Practice Essentials
Undifferentiated connective tissue disease (UCTD) is a disorder characterized by the presence of clinical manifestations and laboratory evidence of systemic autoimmune disease, but failure to meet the criteria for any of the defined connective-tissue diseases (CTDs). [1, 2] UCTD must be distinguished from the CTDs for which diagnostic and classification criteria have been established, including the following:
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Polymyositis (PM)
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Dermatomyositis (DM) [10]
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Mixed connective-tissue disease (MCTD) [11]
Some of these disease criteria overlap, further complicating the diagnostic workup in patients with a potential CTD. Unclassifiable symptoms, physical examination findings, or serologic results suggestive of a CTD frequently lead to diagnoses such as incomplete lupus, latent lupus, overlap syndrome, and UCTD. Conceptually, these terms may seem synonymous; however, specific definitions are necessary for appropriate diagnostic, therapeutic, and prognostic determinations. Unfortunately, no mutual agreement has been reached regarding the criteria for diagnosis of UCTD. [15]
In a minority of cases, UCTDs may enter remission. Others remain stable, while a number evolve into a defined CTDs, typically SLE or RA. [1] See Prognosis for more detail.
Signs and symptoms
Patients with UCTD may present with a wide range of signs and symptoms, including any of those found in the classification criteria for defined CTDs. The most common manifestations at presentation include the following [16, 17, 18, 19, 20] :
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Raynaud phenomenon (48%-59%)
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Arthralgia (37%-81%)
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Arthritis (22%-71%)
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Mucocutaneous symptoms, such as photosensitivity, malar rash, alopecia, and oral ulcerations (23%-52%)
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Fever (15%-23%)
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Sicca symptoms (12%-42%)
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Central nervous system (CNS) symptoms (8.5%)
See Presentation for more detail.
Diagnosis
UCTD is a diagnosis of exclusion. Routine screening tests should include the following:
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Complete blood count
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Erythrocyte sedimentation rate (ESR)
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C-reactive protein (CRP)
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Urinalysis with microscopic analysis
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Serum creatinine
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Rheumatoid factor (RF)
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Antinuclear antibodies (ANA)
Other studies may be appropriate on a case-by-case basis.
Proposed diagnostic criteria for UCTD are the presence, for at least 3 years, of signs and symptoms that are suggestive of a CTD but do not fulfill the diagnostic or classification criteria for any of the defined CTDs (ie, SLE, MCTD, SSc, PM/DM, RA, SS), along with the presence of antinuclear antibodies on two different occasions. If the clinical manifestations have been present for less than 3 years, the condition may be defined as early UCTD. [21, 22]
See DDx and Workup for more detail.
Treatment
Nonsteroidal anti-inflammatory drugs (NSAIDs), antimalarials (eg, hydroxychloroquine), and corticosteroids are the mainstay of therapy. Immunosuppressive drugs are generally reserved for treating specific clinical manifestations and for patients with major organ involvement.
Background
In 1980, LeRoy et al proposed the concept of undifferentiated connective-tissue syndromes (UCTS) to characterize mixed or overlapping syndromes. [23] Since that time, innumerable case reports, case series, and clinical studies have used variable criteria to define UCTD. Such variation in the definition of UCTD results in ambiguity of study results and difficulty with interpreting the findings and conclusions.
In 1999, Mosca et al proposed preliminary classification criteria for UCTD that have become increasingly accepted and used. [21] The authors suggested defining cases of UCTD as those in which signs and symptoms are consistent with a CTD but that do not fulfill the classification or diagnostic criteria for any one of the defined CTDs (ie, RA, SLE, SSc, PM/DM, MCTD, SS). In order to fulfill the criteria for UCTD, antinuclear antibodies must be present, along with a disease duration of at least 3 years. Cases with a shorter duration should be described as early UCTD.
Other definitions for UCTD have been proposed. [23, 16, 24, 25, 26, 17, 27, 28] However, many of these definitions are limited by the fact that they may lead to the inclusion of a defined CTD manifesting early or in an incomplete form.
In 2008, Mosca et al admitted that while their proposed classification criteria exclude most patients with an evolving definite CTD, limitations are evident. Their criteria do not allow the diagnosis of UCTD to be made at onset. In addition, the criteria do not exclude a slowly evolving or an incomplete definite CTD. [29] To avoid the misdiagnosis of transitory or early defined CTD, exclusion criteria were appended to the proposed classification criteria above. [22]
Pathophysiology
As with all the CTDs, the etiology of UCTD is unknown, and the lack of validated classification criteria has complicated the task of elucidating the pathophysiology. Generally, autoimmune diseases, including UCTD, are believed to exist in different phases. [30, 31]
The initial phase may occur many years prior to diagnosis, during which time the patient may be asymptomatic and may lack serum autoantibodies. In the second phase, autoantibodies may appear in the serum despite an absence or paucity of symptoms. The interval between autoantibody appearance and significant symptom onset is highly variable among individual patients and the specific autoantibodies. A clinical diagnosis of early UCTD [21] may be made in the second phase, and some of these cases may evolve into a definite CTD or may remain undifferentiated.
Finally, signs and symptoms of the autoimmune disease appear, leading to a definitive diagnosis. Environmental factors likely trigger the onset of this final stage.
UCTD has been associated with numerous autoantibodies, but whether these autoantibodies are etiopathogenic or simply markers of the disease is unknown. Specific autoantibodies to HSP60, HSP65, and transcription factor Sp1 were identified in patients with UCTD and proposed to be pathogenic; however, further research is necessary to clarify this issue. [32, 33]
Research is being directed to evaluate disease features that may delineate the evolution of UCTD. In 2008, Szodoray et al assessed whether abnormalities in the distribution of various immune-competent T-cell populations exist in patients with UCTD and whether certain immune phenotypes predict subsequent development of defined CTDs. [34] The relative and absolute number of natural regulatory T cells (Tregs) decreased in patients with UCTD when compared with controls.
In the patients who developed a definite CTD, the number of natural Tregs was further decreased, suggesting that patients with lower numbers of Treg cell subsets may be more likely to develop a definite CTD. In a similar study, the levels of Treg cells were significantly lower in patients with systemic sclerosis compared with patients with UCTD or healthy controls; in patients with limited cutaneous systemic sclerosis, Treg cells were inversely correlated to disease duration, suggesting that their levels may represent a marker of disease progression. [35]
Furthermore, it has been proposed that vitamin D deficiency may contribute to pathological changes in the number and function of CD4+ T-helper cell subsets in patients with UCTD, and vitamin D supplementation may improve the fine balance of proinflammatory and anti-inflammatory processes in the disease. [36] However, it remains unclear whether vitamin D deficiency is involved in the pathogenesis of these diseases or is a consequence of them. [37]
Epidemiology
Frequency
International
No epidemiologic studies have been completed for UCTD, and disease prevalence can be estimated only by extrapolating data from small case series. Mosca et al (1999) note that 20%-52% of patients in rheumatology clinics with a CTD may have UCTD. [21] This wide range is attributable to varying selection criteria. Disease duration of less than one year may result in transient disease or early-defined CTD being classified as UCTD.
Guerrero et al conducted a similar study of 94 patients over 12 months in Colombia. They concluded that arthritis, Raynaud phenomenon, and the presence of photosensitivity were predictors for the development of CTD. A consensus is required to establish criteria for the classification of UCTD. [38]
Mortality/Morbidity
UCTD may evolve into a defined CTD in 20%-40% of patients, while 50%-60% remain undifferentiated. [29] Ten to 20% percent of patients have symptoms that eventually subside and never evolve into a defined CTD. [34] In one review, high ANA titers or the presence of cytopenias at baseline, as well as progression of a nailfold capillaroscopy pattern during follow-up, were the leading factors associated with evolution to a defined CTD. [39] The likelihood of evolution to a defined CTD is highest during the first 3-5 years of the disease, [40] and the rate of evolution continues to decrease thereafter. [18] Patients who develop a defined CTD late have been noted to have milder disease with a lower incidence of serious adverse events and a good prognosis. [17, 18]
In contrast to the defined CTDs, UCTD is characterized by a mild clinical picture. However, exceptions are notable, as UCTD has been associated with severe, organ-involving, and life-threatening complications, including thrombotic thrombocytopenic purpura, [41] myocarditis, [42] nonspecific interstitial pneumonia, [43] cardiovascular disease, [44] vasculitis, [45] cardiac tamponade, [46] and hepatic injury. [47] Survival rates associated with UCTD are similar to those associated with RA and SLE. [48]
Race-, Sex-, and Age-related Demographics
One study in the United States reported 72% of patients with UCTD were white. [19] Two Italian studies [16, 18] and a Hungarian study [17] did not report the racial characteristics of UCTD cases. Racial prevalence is still uncertain given the limited available data and possible selection bias introduced in those studies.
As with many other autoimmune CTDs, UCTD is much more likely to be diagnosed in females. Reported percentages of UCTD diagnoses in females are 78% in the United States, [19] 93%-95% in Italy, [16, 18] and 94% in Hungary. [17]
UCTD is typically diagnosed in patients in the 3rd to 5th decade of life. However, pediatric and elderly-onset cases have been reported. [19] Patients with SLE who have a prior history of UCTD are diagnosed with SLE approximately 6 years later than patients with SLE who do not have a prior history of UCTD. [17]
Prognosis
Prognostic considerations include the following:
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The prognosis of UCTD depends primarily on the extent of organ involvement.
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UCTD may evolve into a defined CTD in 20%-40% of patients with UCTD, while 50%-60% of cases remain undifferentiated. [29]
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Leading factors associated with evolution to definite CTD are high antinuclear antibody (ANA) titers, presence of cytopenias at baseline, and progression of nailfold-capillaroscopy patter during follow-up [39]
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Approximately 10%-20% of patients with UCTD have symptoms that subside or remit and never evolve into a defined CTD. [34]
Patient Education
Patients with UCTD, as well as their immediate family members, should be educated about the prognosis of UCTD and the potential for the disease to evolve into a defined CTD (eg, SLE, systemic sclerosis, mixed CTD). Furthermore, education should focus on the following:
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Symptomatic treatment
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Appropriate understanding of treatment medications
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The indications for contacting the primary care physician or rheumatologist
Tables
Inclusion Criteria |
Clinical Exclusion Criteria (Applicable to patients at disease onset) |
Laboratory Exclusion Criteria (Applicable to patients at disease onset) |
1. Signs and symptoms suggestive of a CTD but not fulfilling the diagnostic or classification criteria for any of the defined CTDs (using previously established classification criteria for SLE, MCTD, SSc, PM/DM, RA, SS) for at least 3 years. If the disease duration is less than 3 years, patients may be defined as having an early UCTD. Adapted from Mosca et al [21] and Doria et al. [22] 2. Presence of antinuclear antibodies determined on two different occasions |
Malar rash Subacute cutaneous lupus Cutaneous sclerosis Heliotrope rash Gottron papules Erosive arthritis |
Anti-dsDNA Anti-Smith Anti-U1-RNP Anti-Scl70 Anticentromere Anti-La/SSB Anti-Jo1 Anti-Mi2 |
Connective-Tissue Disease Association |
Signs or Symptoms |
Laboratory Data |
Systemic lupus erythematosus |
Age, fever, photosensitivity, serositis, alopecia |
ANA, Anti-dsDNA, Anti-Smith, Anti-cardiolipin antibodies, Coombs positivity, leukopenia |
Systemic sclerosis |
Sclerodactyly, Raynaud phenomenon, sicca symptoms, esophageal dysfunction |
ANA with nucleolar pattern |
Sjögren syndrome |
Xerostomia, xerophthalmia, Raynaud phenomenon |
Anti-SSA, Anti-SSB |
Rheumatoid arthritis |
Symmetric polyarthritis |
RF, elevated ESR (>70 mm/h) |
Mixed connective-tissue disease |
Esophageal reflux, polyarthritis, Raynaud phenomenon |
ANA, Anti-U1-RNP |
