eMedicine Specialties > Rheumatology > Systemic Rheumatic Disease

Undifferentiated Connective-Tissue Disease

Author: Benjamin Duffy, DO, Staff Physician, Department of Internal Medicine, Brooke Army Medical Center
Coauthor(s): Daniel F Battafarano, DO, FACP, FACR, Adjunct Associate Professor, Department of Medicine, Uniformed Services University of Health Sciences, F Edward Hebert School of Medicine; Chief of Rheumatology Service, Brooke Army Medical Center
Contributor Information and Disclosures

Updated: Apr 25, 2006

Introduction

Background

Many connective-tissue diseases (CTDs) share common signs and symptoms, which frequently makes the diagnosis of a specific rheumatic disease difficult. Rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc), polymyositis (PM), dermatomyositis (DM), mixed connective-tissue disease (MCTD), and Sjögren syndrome (SS) can present with similar clinical features, particularly during the first 12 months of symptoms. Isolated Raynaud phenomenon, inflammatory polyarthritis, anemia, interstitial lung disease, or pleuropericarditis may occur without an obvious diagnosis. Screening serology findings, such as rheumatoid factor (RF) or antinuclear antibody (ANA), may be positive or negative under these clinical circumstances.

However, well-established connective-tissue diseases have defined, discrete diagnostic criteria. Patients who present with symptoms, positive serology results, or physical findings consistent with an established connective-tissue disease but not fulfilling classification criteria for one of these established connective-tissue diseases are diagnosed with undifferentiated connective-tissue disease (UCTD). UCTD is a relatively new entity, suggested by LeRoy et al in 1980. The definition of UCTD is still under debate, although it is becoming more clear. Mosca et al recently reviewed UCTD literature and proposed that preliminary classification criteria include (1) signs and symptoms suggestive of a connective-tissue disease, (2) positive ANA results, and (3) a disease that lasts at least 3 years.

Pathophysiology

The pathophysiology of most connective-tissue diseases is unclear, and UCTD is no different in this respect. The presence of autoantibodies commonly precedes disease onset, suggesting that they are not secondary to tissue damage or disease expression. Therefore, autoantibodies may be etiopathogenic or may only be clinical markers of the disease process. Like most connective-tissue diseases, the theory and research have been concentrated on genetically susceptible hosts, T- and B-cell abnormalities, and environmental triggers, such as ultraviolet light or infection. Recent studies into specific antibodies associated with UCTD have demonstrated significant correspondence with anti-HSP60 and anti-HSP65 antibodies, as well as anti-Sp1 antibodies; however, further research is needed to evaluate the implications of these associations further.

Frequency

United States

Very little information exists on the frequency and/or epidemiology of UCTD. However, studies in the United States and Europe have attempted to examine the prevalence of UCTD by comparing patients over many years from the onset of well-established connective-tissue diseases to patients with UCTD. Although these studies are difficult to compare because of patient enrollment variability, the diagnosis of UCTD clearly is relatively common even after monitoring patients for as long as 10 years.

Mortality/Morbidity

• The vast majority of patients diagnosed with UTCD at onset who do not progress to a definite connective-tissue disease within 12 months of the onset of symptoms remain undifferentiated after 10 years. Progression to definite connective-tissue disease decreases exponentially over time with over 70% of patients who evolve, doing so within 24 months from diagnosis.
• In general, overall survival rates in patients with UCTD are better than patients with rheumatoid arthritis or systemic lupus erythematosus. Patients who do progress from UCTD to a definite connective-tissue disease also have a better prognosis than those diagnosed with a definite connective-tissue disease from the onset especially when compared to systemic lupus erythematosus.
• Mortality and morbidity are directly related to the extent of disabling organ involvement such as progressive interstitial lung disease, pulmonary hypertension, or vascular complications. Thrombosis related to the presence of antiphospholipid antibodies can occur but is rare.

Race

Most of the studies on UCTD have been performed in Europe, and the majority of patients have been white. However, this may not be representative of UCTD patients around the world.

Sex

A female predominance exists in UCTD similar to that observed in the common connective-tissue diseases such as rheumatoid arthritis and systemic lupus erythematosus.

Age

The onset of UCTD is similar to most connective-tissue diseases, peaking in the middle years of life. UCTD has been described in children.

Clinical

History

Patients may present with systemic symptoms, such as fatigue, fever, or weight loss, preceding any organ involvement. The most common symptoms include arthralgias, unexplained or undifferentiated polyarthritis, Raynaud syndrome, mucocutaneous manifestations, and sicca symptoms. It is unusual for a patient with undifferentiated connective-tissue disease (UCTD) to have major organ involvement. However, patients may manifest many signs or symptoms observed with other connective-tissue diseases as described in the potential features listed below.

• Skin - Malar rash, digital skin ulcers, purpura, alopecia, skin tightening, urticaria, or photosensitivity
• Eyes - Dry eyes, conjunctivitis, or ocular inflammation
• Salivary glands - Dry mouth or salivary gland enlargement
• Reticuloendothelial - Lymphadenopathy or splenomegaly
• Lungs - Dyspnea, orthopnea, cough, wheezing, or pleuritic chest pain
• Heart - Angina, atypical chest pain, dyspnea, orthopnea, dependent edema, or pericarditis
• Vascular - Raynaud phenomenon (exaggerated vascular response to cold temperatures leading to episodic color changes in the skin of the digits), history of arterial or venous thrombosis, history of frequent miscarriages, or vasculitis
• Gastrointestinal - Anorexia, dysphagia, dyspepsia, abdominal pain, vomiting, nausea, hematemesis, melena, jaundice, or diarrhea
• Genitalia - Urethral discharge or dysuria
• Muscles - Muscle weakness, muscle pain, or history of myositis
• Joints - Arthralgia or arthritis
• Nervous system - History of seizures, neuropathy or altered mental status

Physical

Physical findings can be limited or may involve many organs. The potential physical manifestations of UCTD are best described by organ systems.

• Skin - Telangiectasia, purpura, petechiae, digital ulcers or scars, sclerodactyly, acroscleroderma, calcinosis, malar rash, discoid rash, erythema nodosum, erythematous knuckle pads, periungual erythema, alopecia, heliotrope eyelids, 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, arrhythmia, or abnormal P₂ sound
• Vascular - Acrocyanosis, absent pulses, arterial and/or venous thrombosis
• Gastrointestinal - Hepatomegaly, gastroesophageal disease, esophageal dysmotility, or malabsorption syndromes
• Genitalia - Ulcerations, rashes, or discharge
• Muscles - Muscle tenderness, muscle atrophy, or proximal muscle weakness
• Joints - Joint tenderness, swelling, effusion, synovitis, or deformity
• Nervous system - Cranial nerve palsy, peripheral motor neuropathy, sensory neuropathy, entrapment neuropathy, psychosis, or personality change

• Search for CME/CE on This Topic »

• Mixed Connective Tissue Disease (Pediatrics: General Medicine)

• Undifferentiated Connective Tissue Disease a Risk Factor in Pregnancy