Continuing Education Activity

Mixed connective tissue disease is a rare autoimmune disease characterized by the presence of the anti-U1-ribonucleoprotein, Raynaud phenomenon, and features of at least 2 connective tissue diseases, including systemic lupus erythematosus, systemic sclerosis, inflammatory myositis, and rheumatoid arthritis. Diagnosis can be challenging due to variable and diverse presenting symptoms and changes in symptoms over time. Nonsteroidal anti-inflammatory drugs, steroids, and immunosuppressive agents are the mainstays of treatment.

This activity reviews the latest knowledge and clinical skills necessary to accurately diagnose and effectively manage patients with mixed connective tissue disease. Participants gain an in-depth understanding of the pathophysiology, clinical manifestations, diagnostic criteria, and emerging treatment options for this complex autoimmune condition. This activity also highlights the role of an interprofessional healthcare team in successfully collaborating to provide comprehensive care for patients with mixed connective tissue disease.

Objectives:

• Identify patients presenting with symptoms and signs of mixed connective tissue disease.

• Differentiate mixed connective tissue disease from other autoimmune rheumatologic conditions based on clinical features and laboratory findings.

• Assess evidence-based treatment options for patients affected by mixed connective tissue disease.

• Collaborate with an interprofessional healthcare team to provide comprehensive care and optimal outcomes for patients with mixed connective tissue disease.

Introduction

Mixed connective tissue disease (MCTD) is a rare systemic autoimmune disease with the main features of at least 2 overlapping connective tissue diseases, including systemic lupus erythematosus, systemic sclerosis, polymyositis, dermatomyositis, and rheumatoid arthritis. The disease is also defined by the presence of anti-U1-ribonucleoprotein (RNP) antibodies and Raynaud phenomenon.[1][2] The condition was initially described by Sharp in 1972 through a case series of 25 patients with features of systemic lupus erythematosus, systemic sclerosis, and inflammatory muscle disease associated with anti-U1-RNP antibodies. However, at that time, MCTD was not described as a separate entity from undifferentiated connective tissue disease, and its characteristics have evolved since then. Although most authors describe MCTD as an independent entity, some believe it may represent an early stage of a definite connective tissue disease, such as systemic lupus erythematosus, systemic sclerosis, or overlap syndrome. MCTD has no unique clinical features, and considerable interindividual variation in clinical manifestations exists.

Multiple attempts have been made to develop classification criteria, but there are currently no internationally agreed-upon diagnostic criteria. Most clinicians agree on a diagnosis if the following criteria are met:[3][4] 

• The presence of a high titer of positive anti-U1-RNP, and
• Raynaud phenomenon, puffy digits, or hand edema

And at least 2 of the following:

• Synovitis
• Myositis
• Leukopenia
• Esophageal dysmotility
• Pleuritis
• Pericarditis
• Interstitial lung disease

In 2019, a consensus panel in Japan proposed another revised set of diagnostic criteria for MCTD, which divides the disease features into 4 categories.[5] 

• The presence of a high titer of positive anti-U1-RNP, and
• Raynaud phenomenon, puffy digits, or hand edema

And either 1 of the following organ involvements or at least 2 overlapping manifestations:

Organ involvement includes:

• Pulmonary arterial hypertension
• Aseptic meningitis
• Trigeminal neuropathy

Overlapping manifestations include:

• Systemic lupus erythematosus: polyarthritis, lymphadenopathy, malar rash, pericarditis or pleuritis, leukopenia or thrombocytopenia
• Systemic sclerosis: sclerodactyly, interstitial lung disease, esophageal dysmotility or dilatation
• Inflammatory myositis: muscle weakness, elevated levels of myogenic enzymes, myogenic abnormalities on electromyogram

Diagnosis is based on at least 1 common manifestation, immunological manifestation, and either 1 characteristic organ involvement or at least 1 feature in 2 or more overlapping manifestations. These criteria have a sensitivity of 90.6% and a specificity of 98.4%, although they have not been formally adopted by the international community.[6]

Etiology

The etiology of MCTD is unclear but is believed to involve the interaction of genetic predisposition with the environment. Sequence-based typing of HLA-B* and DRB1* showed that risk alleles for MCTD are HLA-B*08 and DRB1*04:01, whereas protective alleles are DRB1*04:04, DRB1*13:01, and DRB1*13:02.[7]

No clear environmental risk factor has been identified thus far. However, immune activation due to environmental factors in people with genetic predisposition is believed to play a role. Some environmental factors, such as infections, drugs, toxins, ultraviolet radiation, and chemicals, including vinyl chloride and silica, have some correlation with the development of MCTD.[8]

Molecular mimicry is the leading theory triggering the onset of disease. Amino acid sequences from non-self proteins in the environment may mimic host epitopes and induce autoantibody responses. For example, almost 91% of DNA from the serum of patients with MCTD had an HIV type-1 conserved Pol sequence.[9] Seventy-five percent of patients with MCTD patients had antibodies to HIV GAG proteins p35 and p24.[10]

Epidemiology

MCTD is a rare disease, and its exact incidence is unknown. In a population-based study from Olmsted County, Minnesota, the incidence of MCTD was 1.9 per 100,000 adults per year. The mean age of diagnosis was 48 years, and 84% of those affected were female.[11]

In a study of the Norwegian population, the incidence of MCTD was 2.1 per million per year, the female-to-male ratio was 3.3 to 1, and the mean age at diagnosis was 37.9 years.[12] 

In a French cohort study involving 330 patients over a median time of 8 years, 88% were female, with a median age of 35.[13] This disease affects all races, and its clinical manifestations seem to be similar in all racial/ethnic groups, although some differences are emerging in population-based reports. 

Pathophysiology

Raynaud phenomenon and pulmonary hypertension are typical clinical manifestations supporting abnormal micro- and macrovascular circulation. Nail-fold capillary abnormalities are demonstrated by nail-fold capillaroscopy in up to 41.3% of patients with MCTD.[14][15] Unlike systemic sclerosis, nail-fold capillary abnormalities can improve with immunosuppressive therapy.

Given the anti-U1-RNP antibody is the hallmark of MCTD, it is believed that the anti-U1-RNP antibody and its antigen play a role in the pathogenesis of MCTD.[16] The U1-RNP complex is an intranuclear protein that converts pre-messanger RNA to mature RNA. This complex comprises 3 specific proteins—A, C, and 70 kDa—to which anti-U1 RNP antibodies bind. The 70 kDa antigen is the main target of the anti-RNP antibody in MCTD.[14] The genetic association of MCTD with HLA-DR4 and DR2 phenotypes indicates the involvement of T-cell receptors and HLA molecules in the generation of anti-U1-RNP.[17] 

Two main mechanisms have been proposed for the pathogenic role of anti-U1-RNP antibodies. The first mechanism involves direct binding to endothelial cells through U1-RNP peptides or recognition of nucleosome RNP fragments in endothelial cell apoptotic blebs.[18][19] This mechanism may lead to the phenotype involving vascular diseases such as Raynaud phenomenon, skin sclerosis, and pulmonary hypertension. The second possible pathogenic mechanism is through immune complex formation, which can activate the complement cascade and lead to tissue inflammation and damage, such as myositis, arthritis, and interstitial lung disease.

History and Physical

Initial symptoms of MCTD are typically nonspecific and include arthralgia, malaise, myalgia, and low-grade fever. MCTD can affect nearly any organ system, and symptoms reflect the overlapping nature of this condition with other rheumatological diseases, as there are no unique, singular clinical manifestations of MCTD.

Common Manifestations

Skin: The most common skin change is Raynaud phenomenon, which is also the most common presenting feature of MCTD, occurring between 50.3% and 93.2% at presentation and 57.5% to 99% after follow-up.[20] Puffy digits, characterized by diffuse soft tissue swelling of the fingers, are also characteristic, although not always present, affecting 53% to 72% of patients at presentation and 46% to 92% after follow-up.[20] Nailfold capillary abnormalities may be present on nailfold capillaroscopy. A scleroderma-like pattern to nailfold capillary abnormalities is the most commonly observed, with early-type lesions being predominant.[21] Other possible manifestations include hand edema, acrosclerosis, calcinosis cutis, telangiectasia, erythema nodosum, hair loss, and vasculitis of digits. Discoid plaques and a malar rash similar to systemic lupus erythematosus can also occur. Case reports describe panniculitis involving the abdomen, legs, and breasts.[22][23]

Musculoskeletal: Patients may develop inflammatory arthritis similar to systemic lupus erythematosus or rheumatoid arthritis, and this type of arthritis is reported in 65.3% to 86% of patients at the time of presentation and in 49.7% to 89.6% after follow-up.[20]  

Muscle: Inflammatory myopathy, clinically and histologically similar to polymyositis, often manifests as painless proximal muscle weakness with elevated levels of creatinine kinase and aldolase in the serum. This condition is reported in 13.5% to 27.9% of patients at the time of presentation and in 19% to 32.5% at follow-up.[20] Rarely, myositis can also be the initial presentation.[15]

Cardiopulmonary: Pulmonary involvement occurs in almost 73% of patients, with dyspnea being the most common symptom.[24] Other symptoms include dry cough, pleuritic chest pain, wheezing, and hemoptysis. Interstitial lung disease can occur in 27.8% to 47% of patients, with a nonspecific interstitial pneumonitis pattern being the most common.[20] Pulmonary hypertension can occur in 6.9% to 17.8% of patients.[20] Other pulmonary manifestations may include pleural effusion, pulmonary vasculitis, thromboembolic disease, alveolar hemorrhage, infections, and obstructive airway disease.[25] Pericarditis is the most common variant of cardiac disease involving up to 40% of patients.[26] Pericardial effusion, mitral valve prolapse, myocarditis, accelerated atherosclerosis, and conduction abnormalities can also occur. Patients with MCTD are also at risk for accelerated atherosclerotic disease. 

Gastrointestinal: Esophageal dysmotility leading to dysphagia, odynophagia, gastrointestinal reflux, and regurgitation are all common features, occurring in 34.8% to 38.9% of patients at presentation and in 45.3% to 49.6% during follow-up.[20] Less common manifestations are pancreatitis, megacolon, duodenal bleeding, portal hypertension, and autoimmune hepatitis. Rarely, patients can present with protein-losing enteropathy.[27]

Less Common Manifestations

Renal: Renal involvement is less common and may occur in 15% to 25% of MCTD patients. Most patients are typically asymptomatic.[28] Membranous nephropathy is the most common finding. Nephropathy can sometimes be associated with significant morbidity, risk of hypertension, and progressive kidney disease.[29]

Central nervous system: The involvement of the central nervous system is increasingly recognized as a manifestation of disease. Nervous system involvement has been described in up to 25% of patients.[30] Trigeminal neuralgia is the most common central nervous system manifestation. Other possible symptoms include headaches, peripheral neuropathy, aseptic meningitis, cerebral venous sinus thrombosis, and sensorineural hearing loss.[31]

Hematological involvement: Anemia, leukopenia, and thrombocytopenia may occur. Idiopathic immune–mediated thrombocytopenia and hemolytic anemia are not common manifestations and should prompt further evaluation for systemic lupus erythematosus and other causes. 

Evaluation

Evaluating MCTD requires a comprehensive understanding of its diverse clinical manifestations and overlapping features with other connective tissue diseases. Clinicians must utilize a combination of detailed patient history, physical examination, and targeted diagnostic tests to diagnose and assess MCTD accurately. 

Laboratory Studies

Laboratory studies are useful for evaluating the presence of the U1-RNP antibody, which is helpful for diagnosis. They are also valuable for characterizing the severity of potential organ involvement and assessing the presence of other features of overlapping autoimmune rheumatologic disease.

Immunological markers include high titer speckled pattern anti-nuclear antibody (typically >1280) and high titer anti-U1-RNP. The sensitivity of the U1-RNP antibody is 100%, but its specificity is lower. Another potential marker for MCTD is the presence of survival of motor neuron (SMN) antibody directed to SMN and its complex. In a study comparing the prevalence of anti-SMN complex antibodies between patients with systemic lupus erythematosus and MCTD, the antibodies were present in 40% of MCTD patients, whereas only 10% of patients with systemic lupus erythematosus had the antibody. In this study, the estimated specificity of the anti-SMN antibody was 91.2% for MCTD.[32]

Patients may have other lab and immunological abnormalities depending on the presence of features of systemic lupus erythematosus, systemic sclerosis, or dermatomyositis. Up to 65% of patients with MCTD may have a positive rheumatoid factor, and 50% of patients can have a positive anti-cyclic citrullinated peptide.[33][34] Muscle enzymes may be elevated. Falsely positive VDRL and reduced complement levels are a feature in some patients. Anti-double-stranded DNA, anticentromere, anti-Scl-70, and anti-PM-1 antibodies are typically absent.

A complete blood count may demonstrate anemia and leukopenia in almost 75% of patients. Hypergammaglobulinemia is also present in 75% of patients with MCTD. The erythrocyte sedimentation rate is elevated in nearly all patients.[2] Urinalysis can show proteinuria and hematuria if renal disease is present.

Imaging and Other Diagnostic Studies

Imaging and other diagnostic studies are not necessarily indicated unless there is a suspicion of focal organ involvement. The following diagnostic modalities are not meant to be exhaustive but suggest how certain tests may be used to diagnose patients with MCTD and concerns for a focal organ or system problem.

Cardiopulmonary testing: The diagnostic procedures used to evaluate the cardiopulmonary system include the following:

• Chest x-ray: This technique may serve as a screening test for lung disease, including pulmonary infiltrates, interstitial lung disease, pleural effusions, and cardiomegaly. 

• Computed tomography: High-resolution computed tomography is very sensitive in diagnosing interstitial lung disease. Common findings include ground-glass opacities, linear opacities, subpleural micronodules, septal thickening, and traction bronchiectasis, typically with peripheral and lower lobe predominance. Honeycombing, airspace consolidation, emphysema, and centrilobular nodules are less common findings.[35]

• Echocardiogram: An echocardiogram is a useful tool for screening for right heart disease and pulmonary hypertension and assessing the pericardium for the presence of effusion or thickening, valvular abnormalities, and overall cardiac function. 

• Pulmonary function testing: Patients with interstitial lung disease may show reductions in the diffusion capacity for carbon monoxide, forced vital capacity, and forced expiratory volume.

• Right heart catheterization: Definitive diagnosis of pulmonary hypertension in MCTD requires right heart catheterization demonstrating mean pulmonary arterial pressure at rest >20 mmHg.

Musculoskeletal imaging: The diagnostic techniques used to visualize and assess the bones, joints, muscles, and soft tissues of the musculoskeletal system are as follows:

• X-ray of joints: X-rays of affected joints might reveal evidence of inflammatory arthritis with erosions, joint space narrowing, and periarticular osteopenia.

• Musculoskeletal ultrasound: This imaging modality utilizes ultrasonic sound waves to assess soft tissues, cartilage, bone surfaces, and fluid-containing structures for the presence of abnormalities responsible for joint pain and swelling.

• Magnetic resonance imaging of a limb: This technique is another sensitive tool to evaluate for the presence of subclinical or clinically evident inflammatory muscle disease or inflammatory arthritis. 

Other tests for evaluating gastrointestinal tract symptoms may include an esophagram, upper endoscopy, or colonoscopy. For assessing potential inflammatory muscle or peripheral nerve disease, an electromyogram and nerve conduction study may be used.

Treatment / Management

Due to the rarity of the condition, there are no randomized controlled trials to guide the treatment of patients with MCTD. Therapy's general goals are to control symptoms and are directed by clinical manifestations and organ involvement.

The most significant organ manifestations involve the heart and lungs, with pulmonary hypertension and interstitial lung disease in a nonspecific interstitial pneumonitis pattern being the primary causes of morbidity and mortality.[13] Therapeutic trials for patients with interstitial lung disease tend to combine patients with MCTD, scleroderma, and other connective tissue diseases, and the management recommendations are extrapolated to MCTD. The main medications used to treat interstitial lung disease are mycophenolate mofetil, cyclophosphamide, and rituximab, with mycophenolate mofetil being the preferred initial therapy due to its comparable efficacy and fewer adverse effects compared to cyclophosphamide.[36] More recently, the RECITAL study of connective tissue disease-interstitial lung disease has shown that rituximab and cyclophosphamide are fairly equivalent in pulmonary outcomes with fewer overall adverse effects for rituximab.[37]

Pulmonary hypertension is typically less responsive to steroids, and the guidance of an expert in pulmonary hypertension should direct advanced management. Vasodilators such as prostaglandins, including epoprostenol; endothelin receptor antagonists, including ambrisentan; phosphodiesterase 5 inhibitors, including sildenafil; and immunosuppression with corticosteroids and cyclophosphamide may be appropriate therapeutic considerations.

The management of Raynaud phenomenon includes symptomatic strategies such as avoiding caffeine, smoking, cold temperatures, and injury to the digits. Oral calcium channel blockers, such as nifedipine, which decreases peripheral resistance, are an option. Prostaglandins, endothelin receptor antagonists, phosphodiesterase 5 inhibitors, and topical nitroglycerins are also effective.  

Arthritis and arthralgia typically respond to nonsteroidal anti-inflammatory drugs and hydroxychloroquine. For refractory synovitis, corticosteroids, methotrexate, and other disease-modifying anti-rheumatic drugs can be used.

Pleuritis, pericarditis, myositis, and aseptic meningitis typically respond to steroids. Steroid-sparing agents, such as methotrexate, cyclosporine, azathioprine, and mycophenolate mofetil, are commonly used as second-line agents. Steroid-resistant myositis may respond to intravenous immunoglobulin.

gastrointestinal reflux treatment involves proton pump inhibitors (PPI) or histamine blockers, lifestyle changes, and dietary modifications, such as elevating the head of the bed and avoiding dietary triggers. Prokinetics and gastric fundoplication are possible options for those who fail twice-daily PPI therapy. Individuals with esophageal motility disorder may require prokinetics. Patients with malabsorption should be on a lactose-free diet, and medium-chain triglycerides should substitute for long-chain fatty acids.

Patients with autoimmune hemolytic anemia and thrombocytopenia are initially treated with steroids. Clinicians can consider rituximab in resistant cases.

Differential Diagnosis

Due to nonspecific symptoms and different organ involvement, MCTD mimics several other conditions, especially other connective tissue diseases. Differential diagnoses are as follows:

• Systemic lupus erythematosus is an autoimmune disease characterized by the presence of an anti-nuclear antibody and varied manifestations, which may include inflammatory arthritis, mucocutaneous disease, serositis, pleuritis, pericarditis, renal disease, fevers, neuropsychiatric symptoms, leukopenia, autoimmune hemolysis, thrombocytopenia, antiphospholipid antibodies, low complements, and the presence of an anti-double stranded DNA antibody or anti-Smith antibody.

• Rheumatoid arthritis is typically symmetric polyarthritis, predominantly affecting the small joints of the hands, wrists, ankles, and feet. Up to 70% of patients have an abnormal rheumatoid factor and anti-cyclic citrullinated peptide antibody.                                                               
• Polymyositis is an idiopathic inflammatory myositis that causes proximal over distal muscle weakness. This condition is associated with abnormal muscle biochemistries, signs of muscle edema or inflammation on magnetic resonance imaging, and the absence of autoantibodies.

• Dermatomyositis is an idiopathic inflammatory myositis similar to polymyositis but includes varying presentations involving the skin, lungs, gastrointestinal tract, and joints. This condition is typically associated with either myositis-specific antibodies or myositis-associated antibodies.

• Scleroderma is a chronic multisystem disease characterized by widespread vascular dysfunction and progressive fibrosis of the skin and internal organs, which is associated with autoimmunity.

Prognosis

MCTD generally has a good prognosis, although it depends on which organ is affected, the degree of inflammation, and the rate of disease progression.[1][20] The mortality rate varies between 3.1% and 10% in the literature.[13][3]

In a study involving the Hungarian population, the survival rate for 5 and 10 years after diagnosis was 98% and 96%, respectively. In a French cohort study involving 330 patients with MCTD followed up on average for 8 years, 45.2% of patients achieved remission, 7.6% developed pulmonary hypertension, and 27.9% developed interstitial lung disease.[13]

Pulmonary hypertension is the most common cause of death. Interstitial lung disease, infections, cardiovascular complications, and malignancies are other causes.[38] The presence of immunoglobulin G anticardiolipin antibodies may be associated with more severe disease. 

The identification of the anti-SMN complex antibodies also has prognostic significance. MCTD patients with this autoantibody had poorer disease-related outcomes compared to patients who did not have this autoantibody, and complications were mainly related to pulmonary hypertension and interstitial lung disease.[6] The anti-Ro52 autoantibody also portends a worse prognosis in those with MCTD, specifically related to the severity of interstitial lung disease.[39] 

Epitope spreading, or the development of new autoantibodies during the disease course, can lead to changes in clinical features. For example, a lower rate of skin sclerosis and a higher percentage of interstitial lung disease appeared in patients with epitope spreading compared to those who did not during a follow-up of patients with MCTD.[40] In addition, patients with MCTD can clinically progress to other CTDs, such as systemic sclerosis, rheumatoid arthritis, Sjogren syndrome, and systemic lupus erythematosus. In a retrospective review involving patients with MCTD followed over a median time of 8 years from diagnosis, approximately 25.6% evolved to a definite connective tissue disease.[13] On the other hand, patients with other connective tissue diseases or undifferentiated connective tissue diseases can eventually develop MCTD. 

Complications

Patients with MCTD are at risk for several serious complications, including pulmonary hypertension, interstitial lung disease, and infections, which are significant causes of mortality. In addition, they may develop renal involvement, cardiovascular issues, and gastrointestinal problems, further complicating their clinical management. Early detection and regular monitoring of these complications are essential to improve patient outcomes and reduce the risk of severe health consequences of MCTD.

Consultations

Consultations for patients with MCTD typically involve a multidisciplinary team approach to address the complex and varied manifestations of the condition. Rheumatologists, pulmonologists, cardiologists, nephrologists, and gastroenterologists often collaborate to provide comprehensive care. Regular consultations with these specialists are crucial for monitoring disease progression, managing complications, and adjusting treatment plans. In addition, patients may benefit from consultations with physical therapists, occupational therapists, and mental health professionals to address the physical and psychological impacts of MCTD. This coordinated approach ensures that all aspects of the patient's health are considered, leading to more effective and holistic management.

Deterrence and Patient Education

Patient education about the disease course and management is vital to improving the quality of life. Discussing the potential organ systems involved in MCTD is important for prompt recognition of complications, and encouraging patient follow-up with specialists for ongoing evaluation and management of those complications is key. Self-care and management of Raynaud phenomenon, including protecting extremities from cold environments, using warming techniques, and recognizing related complications such as nonhealing digital pits or ulcers, is important to preventing digit loss. Active involvement of patients in the decision-making process, especially regarding therapeutics, is also important.

Enhancing Healthcare Team Outcomes

MCTD resembles several other CTDs and is easy to misdiagnose. Diagnosis can be challenging due to variable and mixed patient presentations and changes in symptoms over time. Early diagnosis is associated with improved outcomes. Recognizing signs and symptoms and making an early referral to a rheumatologist is crucial. Definitive diagnosis often requires close follow-up and identification of the characteristic clinical, laboratory, and radiologic findings.

An interprofessional team approach is crucial for improving clinical outcomes and patient quality of life. Pulmonologists, cardiologists, gastroenterologists, and other specialist referrals should be made based on concerns for specific organ involvement. Physicians, advanced practitioners, and nurses should provide coordinated patient education to ensure patients understand the associated signs and symptoms and when to seek medical attention. Pharmacists must educate patients about the medications used and their potential adverse effects. Pain management should involve pharmacological and nonpharmacological approaches, such as physical therapy and psychological, social, and emotional support.[41] This collaborative strategy leverages the expertise of various healthcare professionals and the interprofessional healthcare team to address the multifaceted nature of MCTD.