Continuing Education Activity

Mixed connective tissue disease (MCTD) is a rare autoimmune disease diagnosed when a specific antibody known as anti-U1-ribonucleoprotein is present, and there are features of at least two connective tissue diseases, including systemic lupus erythematosus, systemic sclerosis, polymyositis, dermatomyositis, and rheumatoid arthritis. Diagnosis can be challenging due to variable and diverse symptoms upon presentation and the changes in symptoms over time. Non-steroidal anti-inflammatory drugs, steroids, and immunosuppressive agents are mainstays of treatment. This activity reviews the evaluation and treatment of MCTD and highlights the interprofessional team's role in managing patients with this condition.

Objectives:

• Identify the etiology of mixed connective tissue disease.
• Review the typical presentation of a patient with mixed connective tissue disease.
• Outline the treatment options for mixed connective tissue disease.
• Describe the importance of improving care coordination amongst the interprofessional team to optimize outcomes for patients with mixed connective tissue disease patients.

Introduction

Mixed connective tissue disease (MCTD) is a rare systemic autoimmune disease with an overlapping feature of at least two connective tissue diseases (CTD), including systemic lupus erythematosus (SLE), systemic sclerosis (SSc), polymyositis (PM), dermatomyositis (DM) and rheumatoid arthritis (RA) along with the presence of a distinctive antibody, anti-U1-ribonucleoprotein (RNP) previously known as an antibody to extractable nuclear antigen (ENA).[1][2] Most authors describe MCTD as an independent entity, while some believe that it might represent an early stage of a definite connective tissue disease, e.g., SLE, SSc, or overlap syndrome. MCTD has no unique clinical features, and there is a considerable inter-individual variation in clinical manifestations. Alarcon-Segovia is one of the regularly used diagnostic criteria that consists of a high titer of positive anti-U1-RNP (over 1 per 1600) and three or more of the following clinical manifestations: Raynaud phenomenon, hand edema, synovitis, histologically proven myositis, and acrosclerosis.[3] 

A revised set of diagnostic criteria for MCTD, which divides the features of the disease into the following four categories, was proposed by a consensus panel in Japan in 2019.[4] These include

• Raynaud phenomenon
• Immunologic manifestation such as anti–U1-RNP antibody 
• Organ involvement includes pulmonary arterial hypertension, aseptic meningitis, trigeminal neuropathy

Overlapping manifestations of SLE-like, systemic sclerosis, polymyositis, and dermatomyositis may present.

Etiology

The etiology of mixed connective tissue disease is unclear. No clear risk factor has been identified so far. Immune activation due to environmental factors in people with genetic predisposition is thought to play a role. Certain viruses and chemicals have been found to correlate with the disease.

Epidemiology

Mixed connective tissue disease is a rare disease, and the exact incidence is unknown. In a population-based study done in 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 affected populations were females.[5] In a study done on 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.[6] This disease affects all races, and its clinical manifestations are similar in all ethnic groups.

Pathophysiology

Since the anti-U1-RNP antibody is the hallmark of mixed connective tissue disease, the assumption is that anti-U1-RNP and its antigen play a role in the pathogenesis of MCTD.[7] U1-RNP complex is an intranuclear protein that converts pre mRNA to mature RNA. It constitutes three specific proteins A, C, and 70kDa, to which anti-U1 RNP antibodies bind. 70kDa antigen is the main target of the anti-RNP antibody in MCTD.[8] 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.[9] Sequence-based typing of HLA-B* and DRB1* showed that risk alleles for MCTD were HLA-B*08 and DRB1*04:01 while protective alleles were DRB1*04:04, DRB1*13:01, and DRB1*13:02.[10]

Apoptotic modification and molecular mimicry are the two mechanisms by which these intracellular molecules are believed to become autoantigens.[11] During apoptosis, proteins undergo post-translational modification due to the upregulation of different enzyme systems.[12] These modified proteins become concentrated in the surface blebs of apoptotic cells and become available to the immune system. Apoptotic modification of the U1 70kDa antigen is believed to be characteristic of mixed connective tissue disease. Antigens are presented by antigen-presenting cells to T cells that release cytokines, which in turn stimulate B cells to produce antibodies. Anti U1-RNP antibody, anti U1 70kDa antibody, and anti U1 70kDa reactive T lymphocytes circulating in peripheral blood are the hallmark of MCTD. Environmental factors, e.g., infections, drugs, toxins, UV radiation, and chemicals, including vinyl chloride and silica, have correlations with the development of MCTD.[13]

Amino acid sequence from these non-self proteins can mimic host epitope and induce autoantibody response, a phenomenon known as molecular mimicry. For example, almost 91% of DNA from the serum of patients with MCTD had a human immunodeficiency virus type-1 conserved pol sequence.[14] 75% of patients with MCTD patients had antibodies to HIV GAG proteins p35 and p24.[15]

History and Physical

Initial symptoms of mixed connective tissue disease are usually non-specific and include arthralgia, malaise, myalgia, and low-grade fever. Almost any organ system can be affected by MCTD.

Skin: The most common skin change is the Raynaud phenomenon, which is also the most common presenting feature of MCTD. Hand edema, acrosclerosis, calcinosis cutis, telangiectasia, erythema nodosum, hair loss, and vasculitis of digits are other manifestations. Discoid plaques and a malar rash similar to SLE can also occur. Nailfold changes are visible by capillary microscopy. Case reports describe panniculitis involving the abdomen, legs, and breasts.[16][17]

Joint: Joint involvement is usually more severe than in SLE. Arthritis with deformities similar to RA can also occur. Arthritis mutilans resembling psoriatic arthritis is rarely present.

Muscle: Inflammatory myopathy clinically and histologically similar to polymyositis often manifests as myalgia and is a common symptom of MCTD. Rarely myositis can also be the initial presentation.[18]

Lung: Pulmonary involvement occurs in almost 73% of patients, and dyspnea is the most common symptom. Patients can also be asymptomatic until fatal consequences arise.[19] Other symptoms include cough, pleuritic chest pain, wheeze, and hemoptysis. Pulmonary manifestations may include pleural effusion, pulmonary arterial hypertension, interstitial lung disease (ILD), pulmonary vasculitis, thromboembolic disease, alveolar hemorrhage, infections, and obstructive airway disease.[20]

Heart: Pericarditis is the most common variant of cardiac disease involving up to 40% of patients.[21] Pericardial effusion, mitral valve prolapse, myocarditis, accelerated atherosclerosis, and conduction abnormalities can also occur. 

Kidney: Renal involvement occurs in 15 to 25% of MCTD patients. Most patients are usually asymptomatic.[22] Membranous nephropathy is the most common finding. Nephropathy can sometimes be associated with significant morbidity, risk of hypertension, and chronic kidney disease, often requiring dialysis.[23]

The central nervous system(CNS): Though the lack of CNS involvement is characteristic of MCTD, mild involvement has been described in about 25% of patients.[24] Trigeminal neuralgia is the most common CNS manifestation. Psychosis, convulsion, peripheral neuropathy, headache, nuchal rigidity, aseptic meningitis, and sensorineural hearing loss can also occur.

Gastrointestinal tract: Esophageal hypomotility, dilatation, and GERD are frequent features. Less common manifestations are pancreatitis, megacolon, duodenal bleeding, portal hypertension, and autoimmune hepatitis. Rarely patients can present with protein-losing enteropathy. They often have anasarca due to hypoproteinemia.[25]

Hematological involvement: Anemia and leukopenia are common, while there are also reports of thrombocytopenia.

Evaluation

Laboratory Studies

A complete blood count will demonstrate anemia and leukopenia in almost 75% of patients. Hypergammaglobulinemia is also present in 75% of patients with MCTD. Erythrocyte sedimentation rate presents as elevated in nearly all patients.[2] Immunological markers include high titer speckled pattern anti-nuclear antibody (usually greater than 1280), high titer anti-U1-RNP, and anti-U1 70kd antibody. Data shows that 65% of patients with MCTD have positive rheumatoid factor, and 50% of patients have positive anti-CCP.[26][27] Muscle enzyme is above normal in most patients with features of myositis. Falsely positive VDRL and reduced level of complement levels are a feature in some patients. The antiphospholipid antibody is associated with pulmonary hypertension. Urinalysis can show proteinuria. Anti-double-stranded DNA, anticentromere, anti-Scl-70, and anti-PM-1 antibodies are usually absent.

Imaging Studies

Chest X-ray: Chest X-ray helps in evaluation for pulmonary infiltrates, pleural effusion, and cardiomegaly. Dilatation of the pulmonary artery can present in patients with pulmonary hypertension.

X-ray joints: X-ray of affected joints might reveal small, asymmetrical periarticular erosions. Soft tissue swelling, deformities, and destructive arthritis resembling psoriatic arthritis can present. Rarely periarticular osteopenia and aseptic necrosis may be found.

Echocardiogram: Echocardiogram shows Pericardial effusion, mitral valve prolapse, left ventricular hypertrophy, and changes secondary to pulmonary hypertension.

EKG: Abnormal EKG findings include hemiblock, bundle branch block, atrioventricular block, changes secondary to pericarditis, and pericardial effusion.

Pulmonary function testing: Reduction in diffusion capacity for carbon monoxide, forced vital capacity, forced expiratory volume, and six-minute walk tests occur in ILD.

Computed tomogram: High-resolution computed tomogram is very sensitive in diagnosing ILD. Common findings include ground-glass opacities, linear opacities, subpleural micronodules, septal thickening, traction bronchiectasis, usually with peripheral and lower lobe predominance. Honeycombing, airspace consolidation, emphysema, and centrilobular nodules are less common findings.[28]

Angiogram: Medium-sized arterial occlusions can occur in patients with Raynaud phenomenon.

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

Treatment / Management

No randomized controlled trials to guide the treatment of mixed connective tissue disease have yet taken place. The goal of therapy is to control symptoms and is directed by clinical manifestations and organ involvement. 

Raynaud phenomenon: Symptomatic management includes avoiding caffeine, smoking, cold temperature, and injuries. Oral calcium channel blockers (CCB), e.g., nifedipine that decreases peripheral resistance, are an option. Intravenous prostaglandins and topical nitroglycerins are effective. Case reports exist of the Raynaud phenomenon responding to rituximab.[29]

Arthritis and arthralgia usually respond to NSAIDs and hydroxychloroquine. For refractory synovitis, corticosteroids and methotrexate can be used.

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

Pulmonary hypertension is usually less responsive to steroids. Patients who respond to a vasodilator challenge during right heart catheterization receive treatment with CCB. The efficacy of anticoagulation with warfarin is unknown. Prostaglandins (epoprostenol), endothelin receptor antagonists (ambrisentan), phosphodiesterase 5 inhibitors (sildenafil), immunosuppression with corticosteroids and cyclophosphamide are all therapeutic considerations.

Esophageal disorders also respond to steroids. Gastroesophageal reflux disease (GERD) treatment is with proton pump inhibitors (PPI), lifestyle, and dietary modification, e.g., 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. Esophageal motility disorder requires prokinetics. Patients with malabsorption should be on a lactose-free diet, and medium-chain triglycerides should substitute for long-chain fatty acids.

Autoimmune hemolytic anemia and thrombocytopenia receive initial treatment with steroids. Clinicians can consider rituximab in resistant cases.

Differential Diagnosis

Due to the presence of nonspecific symptoms and different organ involvement, MCTD mimics several other conditions, especially CTD. Few differential diagnoses are listed below.

• Systemic lupus erythematosus
• Rheumatoid arthritis
• Polymyositis
• Dermatomyositis
• Scleroderma
• Bacterial infections
• Idiopathic pulmonary arterial hypertension
• Primary Raynaud disease

Prognosis

Mixed connective tissue disease, previously considered a mild and curable condition, can often be life-threatening. Almost one-third of patients with MCTD undergo complete resolution, while another third can develop life-threatening complications. Prognosis depends on which organ is affected, the degree of inflammation, and the rate of progression of the disease. The mortality rate varies between 8 and 36%.[30] In a study done in the Hungarian population, the survival rate for 5 and 10 years after diagnosis was 98% and 96% respectively. Pulmonary hypertension is the most common cause of death. Interstitial lung disease, infections, cardiovascular diseases, and malignancies are other causes.[31] The presence of IgG anticardiolipin antibodies might be associated with severe disease.

Epitope spreading can occur during disease leading to change in clinical features. For example, a lower rate of skin sclerosis and a higher percentage of interstitial lung disease appeared in patients who had epitope spreading compared to those who did not during a follow-up of patients with MCTD.[32] Also, patients with MCTD can clinically progress to other CTD, e.g., SSc, RA, Sjogren syndrome, and systemic lupus erythematosus. On the other hand, patients with other CTD or undifferentiated CTD can eventually develop into MCTD. 

Complications

Life-threatening complications, e.g., thrombotic thrombocytopenic purpura, renal crisis, malignant hypertension, and respiratory failure secondary to pulmonary hypertension, can occur rarely. Cardiovascular complications include dilated cardiomyopathy, cardiac tamponade, coronary sclerosis with ischemic cardiomyopathy, and arrhythmias. Infections accelerate atherosclerosis, and malignancies can occur as side effects of immunosuppressives. Transverse myelitis is a rare central nervous system complication.[33]

Deterrence and Patient Education

Patient education about the disease course and management is vital to improve the quality of life. Active involvement of patients in the decision-making process should be encouraged. Patients with esophageal reflux and malabsorption should receive education about lifestyle and dietary modification. Encouraging an active lifestyle and exercise program can help symptom management in patients with arthritis. 

Enhancing Healthcare Team Outcomes

Mixed connective tissue disease resembles several other connective tissue diseases and is easy to misdiagnose. Diagnosis can be challenging to nurse practitioners and primary care physicians due to variable and mixed presentation and changes in symptoms over time. Early diagnosis and targeted treatment are associated with a better outcome. It is crucial to recognize early signs and symptoms and make an early referral to a rheumatologist. Definitive diagnosis often requires close follow-up and identification of the characteristic evolution of clinical, laboratory, and radiologic findings.

An interprofessional team approach is key to improving the quality of life. Pulmonologists, cardiologists, and other specialist referrals should be made based on organ involvement. Nurses and physicians should provide coordinated patient education to ensure patient understanding of signs and symptoms and when to seek medical attention. Pharmacists should help educate patients about the medications used and their potential adverse effects. Pain should be addressed with pharmacologic and nonpharmacologic approaches, e.g., physical therapy, psychological, social, and emotional support.[34] An interprofessional team approach will result in the best outcomes for patients. [Level 5]