eMedicine Specialties > Rheumatology > Systemic Rheumatic Disease
Mixed Connective-Tissue Disease: Treatment & Medication
Updated: Aug 7, 2008
- Overview
- Differential Diagnoses & Workup
- Treatment & Medication
- Follow-up
Treatment
Medical Care
The overall goal of therapy is to control symptoms and to maintain function. Target medical therapy to specific organ involvement and extent of disease activity. Monitoring for development of complications, such as pulmonary hypertension or infection, is important.
Consultations
- Whenever possible, a rheumatologist experienced in diagnosis and treatment of the disease should co-manage all patients with mixed connective-tissue disease (MCTD).
- Consultation with other specialists or subspecialists may be indicated for the evaluation and/or treatment of specific aspects of disease, such as pulmonary hypertension.
Diet
- Patients with hypertension, esophageal reflux, malabsorption, or other sclerodermatous-type bowel involvement may need special consideration.
- Because atherosclerotic heart disease remains a major risk in all patients, advocate a heart-healthy diet. However, no specific dietary manipulations have been demonstrated to be effective in treating MCTD.
Activity
Convincing data support the value of an active lifestyle and an exercise program tailored to the needs of patients with arthritis of various types. This approach also appears to be appropriate in MCTD.
Medication
The goals of pharmacotherapy are to reduce morbidity and to prevent complications.
Nonsteroidal anti-inflammatory drugs (NSAIDs)
These agents reduce pain and inflammation and allow for improvement in mobility and function. Mild mixed connective-tissue disease (MCTD) may be controlled with NSAIDs. Arthritis/arthralgia can often be controlled with NSAIDs and hydroxychloroquine. Low-dose oral corticosteroids or low-dose methotrexate is reserved for more refractory synovitis.
Naproxen (Naprosyn, Naprelan, Aleve, Anaprox)
Used to treat musculoskeletal manifestation of MCTD, including arthralgia and arthritis. Inhibits inflammatory reactions and pain by decreasing enzyme COX activity, which results in prostaglandin synthesis.
Adult
250-500 mg PO bid
Pediatric
5 mg/kg PO bid
Coadministration with aspirin increases risk of inducing serious NSAID-related adverse effects; 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 PT when taking anticoagulants (instruct patients to watch for signs of bleeding); may increase risk of methotrexate toxicity; phenytoin levels may be increased when administered concurrently
Documented hypersensitivity; peptic ulcer disease; bleeding disorder; anticoagulation; renal dysfunction; hepatic dysfunction
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
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; caution in esophageal dysmotility
Cyclooxygenase-2 (COX-2) inhibitors
Although increased cost can be a negative factor, COX-2 inhibitors may be more effective in reducing the incidence of costly and potentially fatal GI bleeding than traditional NSAIDs. COX-2 inhibitors and many traditional NSAIDs may increase the risk of atherosclerotic cardiovascular endpoints.
Celecoxib (Celebrex)
Used to treat musculoskeletal manifestations of MCTD, including arthralgia and arthritis. Inhibits primarily COX-2, which is considered an inducible isoenzyme (ie, induced during pain and inflammatory stimuli).
Inhibition of COX-1 may contribute to NSAID GI toxicity. At therapeutic concentrations, COX-1 isoenzyme is not inhibited; thus, GI toxicity may be decreased. Seek lowest dose of celecoxib for each patient.
Adult
200 mg PO qd or up to 200 mg PO bid
Pediatric
Not established
Coadministration with fluconazole may cause increase in celecoxib plasma concentrations because of inhibition of celecoxib metabolism; coadministration with rifampin may decrease celecoxib plasma concentrations
Documented hypersensitivity; active peptic ulcer disease; bleeding disorders; renal or hepatic dysfunction
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
May cause fluid retention and peripheral edema; caution in compromised cardiac function, hypertension, conditions predisposing to fluid retention; caution in severe heart failure and hyponatremia because may deteriorate circulatory hemodynamics; NSAIDs may mask usual signs of infection; caution in the presence of existing controlled infections; evaluate therapy when symptoms or laboratory results suggest liver dysfunction
Proton pump inhibitors
Esophageal reflux symptoms can be controlled effectively with these agents.
Omeprazole (Prilosec)
Inhibits gastric acid secretion by inhibition of the H+/K+ -ATPase enzyme system in gastric parietal cells. May be effective to treat reflux symptoms in MCTD.
Adult
20 mg PO qd
Pediatric
Not established
May decrease effects of itraconazole and ketoconazole; may increase toxicity of warfarin, digoxin, disulfiram, benzodiazepines, and phenytoin
Documented hypersensitivity
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
Bioavailability may increase in elderly patients; caution in pregnancy
Antimalarial agents
Mild MCTD can often be controlled with hydroxychloroquine. Hydroxychloroquine may also help prevent disease flares.
Hydroxychloroquine (Plaquenil)
Inhibits chemotaxis of eosinophils, 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.
Adult
200-400 mg PO qd
Pediatric
5 mg/kg PO qd
Serum levels increase with cimetidine; magnesium trisilicate may decrease absorption
Documented hypersensitivity; psoriasis; retinal and visual-field changes attributable to 4-aminoquinolones
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; perform periodic (6 mo) ophthalmologic examinations; test periodically for muscle weakness
Corticosteroids
These agents are reserved for more active or severe disease. They are used in moderate-to-high doses for major organ involvement. They are often used in combination with other drugs.
Prednisone (Deltasone, Orasone, Meticorten)
Used for its anti-inflammatory and immunomodulatory effects.
May decrease inflammation by reversing increased capillary permeability and suppressing PMN activity.
Adult
10-20 mg/d PO qam
30-60 mg/d PO/IV in divided doses for more severe disease activity
Pediatric
Mild disease: 0.2-0.5 mg/kg PO
More severe disease: 1-2 mg/kg PO/IV
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
Documented hypersensitivity; viral infection; peptic ulcer disease; hepatic dysfunction; connective tissue infections; fungal or tubercular skin infections; GI disease
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur with glucocorticoid use; high doses may result in growth retardation of fetus; cleft palate observed in animals
Calcium channel blocking agents
Avoiding exposure to cold temperatures and using long-acting calcium channel blocking agents may control Raynaud phenomenon. Calcium channel blocking agents are used for vasodilation and possible antiplatelet effects.
Nifedipine (Adalat, Procardia XL)
Used to treat Raynaud phenomenon in MCTD. Causes vasodilation in extremities.
Adult
30-90 mg (XL) PO qd
Pediatric
Not established
Caution with coadministration of any agent that can lower BP, including beta-blockers and opioids; H2 blockers (cimetidine) may increase toxicity; PT time in patients on warfarin may be prolonged
Documented hypersensitivity; systemic hypotension; possibly esophageal reflux
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
Teratogenic in rats and rabbits; monitor BP; may cause lower extremity edema; allergic hepatitis has occurred but is rare; may cause orthostatic symptoms, dizziness, or headache
Phosphodiesterase (type 5) Enzyme Inhibitor
Phosphodiesterase inhibitors can ameliorate symptoms of pulmonary hypertension and Raynaud phenomenon in patients with MCTD. These agents may not be as durable as other drug classes in improving pulmonary hypertension, but the adverse-effect profile of phosphodiesterase inhibitors is often more favorable than prostaglandin or anti-endothelin therapies.Sildenafil
Promotes selective smooth-muscle relaxation in lung vasculature, possibly by inhibiting phosphodiesterase type 5 (PDE-5). This reduces blood pressure in pulmonary arteries and increase in cardiac output.
Adult
20 mg PO tid
Pediatric
Not established
Potentiates vasodilatory effect of NO, resulting in potentially fatal drop in blood pressure; coadministration with ketoconazole, erythromycin, or cimetidine increases plasma sildenafil concentrations; coadministration with rifampin decreases plasma levels of sildenafil; coadministration with bosentan increases bosentan levels by 50% and reduces sildenafil levels by 63%
Documented hypersensitivity; concurrent or intermittent using of organic nitrates in any form
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Adverse effects include headaches (16%), flushing (10%), upset stomach (7%), nasal congestion (4%), and a blue haze at the periphery of vision (3%); adverse effects are more common in men taking the 100-mg dose; serious adverse effects occur in patients with severe heart disease and those who are taking nitrates; rates of MI were 1.7 and 1.4 per 100 man-years for sildenafil and placebo groups; sudden vision loss caused by nonarteritic anterior ischemic optic neuropathy (NAION) has been associated with PDE-5 inhibitors following use for ED (analysis is ongoing to determine causality); sudden decreases or loss of hearing has been reported
Endothelin Receptor Antagonist
These agents may be helpful for managing pulmonary hypertension in patients with MCTD. The risk of liver toxicity with endothelin receptor antagonists dictates that these drugs must be prescribed by experts.
Ambrisentan
Endothelin receptor antagonist indicated for pulmonary arterial hypertension in patients with WHO class II or III symptoms. Improves exercise ability and decreases progression of clinical symptoms. Inhibits vessel constriction and elevation of blood pressure by competitively binding to endothelin-1 receptors ETA and ETB in endothelium and vascular smooth muscle. This leads to significant increase in cardiac index associated with significant reduction in pulmonary artery pressure, pulmonary vascular resistance, and mean right atrial pressure. Because of the risks of hepatic injury and teratogenic potential, only available through the Letairis Education and Access Program (LEAP). Prescribers and pharmacies must register with LEAP in order to prescribe and dispense. For more information, see http://www.letairis.com or call (866) 664-LEAP (5327).
Adult
5 mg PO qd initially; may increase to 10 mg PO qd if 5 mg/d tolerated; do not chew, crush, or split tab
Pediatric
Not established
Glycoprotein-P, OATP, UGTs (ie, 1A9S, 2B7S, 1A3S), CYP2C19, and CYP3A substrate; coadministration with CYP3A (eg, cyclosporine, atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin) or 2C19 inhibitors (eg, omeprazole) may decrease elimination and therefore increase serum levels; CYP3A and 2C19 inducers (eg, rifampin) may increase metabolism and therefore decrease serum levels
Pregnancy
Pregnancy
X - Contraindicated; benefit does not outweigh risk
Precautions
Common adverse effects include peripheral edema, nasal congestion, sinusitis, and facial flushing; caution with mild hepatic impairment or history of moderate-to-severe hepatic impairment; hepatic injury may occur (monitor bilirubin, ALT, and AST values at baseline and then monthly); may use in women of childbearing potential only after negative pregnancy test result and must use 2 reliable methods of contraception (unless tubal sterilization or Copper T 380A or LNg 20 IUD inserted); may decrease hemoglobin and hematocrit values (monitor at baseline, 1 mo, and then periodically)
Prostaglandins
These agents may be useful for managing pulmonary hypertension in patients with MCTD, although dose titration and administration should be managed by an expert in this drug.
Epoprostenol (Flolan)
Strong vasodilator of all vascular beds. May decrease thrombogenesis and platelet clumping in the lungs by inhibiting platelet aggregation.
Adult
2 ng/kg continuous IV infusion, increase dose gradually over time
Pediatric
Not established
Coadministration with anticoagulants may increase bleeding risk due to shared effects on platelet aggregation
Documented hypersensitivity; hyaline membrane disease; presence of dominant left-to-right shunt; respiratory distress syndrome
Pregnancy
X - Contraindicated; benefit does not outweigh risk
Precautions
Coadminister with anticoagulants whenever possible to reduce risk of thromboembolism; sudden discontinuation or reduction in therapy may result in rebound pulmonary hypertension; only to be used by physicians with expertise in the diagnosis and treatment of pulmonary hypertension
Cytotoxic agents
Major organ involvement may require moderate-to-high divided daily doses of corticosteroids and cytotoxic agents (eg, PO or pulse IV cyclophosphamide). Recent reports suggest that, in contrast to primary or scleroderma-associated pulmonary hypertension, a subset of MCTD patients with pulmonary hypertension may respond well to aggressive immunosuppression with cytotoxic agents.
Cyclophosphamide (Cytoxan)
Chemically related to nitrogen mustards. As an alkylating agent, the mechanism of action of the active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells.
Administered as monthly IV infusion or, less commonly, as daily PO medication for severe MCTD.
Adult
IV pulses of 750-1500 mg qmo
50-150 mg PO qd
Pediatric
Not established
Allopurinol may increase risk of bleeding or infection and enhance myelosuppressive effects; may potentiate doxorubicin-induced cardiotoxicity; may reduce digoxin serum levels and antimicrobial effects of quinolones; chloramphenicol may increase half-life of cyclophosphamide while decreasing metabolite concentrations; may increase effect of anticoagulants; coadministration with high doses of phenobarbital may increase rate of metabolism and leukopenic activity; thiazide diuretics may prolong cyclophosphamide-induced leukopenia and neuromuscular blockade by inhibiting cholinesterase activity; mesna chemically interacts with the metabolites of the drug in the bladder and decreases the incidence of bladder toxicity; can prolong the activity of succinylcholine
Documented hypersensitivity; severely depressed bone marrow function
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Regularly examine hematologic profile (particularly neutrophils and platelets) to monitor for hematopoietic suppression; regularly examine urine for RBCs, which may precede hemorrhagic cystitis; administer following established protocols (eg, National Institutes of Health)
More on Mixed Connective-Tissue Disease |
| Overview: Mixed Connective-Tissue Disease |
| Differential Diagnoses & Workup: Mixed Connective-Tissue Disease |
 Treatment & Medication: Mixed Connective-Tissue Disease |
| Follow-up: Mixed Connective-Tissue Disease |
| References |
| « Previous Page | Next Page » |
References
Sharp GC, Irvin WS, Tan EM, et al. Mixed connective tissue disease--an apparently distinct rheumatic disease syndrome associated with a specific antibody to an extractable nuclear antigen (ENA). Am J Med. Feb 1972;52(2):148-59. [Medline].
Hoffman RW, Rettenmaier LJ, Takeda Y, et al. Human autoantibodies against the 70-kd polypeptide of U1 small nuclear RNP are associated with HLA-DR4 among connective tissue disease patients. Arthritis Rheum. May 1990;33(5):666-73. [Medline].
Burdt MA, Hoffman RW, Deutscher SL, et al. Long-term outcome in mixed connective tissue disease: longitudinal clinical and serologic findings. Arthritis Rheum. May 1999;42(5):899-909. [Medline].
Jais X, Launay D, Yaici A, et al. Immunosuppressive therapy in lupus- and mixed connective tissue disease-associated pulmonary arterial hypertension: a retrospective analysis of twenty-three cases. Arthritis Rheum. Feb 2008;58(2):521-31. [Medline].
Alarcon-Segovia D, Villareal M. Classification and diagnostic criteria for mixed connective tissue disease. In: Kasukawa R, Sharp GC, eds. Mixed Connective Tissue Disease and Anti-Nuclear Antibodies. Amsterdam: Excerpta Medica; 1987:33-40.
Greidinger EL, Zang Y, Jaimes K, et al. A murine model of mixed connective tissue disease induced with U1 small nuclear RNP autoantigen. Arthritis Rheum. Feb 2006;54(2):661-9. [Medline].
Hoffman RW. Undifferentiated and mixed connective tissue disease. In: Wallace D, Hahn B, eds. Dubois Systemic Lupus Erythematosus. Lippincott, P: In press.
Hoffman RW. Mixed connective tissue disease, overlap syndromes and Sjogren's syndrome. In: Lahita RG, ed. Systemic Lupus Erythematosus. 4th ed. San Diego, Calif: Academic Press; 2004.
Hoffman RW. T cells in the pathogenesis of systemic lupus erythematosus. Clin Immunol. Oct 2004;113(1):4-13. [Medline].
Hoffman RW, Cassidy JT, Takeda Y, et al. U1-70-kd autoantibody-positive mixed connective tissue disease in children. A longitudinal clinical and serologic analysis. Arthritis Rheum. Nov 1993;36(11):1599-602. [Medline].
Hoffman RW, Greidinger EL. Mixed connective tissue disease. Curr Opin Rheumatol. Sep 2000;12(5):386-90. [Medline].
Maldonado ME, Perez M, Pignac-Kobinger J, et al. Clinical and immunologic manifestations of mixed connective tissue disease in a Miami population compared to a Midwestern US Caucasian population. J Rheumatol. Mar 2008;35(3):429-37. [Medline].
Perkins K, Hoffman RW, Bezruczko N. A Rasch analysis for classification of systemic lupus erythematosus and mixed connective tissue disease. J Appl Meas. 2008;9(2):136-50. [Medline].
Smolen JS, Steiner G. Mixed connective tissue disease: to be or not to be?. Arthritis Rheum. May 1998;41(5):768-77. [Medline].
Further Reading
Keywords
mixed connective-tissue disease, MCTD, arthritis, arthralgia, esophageal reflux, secondary pulmonary hypertension, Raynaud phenomenon, systemic lupus erythematosus, SLE, scleroderma, myositis, anti–U1-ribonucleoprotein, anti–U1-RNP, acrosclerosis, esophageal dysmotility, myositis, rheumatic disease, antibodies against U1-70 kd, small nuclear ribonucleoprotein, snRNP
