Connective-tissue diseases (CTDs) manifest with a wide range of clinical findings and laboratory abnormalities. The diversity of signs and symptoms frequently complicates the diagnosis of a rheumatic disease.
Diagnostic and classification criteria have been established for many CTDs, including the following:
Rheumatoid arthritis (RA)[1, 52]
Systemic lupus erythematosus (SLE)[2, 3]
Systemic sclerosis (SSc)[4, 50]
Polymyositis (PM)
Dermatomyositis (DM)[5]
Mixed connective-tissue disease (MCTD)[6]
Sjögren syndrome (SS)[7, 8, 51]
Some of these disease criteria overlap, further complicating the diagnostic workup in patients with a potential CTD. Unclassifiable symptoms, physical examination findings, or serological results suggestive of a CTD frequently lead to diagnoses such as incomplete lupus, latent lupus, overlap syndrome, and undifferentiated connective-tissue disease (UCTD). Conceptually, these terms may seem synonymous; however, specific definitions are necessary for appropriate diagnostic, therapeutic, and prognostic determinations.
In 1980, LeRoy et al proposed the concept of undifferentiated connective-tissue syndromes (UCTS) to characterize mixed or overlapping syndromes.[9] 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.[10] 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.[9, 11, 12, 13, 14, 15, 16, 17] 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.[18] To avoid the misdiagnosis of transitory or early defined CTD, exclusion criteria were appended to the proposed classification criteria above.[19] These preliminary classification criteria for UCTD are listed in Table 1, although no mutual agreement has been reached regarding the criteria for diagnosis of UCTD.[20]
Table 1. Preliminary Classification Criteria for Undifferentiated Connective-Tissue Disease
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.[21, 22]
The initial phase may occur many years prior to diagnosis, during which time the patient may be asymptomatic and may lack serum autoantibodies. Currently, patients with autoimmune disease are believed to have a genetic predisposition. 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. Finally, signs and symptoms of the autoimmune disease appear, leading to a definitive diagnosis. Environmental factors likely trigger the onset of this final stage. A clinical diagnosis of early UCTD[10] may be made in the second phase, and some of these cases may evolve into a definite CTD or may remain undifferentiated.
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.[23, 24]
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.[25] 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.[49]
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.[26]
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.[10] 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.[27]
Mortality/Morbidity
UCTD may evolve into a defined CTD in 20%-40% of patients, and 50%-60% remain undifferentiated.[18] Ten to 20% percent of patients have symptoms that eventually subside and never evolve into a defined CTD.[25] The likelihood of evolution to a defined CTD is highest during the first 3-5 years of the disease,[28] and the rate of evolution continues to decrease thereafter.[29] 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.[15, 29]
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,[30] myocarditis,[31] nonspecific interstitial pneumonia,[32] cardiovascular disease,[33] vasculitis,[34] cardiac tamponade,[35] and hepatic injury.[36] Survival rates associated with UCTD are similar to those associated with RA and SLE.[37]
Race-, Sex-, and Age-related Demographics
One study in the United States reported 72% of patients with UCTD were white.[38] Two Italian studies[11, 29] and a Hungarian study[15] 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,[38] 93%-95% in Italy,[11, 29] and 94% in Hungary.[15]
UCTD is typically diagnosed in patients in the 3rd to 5th decade of life. However, pediatric and elderly-onset cases have been reported.[38] 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.[15]
Patients with undifferentiated connective-tissue disease (UCTD) may present with various signs and symptoms. The most common manifestations at presentation include the following[11, 15, 29, 38, 39] :
Raynaud phenomenon (48%-59%)
Arthralgia (37%-81%)
Arthritis (22%-71%)
Mucocutaneous symptoms, such as photosensitivity, malar rash, alopecia, and oral ulcerations (23%-52%)
Fever (15%-23%)
Sicca symptoms (12%-42%)
Central nervous system (CNS) symptoms (8.5%)
The proposed classification criteria for UCTD[10] include any sign or symptom that may be included in the classification criteria of systemic lupus erythematosus (SLE), mixed CTD (MCTD), systemic sclerosis (SSc), polymyositis/dermatomyositis (PM/DM), rheumatoid arthritis (RA), and Sjögren syndrome (SS). The following incomplete list of symptoms may be noted in patients with UCTD and are included as criteria for the classification of UCTD:
Mucocutaneous - Malar rash, discoid rash, oral or nasopharyngeal ulcerations, digital skin pitting or loss of the digital pad tissue, skin tightening or thickening, photosensitivity, heliotrope rash, Gottron sign, Gottron papules, shawl sign, mechanic's hands
Eyes - Dry eyes
Salivary glands - Dry mouth or salivary gland enlargement
Lungs - Pleuritic chest pain
Heart - Pericarditis
Musculoskeletal - Erosive or nonerosive arthritis; muscle weakness of the limb girdle, neck flexors, or muscles of mastication; history of myositis; swollen hands; acrosclerosis
Nervous system - Mental status changes, psychosis, personality changes, signs of a cranial nerve palsy, peripheral motor neuropathy, sensory neuropathy, or entrapment neuropathy
Laboratory test screening is helpful to identify markers that may suggest autoimmune inflammatory disease. Routine screening tests for undifferentiated connective-tissue disease (UCTD) should include the following:
Complete blood count
Erythrocyte sedimentation rate (ESR)
C-reactive protein (CRP)
Urinalysis with microscopic analysis
Serum creatinine
Rheumatoid factor (RF)
Antinuclear antibodies (ANA): The American College of Rheumatology Antinuclear Antibody Task Force recommends ANA screening be performed using an immunofluorescence assay (IFA).[43] Any ANA detected by an enzyme immunoassay (EIA) or enzyme-linked immunosorbent assay (ELISA) should be confirmed with IFA testing.[44]
Other studies to consider on a case-by-case basis include the following:
Creatine kinase and aldolase
Complement components (C3, C4, CH50)
Thyroid-stimulating hormone
Anti–cyclic citrullinated peptide (CCP)
Anti-Ro/SSA
Anti-La/SSB
Anti-Smith
Anti-U1-RNP
Anti-Jo1
Anti-Mi2
Anti-Scl70 (topoisomerase antibody)
Anti-cardiolipins
Anti-beta-2 glycoprotein 1
Lupus anticoagulant
Anti-Ku
Rapid plasma reagin (RPR)
Vitamin D (25[OH]D3)
Anti-U1-RNP and Anti-Ro/SSA antibodies represent the antinuclear specificities most frequently detected in UCTD. Anti-Ro/SSA immunoglobulin G (IgG) antibodies are very common in UCTD.[45] A 2008 study by Zold et al suggested that vitamin D deficiency in patients with UCTD may play a role in progression to a defined CTD.[46]
Chest radiography in patients with UCTD may be normal or may show signs of pleural effusion, pericardial effusion, enlarged cardiac silhouette, longstanding pulmonary hypertension, or interstitial lung disease. Features of interstitial pneumonia may overlap with diagnostic criteria for interstitial pneumonia with autoimmune features.[32] Computed tomography (CT) of the chest, particularly high-resolution CT scanning, may better characterize pulmonary disease associated with CTD.
Salivary gland ultrasonography (SGUS) was found to have good sensitivity and high specificity in differentiating Sjögren syndrome (SS) from UCTD. In a study that included 55 patients with SS and 54 with UCTD, patients with SS showed a higher SGUS score than those with UCTD [mean 2.2 vs 0.2, P < 0.0001). An SGUS cut-off >2 showed a sensitivity of 65%, a specificity of 96%, a positive predictive value of 95%, and a negative predictive value of 73% for SS diagnosis.[53]
Pulmonary function studies, including spirometry, lung volumes, and carbon monoxide–diffusing capacity assists in identifying interstitial lung disease or reactive airway disease.
Electrocardiography may be useful in patients with cardiopulmonary signs and symptoms. Nonspecific ischemic changes, axis deviation, or findings consistent with chamber enlargement may direct further evaluation.
Echocardiography can best clarify chamber sizes and function, estimate physiologic pressures (including pulmonary arterial pressures), and identify or quantitate the size of a pericardial effusion.
The Schirmer test is a useful screen for dry eyes and may be used to detect decreased tearing associated with primary or secondary SS. This test is very sensitive, but the results may be abnormal in patients taking anticholinergic medications.
Rose Bengal staining of the cornea can reveal keratitis associated with diminished tearing in SS.
Nailfold capillary microscopy may be used to identify dilated tortuous capillary loops, irregular capillary loops, and areas of avascularity or "dropout" in patients with Raynaud phenomenon. These findings indicate an underlying CTD, including UCTD.[47]
A patient with undifferentiated connective-tissue disease (UCTD) can be evaluated and treated primarily as an outpatient. 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 when there is major organ involvement.
Surgery for patients with UCTD is not routinely necessary and should be initiated only when indicated for diagnosis or treatment.
Consultations with other specialists may be clinically indicated, including with a dermatologist, ophthalmologist, pulmonologist, cardiologist, neurologist, physical medicine specialist, physical therapist, and/or occupational therapist.
In general, activities are not restricted in the absence of specific functional limitations associated with UCTD.
Patients with photosensitivity should minimize prolonged exposure to sunlight and should use protective clothing and sunblock lotions/creams to protect against ultraviolet light.
Patients with severe Raynaud phenomenon should avoid prolonged exposure to severe cold temperatures (<40° F) to avoid digital vasospasm. Layered clothing, hats, and gloves help to maintain a warm core body temperature and decreased vasospastic symptoms. Tobacco use should be avoided.
Nonsteroidal anti-inflammatory drugs (NSAIDs), antimalarials (eg, hydroxychloroquine), and corticosteroids are the mainstay of therapy in patients with undifferentiated connective-tissue disease (UCTD). Immunosuppressive drugs are generally reserved for treating specific clinical manifestations and when there is major organ involvement.
Mosca et al (2008) found that 93% of patients with UCTD were initially treated with corticosteroids and/or antimalarials, and 2% were started on immunosuppressive medications. After 10 years of follow-up, 16% of patients were no longer receiving therapy, 36% were being treated with hydroxychloroquine plus corticosteroids, 10% were taking corticosteroids alone, and no patients were receiving cytotoxic immunosuppressive therapy.[18]
Bodolay et al (2003) prescribed low-dose corticosteroids only when NSAIDs were deemed ineffective.[15] Common indications for systemic corticosteroids included recurrent serositis, skin vasculitis, and synovitis. Antimalarials were administered for photosensitivity and severe rash. The authors concluded that aggressive immunosuppressive therapy for "true" UCTD is neither necessary nor justified.
Clinical Context:
For relief of mild-to-moderate pain. Inhibits inflammatory reactions and pain by decreasing activity of cyclooxygenase, which is responsible for prostaglandin synthesis.
NSAIDs may be beneficial for analgesic, antipyretic, anti-inflammatory, or antiplatelet effects. These medications inhibit the enzyme cyclooxygenase, resulting in a generalized decrease in prostaglandin production, ultimately reducing pain and inflammation. Other mechanisms may also exist, such as inhibition of leukotriene synthesis, lysosomal enzyme release, lipoxygenase activity, neutrophil aggregation, and various cell-membrane functions.
Arthritis and arthralgias may respond to NSAIDs alone or in combination with an antimalarial (see below).
The inducible cyclooxygenase-2 (COX-2) isoenzyme is produced during inflammatory conditions, resulting in increased production of proinflammatory prostaglandins that cause pain and swelling. COX-2 inhibitors selectively block the COX-2 isoenzyme and may minimize adverse effects associated with traditional NSAIDs (eg, gastrointestinal bleeding).
Clinical Context:
Inhibits chemotaxis of eosinophils and locomotion of neutrophils and impairs complement-dependent antigen-antibody reactions. Hydroxychloroquine sulfate 200 mg is equivalent to 155 mg hydroxychloroquine base and 250 mg chloroquine phosphate.
These agents may inhibit the chemotactic properties of pro-inflammatory leukocytes (eg, polymorphonuclear cells, lymphocytes). They may also interfere with intracellular processing of autoantigenic peptides.
Antimalarials may be used with or without NSAIDs to control arthralgias/arthritis, constitutional symptoms, and mucocutaneous manifestations.
Clinical Context:
Immunosuppressant for treatment of autoimmune disorders. May decrease inflammation by reversing increased capillary permeability and suppressing PMN activity.
Corticosteroids inhibit the cascade of inflammatory and immune mechanisms at the cellular level, resulting in profound anti-inflammation and modification of the immune response. The pharmacologic effects and adverse effects of corticosteroids are influenced by the drug preparation, dose, dosing schedule, and route of administration. They vary with the individual patient and disease process.
These drugs are commonly used in combination with other medications to control the signs and symptoms of inflammation.
Clinical Context:
Unknown mechanism of action. Analog of folic acid and inhibits dihydrofolate reductase and, ultimately, DNA synthesis. Methotrexate also inhibits the enzyme 5-aminoimidazole-4-carboxamidoribonucleotide (AICAR) transformylase, leading to intracellular accumulation of AICAR and extracellular adenosine release. The adenosine has anti-inflammatory properties.
Methotrexate is very effective in the treatment of inflammatory arthritis and other systemic manifestations of UCTD. Ameliorates symptoms of inflammation (eg, pain, swelling, stiffness).
Clinical Context:
A purine analog that interferes with the synthesis of adenosine and guanine resulting in inhibited synthesis of DNA, RNA, and proteins. May decrease proliferation of immune cells and may be effective for treatment of articular and extra-articular manifestations of connective-tissue disease.
These agents relax vascular smooth muscle and decrease peripheral vascular resistance. They may help control the signs and symptoms of Raynaud phenomenon.
Patients with undifferentiated connective-tissue disease (UCTD) are typically monitored for progression of specific manifestations, evolution to a defined CTD, and safety and efficacy of treatment. The frequency of outpatient visits necessary depends on the severity of disease. During the first 5 years postdiagnosis, the frequency of follow-up visits may be greater, given the propensity for UCTD to evolve early in the disease course.
The prognosis of UCTD depends primarily on the extent of organ involvement.
UCTD may evolve into a defined CTD in 20%-40% of patients with UCTD, while 50%-60% of cases remain undifferentiated.[18]
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[54]
Approximately 10%-20% of patients with UCTD have symptoms that subside or remit and never evolve into a defined CTD.[25]
The incidence of evolution to a defined CTD is highest during the first 3-5 years of the disease course,[28] and the rate of evolution continues to decrease over time.[29]
Patients who develop a defined CTD late have been noted to have milder disease with a lower incidence of serious adverse events and a better prognosis.[15, 29]
Survival rates in UCTD are similar to those associated with rheumatoid arthritis and systemic lupus erythematosus (SLE).[37]
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:
Symptomatic treatment
Appropriate understanding of treatment medications
The indications for contacting the primary care physician or rheumatologist
Bernard Hildebrand, MD, MA, Associate Program Director, San Antonio Military Medical Center Rheumatology Fellowship
Disclosure: Nothing to disclose.
Coauthor(s)
Daniel F Battafarano, DO, MACP, FACR, Program Director, Rheumatology Fellowship, San Antonio Uniformed Services Health Education Consortium, San Antonio Military Medical Center; Professor of Medicine, Uniformed Services University of the Health Sciences, F Edward Hebert School of Medicine; Adjunct Professor of Medicine, University of Texas Health San Antonio
Disclosure: Nothing to disclose.
Specialty Editors
Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Elliot Goldberg, MD, Dean of the Western Pennsylvania Clinical Campus, Professor, Department of Medicine, Lewis Katz School of Medicine at Temple University
Disclosure: Nothing to disclose.
Chief Editor
Herbert S Diamond, MD, Visiting Professor of Medicine, Division of Rheumatology, State University of New York Downstate Medical Center; Chairman Emeritus, Department of Internal Medicine, Western Pennsylvania Hospital
Deng XL, Liu XY. Comparative Study of 181 Cases of Diffuse Connective Tissue Disease Complicated by Cardiovascular Disease. International Journal of Rheumatic Diseases. Nov 2008. 11 (Suppl. 1):A462.
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 and 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[10] and Doria et al.[19]
2. Presence of antinuclear antibodies determined on two different occasions
