Mixed Connective-Tissue Disease (MCTD)

Pathophysiologic abnormalities that are believed to play a role in MCTD include the following:

• B-lymphocyte hyperactivity, resulting in high levels of anti–U1-RNP and anti–U1-70 kd autoantibodies
• T-lymphocyte activation, with anti–U1-70 kd–reactive T lymphocytes circulating in the peripheral blood
• Apoptotic modification of the U1-70 kd antigen
• Immune response against apoptotically modified self-antigens
• Genetic association with major histocompatibility genes human leukocyte antigen (HLA)–DRB1*04/*15 ^[13]
• Vascular endothelial pathology, including features of hyperproliferation and increased endothelial apoptosis ^[14]
• Lymphocytic and plasmacytic infiltration of tissues
• Activation of Toll-like receptors in a pattern that may differ from that of classic SLE
• A strong Type I Interferon activation signature in circulating cells ^{[15, 16, 17]}

In a study of a nationwide MCTD cohort in Norway, Flåm and colleagues found that HLA-B*08 and DRB1*04:01 were risk alleles for MCTD, while DRB1*04:04, DRB1*13:01 and DRB1*13:02 were protective. Risk alleles for SLE, systemic sclerosis, and polymyositis/dermatomyositis were distinct from those for MCTD.[18]

Oka and colleagues performed genotyping of HLA-DRB1 and -DQB1 in 116 Japanese MCTD patients and 413 controls and analyzed the genotype frequencies. The analysis showed that HLA-DRB1*04:01 and DRB1*09:01 were risk alleles for Japanese MCTD. DRB1*13:02 was also confirmed to be protective against MCTD in Japanese patients.[19]

Over time, some patients with MCTD also develop anti-Sm autoantibodies—an expansion of the autoimmune response known as epitope spreading. Escolà-Vergé reported that epitope spreading occurred in 13 (43%) of 40 patients with MCTD, mainly during the first 2 years after diagnosis. Compared with patients who did not have epitope spreading, patients with epitope spreading had a significantly lower prevalence of skin sclerosis (0% vs 44%, P = 0.004) and a higher prevalence of interstitial lung disease (46% vs 15%, P = 0.05).[20]

The fundamental cause of MCTD remains unknown. Autoimmunity to components of the U1-70 kd snRNP is a hallmark of disease. Anti-RNP antibodies can precede overt clinical manifestations of MCTD, but overt disease generally develops within 1 year of anti-RNP antibody induction.

The loss of T-lymphocyte and B-lymphocyte tolerance, due to cryptic self-antigens, abnormalities of apoptosis, or molecular mimicry by infectious agents, and driven by U1-RNA–induced innate immune responses and other danger signal sensors induced by end-organ injury, are proposed current theories of pathogenesis.

It is notable that the RNA component unique to the U1-small nuclear ribonucleoprotein, U1-RNA, is among the most prevalent RNAs present in cellular apoptotic debris, and that U1-RNA is an agonist for autoimmunity-associated endosomal Toll-lIke receptors, including TLR7 and TLR3.[21, 22] These observations promote the hypothesis that immune recognition of apoptotic debris may play a key role in the etiology of anti-RNP autoimmunity, as in MCTD.

United States

A population-based study from Olmsted County, Minnesota found that MCTD occurred in about 2 persons per 100,000 per year. Diagnosis was frequently delayed, with a median of 3.6 years elapsing from first symptom to fulfillment of diagnostic criteria.[23] A study in American Indian and Alaska Native adults found a  prevalence of 6.4 per 100,000 (95% confidence interval 2.8-12.8).[24]

International

In an epidemiologic survey in Japan, MCTD has a reported prevalence of 2.7 cases per 100,000 population.[25] A population-based study in Norway found the point prevalence rate to be 3.8 cases per 100,000 adult population, with a female-to-male ratio of 3.3, and an annual incidence rate of  2.1 per million.[26]  

Mortality/Morbidity

Long-term outcome studies have established pulmonary hypertension as the most common disease-related cause of death.[27] Immunoglobulin G (IgG) anticardiolipin antibodies are a marker for development of pulmonary hypertension. Infections are also a major cause of death.

Cardiac disease, most often pericarditis, is also common in MCTD patients, with prevalence estimates ranging from 13% to 65%. Other cardiac abnormalities include conduction abnormalities, pericardial effusion, mitral valve prolapse, diastolic dysfunction, and accelerated atherosclerosis. In three prospective studies with 13-15 years of follow-up, MCTD patients had an overall mortality rate of 10.4%, and 20% of these deaths were directly attributable to cardiac causes.[28]

Race-, Sex-, and Age-related Variances

MCTD has been reported in all races. The clinical manifestations of MCTD are similar among various ethnic groups; however, one study observed ethnic differences in the frequency of end-organ involvement.[29]

MCTD is far more common in females than in males. Estimates of the female-to-male ratio vary from approximately 3:1 to 16:1.[26, 25]

The onset of MCTD is typically at 15-25 years of age, but can occur at any age.

Most patients with MCTD have a favorable outcome. Cases of MCTD with typical clinical or serologic features occasionally evolve into scleroderma, SLE, or another rheumatic disease.

Pulmonary hypertension is the most common disease-associated cause of death. Careful monitoring and aggressive treatment may improve the outcome of pulmonary hypertension. 

A long-term observational nationwide cohort study from Norway found that interstitial lung disease (ILD) was present in 41% of MCTD patients and progressed in 19% of patients across the observation period of a mean of 6.4 years.[30]  The following were the strongest predictors of ILD progression:

• Male sex  (hazard ratio [HR] = 4.0, 95% confidence index [CI]: 1.4, 11.5; P = 0.011)
• Presence of anti-ro52 antibodies (HR = 3.5, 95% CI: 1.2, 10.2; P = 0.023)
• Elevated anti-RNP titer (HR 1.5, 95% CI: 1.1, 2.0; P = 0.008)
• Absence of arthritis (HR = 0.2, 95% CI: 0.1, 0.6; P = 0.004) 

Education about MCTD and its treatment is essential. Active participation in the decision-making process empowers patients in their own care. Education about disease decreases the risk of patients developing learned helplessness and improves functional outcomes. For patient education information, see What Is Mixed Connective Tissue Disease (MCTD)?.

Manifestations of mixed connective-tissue disease (MCTD) can be protean. Most patients experience Raynaud phenomenon, arthralgia/arthritis, swollen hands, sclerodactyly or acrosclerosis, and mild myositis. The following may be revealed by history or physical examination:

• Raynaud phenomenon (96% cumulatively, 74% at presentation); see the image below
• Arthralgia/arthritis (96% cumulatively, 68% at presentation)
• Esophageal hypomotility (66% cumulatively, 9% at presentation)
• Pulmonary dysfunction (66% cumulatively, rare at presentation)
• Swollen hands (66% cumulatively, 45% at presentation)
• Myositis (51% cumulatively, 2% at presentation)
• Rash (53% cumulatively, 13% at presentation)
• Leukopenia (53% cumulatively, 9% at presentation)
• Sclerodactyly (49% cumulatively, 11% at presentation)
• Pleuritis/pericarditis (43% cumulatively, 19% at presentation)
• Pulmonary hypertension (23% cumulatively, rare at presentation)

Raynaud phenomenon is a common feature of mixed connective tissue disease.

The experience with a large single-center cohort of MCTD patients suggests that the following three clinical subclusters of MCTD manifestations may exist[31] :

• Predominantly vascular manifestations, including Raynaud phenomenon, pulmonary hypertension, and antiphospholipid syndrome with thromboses (this group is at the greatest risk of mortality)
• A polymyositislike picture, including interstitial lung disease, esophageal dysmotility, and myositis
• Erosive polyarthritis with anti–cyclic citrullinated peptide (anti-CCP) antibodies and sclerodactyly

Physical examination is helpful in confirming or identifying features of MCTD. Seek the following features on examination:

• Fever should prompt a careful search for infection; however, infection may be present in the absence of fever and is one of the primary disease-related causes of mortality and/or morbidity in MCTD; the use of corticosteroids and immunosuppressive agents further increases the risk of infection ^[32]
• Corticosteroids may mask serious intra-abdominal processes, including appendicitis, vasculitis, pancreatitis, and bowel perforation
• Cardiopulmonary symptoms or findings should prompt a careful evaluation for pulmonary hypertension
• Capillary microscopy can assist in finding sclerodermatous-type nailfold changes
• Severe Raynaud phenomenon may result in digital vascular infarcts and ulcerations
• Pericarditis may be occult and can progress rapidly to cardiac tamponade
• Trigeminal neuralgia is common in MCTD
• Secondary Sjögren syndrome occurs in 25% of patients with MCTD and may cause both ocular symptoms and oral dryness

Protein-losing gastroenteropathy is a rare feature of MCTD, but may be the initial manifestation of the disorder. Patients present with generalized edema, ascites, and pleural and pericardial effusions due to to hypoproteinemia from leakage of serum protein into the gastrointestinal tract.[33]

Laboratory studies used in the workup for mixed connective-tissue disorder (MCTD) are as follows:

• Complete blood cell count (CBC)
• Urinalysis
• Routine blood chemistry
• Indicators of acute phase response (erythrocyte sedimentation rate [ESR] or C-reactive protein [CRP])
• Muscle enzymes if myositis is suspected clinically
• Antinuclear antibodies
• Anti–U1-ribonucleoprotein (RNP) antibodies
• Amylase and lipase - To assess for pancreatitis if clinically indicated
• Serologic indicators of pulmonary hypertension (such as brain natriuretic peptide [BNP]) if clinically indicated

Antibody study results

High-titer speckled pattern fluorescent antinuclear antibody (FANA) is typical of MCTD. However, the presence of FANA is not specific to MCTD.

Anti-RNP antibodies are required for diagnosis of MCTD. Titers are typically high. The presence of anti–U1-70 kd is characteristic of MCTD but not specific.

MCTD can enter sustained remission later in the clinical course. Anti-RNP autoantibodies typically become undetectable in patients in remission.

Other immune studies

Further results are as follows:

• Antiphospholipid antibodies (including anticardiolipin antibodies and lupus anticoagulant) may be associated with pulmonary hypertension
• Rheumatoid factor is frequently detected
• Other lupus-specific antibodies (eg, anti–double-stranded DNA antibodies) are typically absent
• Scleroderma-specific antibodies, including anticentromere, anti–Scl-70 (topoisomerase), and anti–PM-1 (Pm-Scl), are typically absent
• C3 and C4 complement levels are more likely to be depleted in lupus than in MCTD

Imaging studies used in the workup of patients with MCTD include the following:

• Chest radiography - To assess for infiltrates, effusion, or cardiomegaly (see the image below)

• Echocardiography - In patients with effusion or chest pain, used to evaluate for pulmonary hypertension or valvular disease (exercise echocardiography may have increased sensitivity for identifying pulmonary hypertension)[35]

• Ultrasonography/CT scanning - Used to evaluate abdominal pain (indicated for evidence of serositis, pancreatitis, or visceral perforation related to vasculitis)

• MRI - Used to assess neuropsychiatric signs or symptoms

Chest radiograph in a patient with pulmonary hypertension reveals enlarged pulmonary arteries.

The following tests may be part of the workup for MCTD:

• Pulmonary function testing is used to screen for declining diffusing capacity of lung for carbon monoxide (DLCO), possibly indicating pulmonary hypertension, ^[36]  or to assess lung volumes and forced vital capacity to screen for suspicion/progression of interstitial lung disease.
• Electrocardiogram and/or cardiac enzymes is helpful to assess for myocardial ischemia and myocarditis.
• Infection, stroke, or neuropsychiatric manifestations may be monitored with cerebrospinal fluid (CFS) analysis.
• The six-minute walk can be helpful to assess for cardiopulmonary insufficiency, possibly indicating pulmonary hypertension. ^[37]
• Right-sided heart catheterization is the criterion standard for confirming the diagnosis of pulmonary hypertension

The overall goals of therapy for mixed connective-tissue disease (MCTD) are to control symptoms, to maintain function, and to reduce the risk of future disease consequences. Medical therapy targets control of disease activity in general and management of specific organ involvement (see Medication), while monitoring for and mitigating the risks of complications either of the condition itself (eg, pulmonary hypertension, interstitial lung disease) or of its treatment (eg, infection) (see Follow-up).

Patients with MCTD may require hospital admission while undergoing assessment for suspected infection or complications related to disease or treatment.  Admit patients to the appropriate service with rheumatology care, if available. Obtain subspecialty consultations as indicated.

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, interstitial lung disease, gastroesophageal reflux, or acute ischemia due to Raynaud's phenomenon.

Aggressive cold avoidance may help to reduce the risk of flares of Raynaud's Phenomenon.

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.

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.

Given that other inflammatory rheumatic diseases—including rheumatoid arthritis, lupus, and scleroderma—are reported to be independent risk factors for the development of atherosclerosis and related conditions, patients with MCTD may also be at increased risk for atherosclerosis. As in those other conditions (and modeled after recommendations developed for diabetes mellitus), more aggressive targets for blood pressure and cholesterol control may be appropriate.

Patients with stable disease and no recent changes in medications should be seen approximately every 2-4 months and undergo routine laboratory evaluation, including a complete blood cell count and chemistry studies. Patients with active disease are typically seen approximately every 3-6 weeks, depending on the severity of disease.

Recommendations for screening and early detection of pulmonary artery hypertension (PAH) associated with connective tissue diseases, including MCTD, have been published.[36]  Although these guidelines do not recommend screening of asymptomatic patients with MCTD who lack features of scleroderma, the following studies are recommended for symptomatic patients:

• Pulmonary function testing (spirometry with lung volumes) with single-breath diffusing capacity for carbon monoxide (DLCO)
• Transthoracic echocardiogram (TTE)
• N-terminal pro-B-type natriuretic peptide (NT-Pro BNP) tests

Use of 6-minute walk stress echocardiography has also been proposed as a means of predicting the development of PAH in patients with connective tissue disorders.[37]

Abnormalities on noninvasive tests require confirmation with right heart catheterization, which remains the gold standard for diagnosis of PAH.

Therapeutic options in mixed connective-tissue disease (MCTD) include the following:

• 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.
• Disease-modifying antirheumatic drug (DMARD) therapy is reserved for more refractory synovitis, particularly if showing features of erosive/deforming risk.
• Proton pump inhibitors can control esophageal reflux symptoms.
• In patients with Raynaud phenomenon, calcium channel blocking agents are used.
• Phosphodiesterase inhibitors, endothelin receptor antagonists, or prostaglandins can be used for pulmonary hypertension. 
• In some cases, pulmonary hypertension in MCTD may also respond to aggressive immunosuppression, similar to that used in interstitial lung disease therapy. ^[38]
• 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]

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.

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.

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.

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.

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.

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.

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.

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.

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).

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.

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.

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]).

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.