eMedicine Specialties > Rheumatology > Systemic Rheumatic Disease

Undifferentiated Connective-Tissue Disease

Author: Bernard A Hildebrand Jr, MD, Staff Rheumatologist, Department of Rheumatology, San Antonio Military Medical Center, San Antonio, Texas
Coauthor(s): Daniel F Battafarano, DO, FACP, FACR, Clinical Professor of Medicine, University of Texas Health Science Center, San Antonio, Texas; Associate Professor, Department of Medicine, Uniformed Services University of Health Sciences, F Edward Hebert School of Medicine; Chief of Rheumatology Service, San Antonio Military Medical Center, San Antonio, Texas.
Contributor Information and Disclosures

Updated: Jul 24, 2009

Introduction

Background

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 rheumatoid arthritis (RA),¹ systemic lupus erythematosus (SLE),^2,3 systemic sclerosis (SSc),⁴ polymyositis (PM), dermatomyositis (DM),⁵ mixed connective-tissue disease (MCTD),⁶ and Sjögren syndrome (SS).^7,8

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} 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.¹⁷ To avoid the misdiagnosis of transitory or early defined CTD, exclusion criteria were appended to the proposed classification criteria above.¹⁸ These preliminary classification criteria for UCTD are listed in Table 1.

Open table in new window

^a Applicable to patients at disease onset
^b Using established classification criteria for SLE, MCTD, SSc, PM/DM, RA and SS
^c If the disease duration is less than 3 years, patients may be defined as having an early UCTD.
Adapted from Mosca et al¹⁰ and Doria et al¹⁸

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.¹⁹

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 UCTD¹⁰ 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.^20,21

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.²² 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.

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.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.

Mortality/Morbidity

UCTD may evolve into a defined CTD in 20%-40% of patients, and 50%-60% remain undifferentiated.¹⁷ Ten to 20% percent of patients have symptoms that eventually subside and never evolve into a defined CTD.²² The likelihood of evolution to a defined CTD is highest during the first 3-5 years of the disease,²³ and the rate of evolution continues to decrease thereafter.²⁴ 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.^15,24

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,²⁵ myocarditis,²⁶ nonspecific interstitial pneumonia,²⁷ cardiovascular disease,²⁸ vasculitis,²⁹ cardiac tamponade,³⁰ and hepatic injury.³¹ Survival rates associated with UCTD are similar to those associated with RA and SLE.³²

Race

One study in the United States reported 72% of patients with UCTD were white.³³ Two Italian studies^11,24 and a Hungarian study¹⁵ 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.

Sex

As with many other autoimmune CTDs, UCTD is much more likely to be diagnosed in females. In the United States, 78% of UCTD diagnoses are in females,³³ 93%-95% in Italy,^11,24 and 94% in Hungary¹⁵ .

Age

UCTD is typically diagnosed in patients in the 3rd to 5th decade of life. However, pediatric and elderly-onset cases have been reported.³³ 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

Clinical

History

Patients with undifferentiated connective-tissue disease (UCTD) may present with various symptoms. The most common symptoms at presentation include 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%); and CNS symptoms (8.5%).^{11,15,24,33,34}

The proposed classification criteria for UCTD¹⁰ include any sign or symptom that may be included in the classification criteria of SLE, MCTD, SSc, PM/DM, RA, and 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 - History of seizures or psychosis
• Vascular - Raynaud phenomenon

Physical

Physical findings of UCTD may be localized or diffuse. The potential physical manifestations of UCTD are best described by organ systems, as follows:

• Skin - Telangiectasias, purpura, petechiae, digital ulcers or scars, sclerodactyly, acrosclerosis, calcinosis, malar rash, discoid rash, erythema nodosum, scaly/erythematous extensor surfaces (eg, dorsum of the hands, metacarpophalangeal joints, proximal interphalangeal joints, knees, elbows, medial malleoli), periungual erythema, dilated or irregular nailfold capillaries, digital cracking or fissuring (mechanic's hands), alopecia, lilac discoloration of the eyelids with periorbital edema (heliotrope rash), subcutaneous nodules
• Eye - Conjunctivitis, scleral-episcleral disease, uveitis, iritis, or keratoconjunctiva sicca
• Salivary glands - Xerostomia or salivary gland enlargement
• Reticuloendothelial - Lymphadenopathy or splenomegaly
• Lungs - Rales, wheezing, pleural effusion, or pleural rub
• Heart - Enlarged heart, murmur, pericardial rub, dependent edema, irregular heartbeat, or abnormal P₂ heart tone
• Vascular - Acrocyanosis, absent pulses, arterial and/or venous thrombosis
• Gastrointestinal - Hepatomegaly, abdominal tenderness
• Genitalia - Ulcerations, rashes, or discharge
• Muscles - Muscle tenderness, muscle atrophy, proximal muscle weakness, or tendon friction rubs
• Joints - Joint tenderness, swelling, warmth, erythema, effusion, synovitis, or deformity
• Nervous system - Mental status changes, psychosis, personality changes, signs of a cranial nerve palsy, peripheral motor neuropathy, sensory neuropathy, or entrapment neuropathy

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