AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Definite connective-tissue disease should be included in the differential diagnoses for any patient who presents with features of undifferentiated connective-tissue disease (UCTD). Brief descriptions of the characteristics of the diseases considered in the differential diagnosis of UCTD are provided below (see Table 1). Recent studies have demonstrated that certain manifestations at the time of diagnosis of UCTD are predictive of potential progression to definite connective-tissue disease, as illustrated in Table 1.

Table 1. Predictors of Progression to Definite Connective-Tissue Disease Diagnosis

Systemic lupus erythematosus

Systemic lupus erythematosus is a classic autoimmune disease characterized by antinuclear antibodies and multiorgan involvement. The peak incidence of systemic lupus erythematosus is in people aged 15-40 years, with a female-to-male ratio of at least 5:1. A patient with systemic lupus erythematosus usually has 4 or more of the 11 classification criteria for diagnosis. The criteria include malar rash, discoid rash, photosensitivity, oral ulcers, arthritis, serositis, renal disorder, neurologic disorder, hematologic disorder, immunologic disorder, and positive ANA.

Systemic sclerosis

Systemic sclerosis is an uncommon connective-tissue disease involving both the skin and internal organs. This most often is diagnosed in people aged 35-64 years, with a female-to-male ratio of 3:1. A patient will be classified as having systemic sclerosis if one major or 2 or more minor criteria are present. The major criterion is scleroderma proximal to the metacarpophalangeal or metatarsophalangeal joints. Minor criteria include sclerodactyly, digital pitting scars, or bibasilar pulmonary fibrosis. Virtually all patients with systemic sclerosis have Raynaud phenomenon.

Polymyositis/dermatomyositis

The diagnosis of polymyositis/dermatomyositis is uncommon, with an incidence range from 2-10 cases per million. A bimodal age distribution exists, with peaks at ages 10-15 years and at ages 45-60 years. The overall female-to-male ratio is 3:1. The 5 possible criteria for diagnosis are symmetrical weakness, elevation of muscle enzymes, electromyographic evidence, muscle biopsy evidence, and dermatologic features. A definite diagnosis of polymyositis must include 4 criteria without a rash. The diagnosis of dermatomyositis is made when 3 criteria are present plus the rash.

Mixed connective-tissue disease

Mixed connective-tissue disease is characterized by clinical manifestations that are observed in systemic lupus erythematosus, systemic sclerosis, and/or polymyositis. The incidence of mixed connective-tissue disease is considered less frequent than systemic lupus erythematosus but occurs more frequently than systemic sclerosis or polymyositis. It is much more common in women, with a ratio of 15:1, and occurs at a mean age of 37 years. The most common features are arthritis, sclerodactyly, Raynaud phenomenon, esophageal dysmotility, and myositis. In addition to a positive ANA, patients with mixed connective-tissue disease have high titer antibodies to RNP.

Sjögren syndrome

Sjögren syndrome results from lymphocytic infiltration of exocrine glands. The frequency of Sjögren syndrome is similar to systemic lupus erythematosus in that it occurs in 1 per 1000 people. Primary Sjögren syndrome is diagnosed predominantly in women, with a female-to-male ratio of 9:1 and an age range of 30-50 years. The classic clinical presentation for Sjögren syndrome is the combination of dry eyes (keratoconjunctiva sicca) and dry mouth (xerostomia). The criteria for diagnosis of primary Sjögren syndrome include symptoms and objective signs of ocular dryness, symptoms and objective signs of dry mouth, and serologic evidence of a systemic autoimmunity by the presence of RF, ANA, or antibodies to SSA (Ro) or SSB (La). Primary Sjögren syndrome may involve multiple organs other than the eyes and mouth. Secondary Sjögren syndrome occurs when the symptoms and signs of Sjögren syndrome are present with another connective-tissue disease and most frequently with rheumatoid arthritis.

Rheumatoid arthritis

Rheumatoid arthritis is a chronic inflammatory systemic disease primarily characterized by diarthrodial joint involvement. The prevalence of rheumatoid arthritis increases with age and has a peak incidence in persons aged 40-60 years, with a female-to-male ratio of 3:1. A patient has rheumatoid arthritis if he or she satisfies at least 4 of 7 classification criteria. The criteria include morning stiffness for at least 1 hour, arthritis of 3 or more joint areas, arthritis of the hands, symmetric arthritis, rheumatoid nodules, serum RF, and radiographic changes. RF is found in the serum of approximately 85% of patients with rheumatoid arthritis.

Overlap syndrome

An individual patient may satisfy diagnostic criteria for 2 or more connective-tissue diseases. This is referred to as an overlap syndrome. Examples include an overlap of systemic lupus erythematosus and rheumatoid arthritis, mixed connective-tissue disease and polymyositis, and systemic sclerosis and mixed connective-tissue disease.

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Laboratory test screening is helpful to identify markers that may suggest systemic disease, autoimmune disease, or specific organ involvement. Routine screening tests for undifferentiated connective-tissue disease (UCTD) should include CBC count, erythrocyte sedimentation rate (ESR), urinalysis, chemistry panel, RF, ANA, and VDRL. Other studies to consider, if clinically indicated, would be creatine kinase (CK), C3, C4, Jo-1 antibody, anti-SSA antibody, anti-SSB antibody, Smith antibody, RNP, antitopoisomerase antibody, sclerosis (Scl)-70 antibody, and anticardiolipin antibody.

Imaging Studies

• Findings on chest x-ray (CXR) in patients with cardiopulmonary signs and symptoms can be normal or can show evidence of mediastinal lymphadenopathy, interstitial lung disease, pleural effusion, pulmonary infiltrate, pericardial effusion, or cardiac chamber enlargement.
• Computed tomography (CT) scan, especially high-resolution CT scan, can define anatomical intrapulmonary abnormalities more clearly.

Other Tests

• Pulmonary function tests, including total lung volumes and carbon monoxide diffusion capacity, will assist in identifying patients with interstitial lung disease or reactive airway disease.
• Electrocardiogram may be useful in patients with cardiopulmonary signs and symptoms reflecting ST–T-wave abnormalities, axis deviation, or findings consistent with atrial or ventricular enlargement.
• Echocardiogram can best clarify chamber sizes and function, estimate physiologic pressures, and identify and quantitate the size of a pericardial effusion.
• The Schirmer test is useful to screen for dry eyes secondary to decreased tearing in association with primary or secondary Sjögren syndrome. This test also can have an abnormal result in patients taking medications that have anticholinergic side effects.
• Rose Bengal stain of the cornea can detect keratitis associated with Sjögren syndrome.
• Nailfold capillary microscopy may demonstrate dilated tortuous capillary loops and areas of avascularity ("dropout") in patients with secondary Raynaud syndrome associated with an underlying connective-tissue disease, particularly systemic sclerosis, polymyositis/dermatomyositis, and mixed connective-tissue disease.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

A patient with possible undifferentiated connective-tissue disease (UCTD) can be evaluated primarily as an outpatient. A holistic approach to therapy should be offered to the patient once a comprehensive evaluation is completed.

Surgical Care

Surgery for patients with UCTD is not routinely necessary and should be initiated only when indicated for diagnosis or treatment.

Consultations

• Rheumatology consultation
• Patient education consultation
• Other consultations that may be clinically indicated include dermatology, ophthalmology, pulmonary, cardiology, neurology, physical medicine, physical therapy, or occupational therapy.

Diet

No special diet is recommended for patients with UCTD.

Activity

• In general, activities are not restricted unless specific functional limitations associated with UCTD are present (eg, interstitial lung disease).
• Patients with photosensitivity should minimize prolonged exposure to the sunlight and use protective clothing and sun block lotions/creams to protect against ultraviolet light, which may flare UCTD.
• Patients with severe Raynaud syndrome should minimize unnecessary exposure to severe cold to avoid digital vasospasm. Layered clothing, hats, and gloves help to maintain a warm core body temperature and limit extremity symptoms. Tobacco use should be avoided.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Nonsteroidal anti-inflammatory drugs

Nonsteroidal anti-inflammatory drugs (NSAIDs) may be beneficial for analgesia, antipyresis, anti-inflammation, or for antiplatelet reasons. They cause inhibition of the enzyme cyclooxygenase, resulting in a generalized decrease in prostaglandin production and ultimately reducing pain and inflammation. The majority of NSAIDs inhibit the cyclooxygenase-1 (COX1) isoenzyme found in many tissues and can be associated with adverse effects. The cyclooxygenase-2 (COX2) isoenzyme only is produced during inflammatory conditions, resulting in proinflammatory prostaglandins producing pain and swelling. Newer NSAIDs selectively can block the COX2 isoenzyme and minimize adverse effects in high-risk patients. In theory, any NSAID can be prescribed at therapeutic dosages. However, NSAIDs are selected and prescribed best based on patient response and tolerance. Compliance is optimal with once- or twice-a-day preparations.

Corticosteroids

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.

Antimalarials

Antimalarials have been used in the treatment of connective-tissue disease for over 40 years. The drug effect is through the inhibition of polymorphonuclear cell and lymphocyte responses involved in the inflammatory cascade. They are useful in the treatment of milder forms of inflammatory arthritis and cutaneous disease and have potential benefits for serositis and constitutional symptoms.

Immunosuppressant agents

Methotrexate is an analog of folic acid and inhibits dihydrofolate reductase and, ultimately, DNA synthesis. Methotrexate has been very effective in the treatment of inflammatory arthritis in rheumatoid arthritis but also has been used successfully in treating the articular and some systemic manifestations of the spondyloarthropathies, polymyositis/dermatomyositis, systemic lupus erythematosus, and vasculitis.

Azathioprine is a purine analog that interferes with the synthesis of adenosine and guanine. It can be effective for both articular and extra-articular manifestations of connective-tissue disease. It commonly is used in the treatment of rheumatoid arthritis and systemic lupus erythematosus, as well as other connective-tissue diseases.

Calcium channel blockers

Calcium channel blockers, such as nifedipine, relax vascular smooth muscle and decrease peripheral vascular resistance; therefore, they are very effective in the treatment of Raynaud syndrome.

Drug Category: Nonsteroidal anti-inflammatory drugs (NSAIDs)

These agents have analgesic, antiinflammatory, and antipyretic activities. One mechanism of action is the inhibition of cyclooxygenase activity and prostaglandin synthesis. Other mechanisms may exist as well, such as inhibition of leukotriene synthesis, lysosomal enzyme release, lipoxygenase activity, neutrophil aggregation, and various cell-membrane functions.

Drug Category: Antimalarials

These agents may inhibit certain immune reactions.

Drug Category: Immunosuppressant agents

These agents suppress key factors of the immune system.

Drug Category: Calcium channel blockers

These agents decrease peripheral resistance.

Drug Category: Corticosteroids

These agents have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Inpatient care may only be necessary for complex diagnostic or therapeutic reasons.

Further Outpatient Care

• Patients typically are monitored for possible progression of undifferentiated connective-tissue disease (UCTD) organ involvement, evolution to a specific connective-tissue disease, and for safety and efficacy of treatment. The frequency of outpatient visits is dependent on the severity of disease.

In/Out Patient Meds

• Medications will be prescribed, adjusted, and monitored as indicated for symptoms and safe medical therapy.

Transfer

• Transfer of care ultimately will depend on any complications of UCTD that might require subspecialty medical or surgical care.

Deterrence/Prevention

• Deterrence and prevention is directly related to the organ(s) involved. However, appropriate preventive medicine screening and immunizations should be considered annually.

Complications

• The complications of UCTD are related directly to organ involvement, susceptibility to infections, drug intolerance, or drug interactions.

Prognosis

• The overall prognosis for UCTD is better than that of other connective-tissue diseases.
• UCTD may remit permanently, progress to an established connective-tissue disease, or remain a stable chronic disease with a wide manifestation of symptoms that involve many organ systems.
• In 2004, Mosca et al best summarized the literature regarding the rate of evolution of UCTD to differentiated connective-tissue disease and the factors predictive of this evolution. A comparison of various studies suggested that patients with UCTD monitored in a primary clinical setting appear to have a better prognosis than those followed at a tertiary care center.
• In general, less than 40 percent of patients with UCTD develop systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, mixed connective-tissue disease, Sjögren syndrome, or polymyositis/dermatomyositis over a 2- to 5-year period. Organ involvement and disease-specific autoantibodies were most predictive of UCTD evolving to a differentiated connective-tissue disease. Therefore, most patients with UCTD still have the same diagnosis after 10 years of clinical monitoring.
• A positive ANA is common, ranging from 60-100%, and has a stable profile over time. The incidence of isolated disease-specific autoantibodies is low. As detailed in Table 1, certain serologies and presenting symptom complexes are associated with higher rates of evolution to a definite connective-tissue disease. The extent of organ involvement primarily influences the prognosis in patients with UCTD.

Patient Education

• Patients with UCTD, as well as their immediate family members, should be educated about the prognosis of UCTD and the likely possibility of the disease evolving into systemic lupus erythematosus, systemic sclerosis, or mixed connective-tissue disease. Furthermore, education should concentrate on symptomatic treatment, an acceptable understanding of treatment medications, and the indications for contacting the primary care physician or rheumatologist.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to refer a undifferentiated connective-tissue disease (UCTD) patient to a rheumatologist for diagnosis or treatment if unresponsive to initial therapy
• Failure to monitor or recognize the complications of UCTD

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Alarcon GS. Unclassified or undifferentiated connective tissue disease. Baillieres Best Pract Res Clin Rheumatol. Mar 2000;14(1):125-37. [Medline].
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• Arnett FC, Edworthy SM, Bloch DA, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. Mar 1988;31(3):315-24. [Medline].
• Bodolay E, Csiki Z, Szekanecz Z, et al. Five-year follow-up of 665 Hungarian patients with undifferentiated connective tissue disease (UCTD). Clin Exp Rheumatol. May-Jun 2003;21(3):313-20. [Medline].
• Bohan A, Peter JB. Polymyositis and dermatomyositis (first of two parts). N Engl J Med. Feb 13 1975;292(7):344-7. [Medline].
• Calvo-Alen J, Alarcon GS, Burgard SL, et al. Systemic lupus erythematosus: predictors of its occurrence among a cohort of patients with early undifferentiated connective tissue disease: multivariate analyses and identification of risk factors. J Rheumatol. Mar 1996;23(3):469-75. [Medline].
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• Clegg DO, Williams HJ, Singer JZ, et al. Early undifferentiated connective tissue disease. II. The frequency of circulating antinuclear antibodies in patients with early rheumatic diseases. J Rheumatol. Sep 1991;18(9):1340-3. [Medline].
• Danieli MG, Fraticelli P, Franceschini F, et al. Five-year follow-up of 165 Italian patients with undifferentiated connective tissue diseases. Clin Exp Rheumatol. Sep-Oct 1999;17(5):585-91. [Medline].
• Fox RI, Saito I. Criteria for diagnosis of Sjogren''s syndrome. Rheum Dis Clin North Am. May 1994;20(2):391-407. [Medline].
• Horvath L, Czirjak L, Fekete B, et al. Levels of antibodies against C1q and 60 kDa family of heat shock proteins in the sera of patients with various autoimmune diseases. Immunol Lett. Jan 1 2001;75(2):103-9. [Medline].
• LeRoy EC, Maricq HR, Kahaleh MB. Undifferentiated connective tissue syndromes. Arthritis Rheum. Mar 1980;23(3):341-3. [Medline].
• Mosca M, Baldini C, Bombardieri S. Undifferentiated connective tissue diseases in 2004. Clin Exp Rheumatol. Jan-Feb 2004;17(5):22(3 Suppl 33). [Medline].
• Spain TA, Sun R, Gradzka M, et al. The transcriptional activator Sp1, a novel autoantigen. Arthritis Rheum. Jun 1997;40(6):1085-95. [Medline].
• Tan EM, Cohen AS, Fries JF, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. Nov 1982;25(11):1271-7. [Medline].
• Williams HJ, Alarcon GS, Joks R, et al. Early undifferentiated connective tissue disease (CTD). VI. An inception cohort after 10 years: disease remissions and changes in diagnoses in well established and undifferentiated CTD. J Rheumatol. Apr 1999;26(4):816-25. [Medline].
• Wise CM, Vuyyuru S, Roberts WN. Methotrexate in nonrenal lupus and undifferentiated connective tissue disease--a review of 36 patients. J Rheumatol. June 1996;23(6):1005-10.

Article Last Updated: Apr 25, 2006