previously reported, 8–30% of UCTD patients have anti-Ro/SSA antibodies and the characteristics of this subset of patients have been described. In 2001, Cavazzana et al. have described 148 UCTD patients with antibodies to Ro/SSA . The most common clinical manifestations of these patients were artralgias (86%), skin lesions (37%) (livedo, purpura, urticaria, acrocyanosis, sclerodactily and teleangectasias), Raynaud’s phenomenon (33%) and sicca symptoms (30%). Twenty-four percent developed a defined CTD during follow-up, mostly SLE and SS. In our cohort, 30% of UCTD patients presented anti-Ro/SSA antibodies alone; similarly to the data reported by Cavazzana, these patients presented mainly joint involvement, sicca symptoms and, less frequently, Raynaud’s phenomenon.

The analysis of the fine specificity of anti-Ro/SSA antibodies showed that most UCTD sera were reactive with Ro 52 kD, alone or in combination with Ro 60 kD (34% and 55%, respectively), while only 4% of the sera were reactive to isolated Ro 60 kD. No correlations were possible between anti-Ro/SSA specificity and the evolution of UCTD to SLE, or SS in view of the small number of patients with antibodies to isolated 60 Kd . Belfiore et al., on the contrary, observed that the presence of antibodies to isolated Ro60 kD was correlated with an evolution of UCTD to SLE, while the presence of antibodies to both 52 and 60 kD antigen was correlated with a progression to pSS. None of those patients with antibodies to the isolated 52 kD antigen evolved to defined CTD .

Anti-RNP positive UCTD

Anti-RNP antibodies alone have been observed in 28% of UCTD patients in our cohort and in up to 30% of patients in other cohorts. In our experience, these patients mainly present Raynaud’s phenomenon with a capillaroscopy showing non-specific lesions. Raynaud’s phenomenon in these patients appears as a benign form without digital ulcers and pitting scars .