eMedicine Specialties > Rheumatology > Systemic Rheumatic Disease

Undifferentiated Connective-Tissue Disease

Bernard A Hildebrand Jr, MD, Staff Rheumatologist, Department of Rheumatology, San Antonio Military Medical Center, San Antonio, Texas
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.

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.

^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 al^{[10 ]}and Doria et al^{[18 ]}

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 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.^{[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 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.

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 Hungary^{[15 ]}.

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 UCTD^{[10 ]}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

Differential Diagnoses

Other Problems to Be Considered

Undifferentiated connective-tissue disease (UCTD) is a diagnosis of exclusion. Therefore, a diagnosis of UCTD should not be applied until an appropriate exhaustive workup has been pursued based on the patient's signs and symptoms. Definite CTDs should be considered in the evaluation of any patient who presents with features of UCTD. Despite the overlapping features of specific CTDs, early differentiation is necessary for initiation of appropriate therapy, monitoring, and prognosis determination.^{[35 ]}Heinlen et al (2007) report that 80% of patients with SLE have at least one defined clinical criterion 4-5 months prior to the diagnosis being established.^{[36 ]}

A thorough history and physical examination can identify many signs and symptoms that may differentiate the diagnosis, and appropriate laboratory studies and testing may also help delineate a specific diagnosis. Data suggest that particular signs and symptoms may predict the evolution of UCTD to specific defined CTDs, as shown in Table 2.^{[10,11,15,34,35,37 ]}

Table 2. Predictors of Progression to Definite Connective-Tissue Disease

Workup

Laboratory Studies

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)

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
• 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.^{[38 ]}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.^{[39 ]}

Imaging Studies

• Chest radiography findings may be normal or may show signs of pleural effusion, pericardial effusion, enlarged cardiac silhouette, longstanding pulmonary hypertension, or interstitial lung disease. Kinder et al (2007) suggested that idiopathic nonspecific interstitial pneumonia is an autoimmune pneumonitis and a lung manifestation of UCTD.^{[27 ]}
• CT scanning of the chest, particularly high-resolution CT scanning, may better characterize pulmonary disease associated with CTD.

Other Tests

• 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.^{[40 ]}

Treatment

Medical Care

A patient with undifferentiated connective-tissue disease (UCTD) can be evaluated and treated primarily as an outpatient.

Surgical Care

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

Consultations

• A rheumatologist should be consulted.
• 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.

Diet

No special diet is recommended for patients with UCTD.

Activity

• 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.

Medication

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.^{[17 ]}

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.

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

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).

Naproxen (Naprosyn)

For relief of mild-to-moderate pain. Inhibits inflammatory reactions and pain by decreasing activity of cyclooxygenase, which is responsible for prostaglandin synthesis.

Dosing

Adult

250-500 mg PO bid

Pediatric

<2 years: Not established
>2 years: 2.5 mg/kg/dose PO; not to exceed 10 mg/kg/d

Interactions

Reports suggest that NSAIDs may diminish the antihypertensive effect of angiotensin-converting enzyme (ACE) inhibitors; concomitant administration of aspirin increases the risk of GI complication; may interfere with beneficial antiplatelet effect of aspirin; probenecid may increase concentrations and, possibly, toxicity of NSAIDs; may decrease effect of hydralazine, captopril, and beta-blockers; may decrease diuretic effects of furosemide and thiazides; may increase the bleeding risk in patients taking other anticoagulants; monitor the prothrombin (PT) closely (instruct patients to watch for signs of bleeding); may increase risk of methotrexate toxicity; phenytoin levels may be increased when administered concurrently

Contraindications

Documented hypersensitivity; peptic ulcer disease; recent GI bleeding or perforation; renal insufficiency

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Some studies suggest there is an increased risk of myocardial infarction or stroke in patients taking certain NSAIDs; acute renal insufficiency, interstitial nephritis, hyperkalemia, hyponatremia, and renal papillary necrosis may occur; patients with preexisting renal disease or compromised renal perfusion risk acute renal failure; leukopenia occurs rarely, is transient, and usually returns to normal during therapy; persistent leukopenia, granulocytopenia, or thrombocytopenia warrants further evaluation and may require discontinuation of drug

Nonsteroidal Anti-Inflammatory Drug (NSAID), Cox-2 Selective

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).

Celecoxib (Celebrex)

Selectively inhibits cyclooxygenase-2 and reduces prostaglandin synthesis

Dosing

Adult

100-200 mg PO bid

Pediatric

Not established

Interactions

Reports suggest that NSAIDs may diminish antihypertensive effect of angiotensin-converting enzyme (ACE) inhibitors; concomitant administration of aspirin increases rate of GI ulceration or other complications; concomitant administration of fluconazole at 200 mg daily resulted in 2-fold increase in celecoxib plasma concentration; NSAIDs can reduce natriuretic effects of furosemide and thiazides in some patients; lithium plasma levels increase approximately 17% when administered concomitantly; celecoxib does not alter anticoagulant effects of warfarin as determined by prothrombin time

Contraindications

Documented hypersensitivity to celecoxib or sulfonamides; preoperative pain prior to coronary artery bypass surgery

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Studies suggest high doses of celecoxib are associated with increased cardiovascular risk; elderly patients may require lower doses; caution in hepatic and renal impairment

Antimalarials

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.

Hydroxychloroquine (Plaquenil)

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.

Dosing

Adult

200 mg PO bid for several weeks depending on response
Prolonged maintenance therapy: 200-400 mg PO qd (not to exceed 6.5 mg/kg/d)

Pediatric

5 mg base/kg/d PO qd or divided bid; not to exceed 7 mg/kg/d

Interactions

Serum levels increase with cimetidine; magnesium trisilicate may decrease absorption

Contraindications

Documented hypersensitivity; retinal and visual field changes attributable to 4-aminoquinolones

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in hepatic disease, G-6-PD deficiency, psoriasis, and porphyria; not recommended for long term in children; perform periodic (6 mo) ophthalmologic examinations; test periodically for muscle weakness

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.

These drugs are commonly used in combination with other medications to control the signs and symptoms of inflammation.

Prednisone (Deltasone, Orasone, Meticorten)

Immunosuppressant for treatment of autoimmune disorders. May decrease inflammation by reversing increased capillary permeability and suppressing PMN activity.

Dosing

Adult

5 mg PO qd, titrate up to 1 mg/kg/d PO in divided doses

Pediatric

Administer as in adults

Interactions

Coadministration with estrogens may decrease prednisone clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics

Contraindications

Documented hypersensitivity; viral infection; peptic ulcer disease; hepatic dysfunction; connective-tissue infections; fungal or tubercular skin infections; GI disease

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, cognitive impairment, myasthenia gravis, growth suppression, and infections may occur with glucocorticoid use, particularly at high doses (>20 mg/d); patients on glucocorticoids for extended periods should be evaluated for osteoporosis and treated according to published guidelines

Immunosuppressant agents

These agents suppress key factors of the immune system and are typically reserved for severe manifestations of UCTD.

Methotrexate (Rheumatrex, Folex PFS)

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).
Available as 2.5-mg tab or 25-mg/mL vial.

Dosing

Adult

7.5-25 mg PO/IM/SC weekly

Pediatric

Administer as in adults

Interactions

Oral aminoglycosides may decrease absorption and blood levels of concurrent oral methotrexate (MTX); charcoal lowers MTX levels; coadministration with etretinate may increase hepatotoxicity of MTX; folic acid 1 mg/d or its derivatives contained in some vitamins may decrease response to MTX; coadministration with NSAIDs may be fatal; indomethacin and phenylbutazone can increase MTX plasma levels; may decrease phenytoin serum levels; probenecid, salicylates, procarbazine, and sulfonamides, including TMP-SMZ, may increase effects and toxicity of MTX; may increase plasma levels of thiopurines

Contraindications

Documented hypersensitivity; alcoholism; hepatic insufficiency; documented immunodeficiency syndromes; preexisting blood dyscrasias (eg, bone marrow hypoplasia, leukopenia, thrombocytopenia, significant anemia)

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Monitor CBC count monthly and liver and renal function q1-3mo during therapy (monitor more frequently during initial dosing, dose adjustments, or when risk of elevated MTX levels, eg, dehydration); follow published guidelines for performing liver biopsy; MTX has toxic effects on hematologic, renal, GI, pulmonary, and neurologic systems; discontinue if significant drop in blood counts occurs; aspirin, NSAIDs, or low-dose steroids may be administered concomitantly with MTX

Azathioprine (Imuran)

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.

Dosing

Adult

1-2.5 mg/kg/d PO

Pediatric

Up to 1 mg/kg/d PO

Interactions

Toxicity increases with coadministration of allopurinol (allopurinol reduces the metabolism of azathioprine; reduce azathioprine dose by 75%); concurrent use with ACE inhibitors may induce severe leukopenia; may increase levels of methotrexate metabolites and decrease effects of anticoagulants, neuromuscular blockers, and cyclosporine

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Prior treatment with alkylating agents may increase risk of neoplasia; caution with liver disease and renal impairment; hematologic toxicities may occur

Calcium channel blockers

These agents relax vascular smooth muscle and decrease peripheral vascular resistance. They may help control the signs and symptoms of Raynaud phenomenon.

Nifedipine (Procardia, Procardia XL, Adalat CC)

During depolarization, inhibits calcium ions from entering the slow channels and voltage-sensitive areas of vascular smooth muscle.

Dosing

Adult

10-30 mg PO tid
Alternatively, 30-90 mg PO qd (ER form)

Pediatric

Not established

Interactions

Caution with coadministration of any agent that can lower BP, including beta-blockers and opioids; H2 blockers (cimetidine) may increase toxicity

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

May cause lower extremity edema; allergic hepatitis has occurred but is rare; excessive hypotension, peripheral edema, or significant left ventricular dysfunction

Diltiazem (Cardizem, Cardizem SR)

During depolarization, inhibits calcium ions from entering the slow channels and voltage-sensitive areas of vascular smooth muscle.

Dosing

Adult

30 mg PO qid
Alternatively, 60-120 mg PO qd (SR dosage)

Pediatric

Not established

Interactions

May increase carbamazepine, digoxin, cyclosporine, and theophylline levels; when administered with amiodarone, may cause bradycardia and a decrease in cardiac output; when administered with beta-blockers, may increase cardiac depression; cimetidine may increase diltiazem levels

Contraindications

Documented hypersensitivity; severe CHF; sick sinus syndrome; second- or third-degree AV block; hypotension (<90 mm Hg systolic)

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in impaired renal or hepatic function; may increase LFT levels, and hepatic injury may occur; cardiac conduction abnormalities

Follow-up

Further Inpatient Care

• Inpatient care in patients with undifferentiated connective-tissue disease (UCTD) may be necessary only for complex/urgent diagnostic evaluations or therapeutic reasons.

Further Outpatient Care

• Patients with 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 more frequent given the propensity for UCTD to evolve early in the disease course.

Inpatient & Outpatient Medications

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

Transfer

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

Deterrence/Prevention

• Deterrence and prevention of UCTD is directly related to the organ or organs involved. However, appropriate preventive medicine screening and immunizations should be considered annually.

Complications

• The complications of UCTD are related directly to specific organ involvement, susceptibility to infections, drug intolerance/reactions, and drug interactions.

Prognosis

• 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.^{[17 ]}
• Approximately 10%-20% of patients with UCTD have symptoms that subside or remit and never evolve into a defined CTD.^{[22 ]}The incidence of evolution to a defined CTD is highest during the first 3-5 years of the disease course,^{[23 ]}and the rate of evolution continues to decrease over time.^{[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 better prognosis.^{[15,24 ]}
• Survival rates in UCTD are similar to those associated with RA and SLE.^{[32 ]}

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, SSc, MCTD).
• Furthermore, education should focus on symptomatic treatment, an appropriate understanding of treatment medications, and the indications for contacting the primary care physician or rheumatologist.

Miscellaneous

Medicolegal Pitfalls

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

Special Concerns

Pregnancy

Pregnant patients with newly diagnosed UCTD are at increased risk of impaired intrauterine growth, prematurity, and delivery of infants small for gestational age. The high prevalence of anti-Ro (SSA) antibodies in patients with UCTD suggests an increased potential for neonatal lupus syndrome and congenital cardiac conduction abnormalities.^{[41 ]}

References

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Keywords

undifferentiated connective-tissue disease, UCTD, undifferentiated connective-tissue syndromes, UCTS, early connective-tissue disease, rheumatoid arthritis, RA, systemic lupus erythematosus, SLE, systemic sclerosis, SSc, polymyositis, PM, dermatomyositis, DM, mixed connective-tissue disease, MCTD, Sjögren's syndrome, Sjögren syndrome, SS

Contributor Information and Disclosures

Author

Bernard A Hildebrand Jr, MD, Staff Rheumatologist, Department of Rheumatology, San Antonio Military Medical Center, San Antonio, Texas
Bernard A Hildebrand Jr, MD is a member of the following medical societies: American College of Physicians and American College of Rheumatology
Disclosure: Nothing to disclose.

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.
Daniel F Battafarano, DO, FACP, FACR is a member of the following medical societies: American College of Physicians, American College of Rheumatology, and Association of Military Surgeons of the US
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Elliot Goldberg, MD, Dean of the Western Pennsylvania Clinical Campus, Professor, Department of Medicine, Temple University School of Medicine
Elliot Goldberg, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, and American College of Rheumatology
Disclosure: Nothing to disclose.

CME Editor

Alex J Mechaber, MD, FACP, Associate Dean for Undergraduate Medical Education, Associate Professor of Medicine, University of Miami Miller School of Medicine
Alex J Mechaber, MD, FACP is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians-American Society of Internal Medicine, and Society of General Internal Medicine
Disclosure: Nothing to disclose.

Chief Editor

Herbert S Diamond, MD, Professor of Medicine, Temple University School of Medicine; Chairman Emeritus, Department of Internal Medicine, Western Pennsylvania Hospital
Herbert S Diamond, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American College of Rheumatology, American Medical Association, and Phi Beta Kappa
Disclosure: medifocus Honoraria Review panel membership; health dialogs Honoraria Consulting; West Penn Allegheny Health System None Board membership

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