23-year-old young female, presented with a history of joint pain involving both small and large joints from the past two years

Discussion of the case

23 year, young female, with symmetrical non-deforming polyarthritis involving both small and large joints from the past 2 years, intermittently on NSAID and steroids. Except for minimal eye irritation, no other organs were involved. Inflammatory parameters are high and ANA positive with the profile being negative. RF and Anti-CCP were negative. The disease being more than 2 years, and the possible causes are auto-immune diseases. The probable differential diagnoses are Rheumatoid arthritis, connective tissue disease, seronegative spondyloarthropathy, and probable fibromyalgia.

Application of the current ACR/EULAR criteria to this patient indicated a total score of 7 (scoring: more than 10 joints including small joints (score 5), duration of more than 6 weeks (score 1), and elevated inflammatory parameters (score 1)) and the patient was classified to have RA.¹ However, the patient was both Rheumatoid factor and Anti-CCP-, but ANA+ and profile negative. ANA suggests a possibility of connective tissue disease. X-ray of the hand did not show erosions to indicate RA, despite 2 years of disease and lack of treatment with DMARD. On the other hand, an important aspect of ACR/EULAR criteria is that they are applicable after the exclusion of all other possibilities. ANA suggests a possibility of connective tissue disease. Hand x-ray despite 2 years of disease and not being treated with DMARD without erosions suggest the possibility of RA is less likely. The present case thus typically qualifies to be non-erosive synovitis, with ANA positivity.

This patient could also be diagnosed to have unclassified polyarthritis or undifferentiated connective tissue disease (UCTD). The current patient presented with signs and symptoms suggestive of a systemic autoimmune disease but does not meet the existing classification criteria for a connective tissue disease (CTD). She could not be diagnosed with a specific CTD on clinical grounds as her manifestations and autoantibody profile were not specific for any of the most common CTDs. Such indeterminate conditions are presently classified as UCTD based on the criteria proposed by Moscaet al.² The criteria include (i) signs and symptoms suggestive of CTD but do not fulfill the criteria for a defined CTD, (ii) the presence of ANA, (iii) disease duration of at least 3 years.

UCTD is characterized by a mild clinical picture with the absence of manifestations specific to any major CTD, such as erosive arthritis or pulmonary fibrosis.^2,3 There are many manifestations of stable UCTD; the most frequent ones include arthralgias, arthritis, Raynaud's phenomenon, mucocutaneous involvement, sicca symptoms, and leukopenia.^{4, 5}

Patients with stable UCTD usually have a simple autoantibody profile with a single specificity - usually anti-Ro/SSA or anti-RNP antibodies, and rare observation of autoantibodies specific to a particular CTD, such as anticentromere, anti-dsDNA, or anti-Sm antibodies. In the present case, the disease duration is less than 3 years. The presence of non-erosive arthritis and ANA positivity suggest a probable diagnosis of UCTD. Alarcon et al⁶ have defined the disease duration to be more than 12 months.

The biggest challenge in the diagnosis of UCTD is the three probabilities or the differential diagnosis - a transient auto-immune phenomenon, a transitory stage of a definite CTD (evolving CTD), or evolving RA where both antibodies are negative. However, one should watch for the development of newer symptoms. In a patient with UCTD, the normally recommended treatment is hydroxychloroquine or other symptomatic therapy. Fewer follow-up visits are required in UCTD compared to any other CTD.

The correct diagnosis of patients with stable UCTD has important implications in routine clinical practice. The ability to distinguish a relatively benign disease aids in the most appropriate follow-up protocol, the avoidance of over-treatment, and a reduction in the psychological stress and other consequences associated with the diagnosis of potentially severe disease.⁷

Final Diagnosis

The final diagnosis was undifferentiated CTD. The Patient is in follow-up with hydroxychloroquine and continues to be asymptomatic with few episodes of pain.

Learning Points

Not all ANA-positive arthritis is lupus or other serious connective tissue diseases. One has to consider UCTD in a situation of undifferentiated status. UCTD is a benign disease and needs to be recognized appropriately.

References

1. Daniel A, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO, et al. 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis & Rheumatism2010;62(9):2569-2581.
2. Mosca M et al. Undifferentiated connective tissue diseases (UCTD): a review of the literature and a proposal for preliminary classification criteria. Clin Exp Rheumatol1999;17:615-620.
3. Mosca M et al. Undifferentiated connective tissue diseases: the clinical and serological profiles in 91 patients followed for at least 1 year. Lupus 1998;7:95-100.
4. Danieli MG et al. Five-year follow-up of 165 Italian patients with undifferentiated connective tissue diseases. Clin Exp Rheumatol 1999;17:585-591.
5. Alarcón GS et al. Early undifferentiated connective tissue disease. I. Early clinical manifestations in a large cohort of patients with undifferentiated connective tissue diseases compared with cohorts of well-established connective tissue disease. J Rheumatol1991;18:1332-1339.
6. Mosca, M, Chiara T, Bombardieri S. A case of undifferentiated connective tissue disease: is it a distinct clinical entity? Nature Clin Pract Rheumatol2008;4(6):328-332.