Medication Summary
Therapeutic options in mixed connective-tissue disease (MCTD) include the following:
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Arthritis/arthralgia can often be controlled with prostaglandin inhibitors (nonsteroidal anti-inflammatory drugs (NSAIDs) or omega-3 fatty acids); antimalarials (hydroxychloroquine); and, if needed, infrequent oral or intra-articular corticosteroid courses, typically at low dose.
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Disease-modifying antirheumatic drug (DMARD) therapy is reserved for more refractory synovitis, particularly if showing features of erosive/deforming risk.
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Proton pump inhibitors can control esophageal reflux symptoms.
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In patients with Raynaud phenomenon, calcium channel blocking agents are used.
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Phosphodiesterase inhibitors, endothelin receptor antagonists, or prostaglandins can be used for pulmonary hypertension.
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In some cases, pulmonary hypertension in MCTD may also respond to aggressive immunosuppression, similar to that used in interstitial lung disease therapy. [38]
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MCTD-related interstitial lung disease is conventionally treated with corticosteroids, in combination with steroid-sparing agents such as cyclophosphamide, azathioprine, or mycophenolate. [39] The INBUILD trial, which included patients with MCTD, reported that treatment with the antifibrotic tyrosine kinase inhibitor nintedanib can significantly slow the annual rate of decline in forced vital capacity (FVC) in patients with progressive fibrosing interstitial lung diseases. [40]
Nonsteroidal anti-inflammatory drugs (NSAIDs)
Class Summary
These agents reduce pain and inflammation and allow for improvement in mobility and function. Side effects of this class include GI toxicity, risk of elevated blood pressure, and other renal effects. NSAIDs may be assocaited with increased risk of aseptic meningitis in MCTD.
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.
Cyclooxygenase-2 (COX-2) inhibitors
Class Summary
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.
Omega-3 fatty acids
Class Summary
When used at high dose, omega-3 fatty acids have been reported to inhibit the production of pro-inflammatory prostaglandins. Arthritis Foundation guidelines are to use 1200-1800 mg of omega-3's per day; dosing typically needs to continue for at least two weeks before a benefit of therapy is noted. Omega-3's may thus have similar benefits to the long-term use of NSAIDs, with less risk of worsening of hypertension and less risk of GI or kidney toxicity. However, omega-3's at this dose have platelet inhibitory effects that can increase bleeding risk in susceptible patients.
Proton pump inhibitors
Class Summary
Esophageal reflux symptoms can be controlled effectively with these agents. Patients requiring long term PPIs should be co-managed with a gastroenterologist.
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. As in scleroderma, high dose PPI therapy may be needed. Other Proton Pump Inhibitors are used with similar clinical efficacy.
Antimalarial agents
Class Summary
Mild MCTD can often be controlled with hydroxychloroquine. Hydroxychloroquine may also help prevent disease flares. Though often well tolerated, antimalarials can cause anemia in G6PD-deficient patients, and chronic use can lead to retinal toxicity in a modest percentage of patients. Regular ophthalmomogy follow-up is recommended for long-term users.
Hydroxychloroquine (Plaquenil)
Antimalarials are believed to exert their major antirheumatic effect by inhibiting the function of endosomal Toll-like receptors (a group that includes TLRs -3, -7, -8, and -9).
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.
Corticosteroids
Class Summary
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. While helpful for their ability to have fast-acting immunosuppressive/anti-inflammatory effects in the treatment of severe flares, corticosteroids have a multitude of potential adverse effects with long-term use. As in scleroderma, high-dose corticosteroids may be a risk factor for the development of scleroderma renal crisis in MCTD patients.
Prednisone (Deltasone, Orasone, Meticorten)
Used for its anti-inflammatory and immunomodulatory effects.
May decrease inflammation by reversing increased capillary permeability and suppressing PMN activity.
Calcium channel blocking agents
Class Summary
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.
Phosphodiesterase (type 5) enzyme inhibitor
Class Summary
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 that of prostaglandin or anti-endothelin therapies.
Sildenafil
Promotes selective smooth-muscle relaxation in lung vasculature, possibly by inhibiting phosphodiesterase type 5 (PDE-5). This reduces pulmonary arterial pressure and increases cardiac output.
Endothelin receptor antagonists
Class Summary
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. They are contraindicated in pregnancy.
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).
Prostaglandins
Class Summary
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.
Immunosuppressive agents
Class Summary
Major organ involvement may require moderate-to-high divided daily doses of corticosteroids and immunosuppressive 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.
Cyclophosphamide has serious short- and long-term adverse effect risks, and should be prescribed by an expert in its use.
Mycophenolate (CellCept, MMF, Myfortic)
This purine antagonist inhibits the proliferation of activated lymphocytes. It is contraindicated in pregnancy. It has been found to have effectiveness often similar to cyclophosphamide in the management of rheumatic diseases, with a somewhat less extensive adverse effect profile; for example, while also highly immunosuppressive, mycophenolate does not share cyclophosphamide's risk of bladder toxicity.
Pulmonary, Tyrosine Kinase Inhibitors
Nintedanib (Ofev)
Tyrosine kinase inhibitor; targets growth factors, which have been shown to be potentially involved in pulmonary fibrosis (eg, vascular endothelial growth factor receptor [VEGFR], fibroblast growth factor receptor [FGFR], platelet-derived growth factor receptor [PDGF]).
Disease Modifying Anti-Rheumatic Drugs (DMARDs)
Class Summary
A variety of drugs are frequently used in the management of rheumatoid arthritis, and can be relevant in MCTD, in which a significant subset of patients have clinical manifestations that include those of chronic erosive polyarthritis, as is seen in rheumatoid arthritis. These drugs include agents with immunosuppressive effects (eg, methotrexate, leflunomide), agents without immunosuppressive effects (sulfasalazine), biologics (anti-TNF, anti-IL-6, anti–T-cell second signaling [abetacept], anti–B-cell), and targeted enzyme antagonists (JAK inhibitors).
Increasingly, targeted therapies effective against other rheumatic diseases are emerging that may find a place in therapy for the overlapping rheumatic features in MCTD patients. A notable example is belimumab, a B-cell survival inhibitor, that has been shown to have efficacy in lupus.
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Raynaud phenomenon is a common feature of mixed connective tissue disease.
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Chest radiograph in a patient with pulmonary hypertension reveals enlarged pulmonary arteries.
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- Overview
- Presentation
- DDx
- Workup
- Treatment
- Medication
- Medication Summary
- Nonsteroidal anti-inflammatory drugs (NSAIDs)
- Cyclooxygenase-2 (COX-2) inhibitors
- Omega-3 fatty acids
- Proton pump inhibitors
- Antimalarial agents
- Corticosteroids
- Calcium channel blocking agents
- Phosphodiesterase (type 5) enzyme inhibitor
- Endothelin receptor antagonists
- Prostaglandins
- Immunosuppressive agents
- Pulmonary, Tyrosine Kinase Inhibitors
- Disease Modifying Anti-Rheumatic Drugs (DMARDs)
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