Mixed Connective Tissue Disease


Article Author:
Binita Sapkota


Article Editor:
Yasir Al Khalili


Editors In Chief:
Kranthi Sitammagari
Mayank Singhal


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Frank Smeeks
Kristina Soman-Faulkner
Radia Jamil
Patrick Le
Sobhan Daneshfar
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Pritesh Sheth
Hassam Zulfiqar
Navid Mahabadi
Steve Bhimji
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Nazia Sadiq
Hajira Basit
Phillip Hynes
Tehmina Warsi


Updated:
6/3/2019 8:05:11 PM

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 presence of a distinctive antibody, anti-U1-ribonucleoprotein (RNP) previously known as 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 considerable inter-individual variation in clinical manifestations. Alarcon-Segovia is one of the regularly used diagnostic criteria that consists of the presence of 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 atherosclerosis.

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 be associated 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.[3] In a study done on the Norwegian population, the incidence of MCTD was 2.1 per million per year, female to male ratio was 3.3 to 1, and the mean age at diagnosis was 37.9 years.[4] This disease affects all races, and its clinical manifestations are similar in all ethnic groups.

Pathophysiology

Since 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.[5] 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 antibody bind. 70kDa antigen is the main target of anti-RNP antibody in MCTD.[6] 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.[7] 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.[8]

Apoptotic modification and molecular mimicry are the two mechanisms by which these intracellular molecules are believed to become autoantigens.[9] During apoptosis, proteins undergo post-translational modification due to upregulation of different enzyme systems.[10] These modified proteins become concentrated in the surface blebs of apoptotic cells and become available to the immune system. Apoptotic modification of 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 antibody. Anti U1-RNP antibody, anti U1 70kDa antibody, and anti U1 70kDa reactive T lymphocytes circulating in peripheral blood is 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.[11] 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.[12] 75% of patients with MCTD patients had antibodies to HIV GAG proteins p35 and p24.[13]

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 in MCTD.

Skin: Most common skin change is 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 abdomen, legs, and breasts.[14][15]

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 manifest as myalgia and is a common symptom of MCTD. Rarely myositis can also be the initial presentation.[16]

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.[17] 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.[18]

Heart: Pericarditis is the most common variant of cardiac disease involving up to 40% of patients.[19] 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.[20] 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.[21]

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.[22] 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.[23]

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. 65% of patients with MCTD have positive rheumatoid factor[24], and 50% of patients have positive anti-CCP.[25] Muscle enzyme is above normal in most of the 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.[26]

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 25mmHg.

Treatment / Management

No randomized controlled trials to guide 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 the peripheral resistance are an option. Intravenous prostaglandins and topical nitroglycerins have been found to be effective. Case reports exist of Raynaud phenomenon responding to rituximab.[27]

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 a second-line agent. 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 a  with CCB. Efficacy of anticoagulation with coumadin 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. GERD treatment is with proton pump inhibitors (PPI), lifestyle and dietary modification, e.g., the elevation of the head of the bed and avoidance of 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 differentials 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%.[28] 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.[29] 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.[30] Also, patients with MCTD can clinically progress to other CTD, e.g., SSc, RA, Sjogren syndrome, and SLE. 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, accelerated atherosclerosis, and malignancies can occur as side effects of immunosuppressives. Transverse myelitis is a rare CNS complication.[31]

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 change 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.

A multidisciplinary team approach is a key to improve the quality of life. Pulmonologist, cardiologist, and other specialist referrals should be made based on organ involvement. Nurses and physicians should provide patient education to ensure patient understanding of signs and symptoms and when to seek medical attention. Pharmacist should help educate patients about the medication and their potential adverse effects. Pain should be addressed not only with pharmacologic but also nonpharmacologic approaches, e.g., physical therapy, psychological, social, and emotional support.[32] (Level V)


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Mixed Connective Tissue Disease - Questions

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A 16-year-old female is being evaluated for a one-year history of Raynaud phenomenon. She also has arthritis involving PIP joints, wrists, ankles, and knees. On physical examination sclerodactyly, ulceration of fingertips, and swelling and tenderness over PIP joints were noted. A presumptive diagnosis of connective tissue disease was made and autoimmune markers were sent. Antibodies against ribonucleoprotein (RNP) would be positive in which of the following autoimmune diseases?



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Which patients often have elevated levels of anti-RNP?



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A 32-year-old male is being evaluated for a five days history of chest pain. He describes chest pain as sharp, non-radiating, exacerbated by deep inspiration and alleviated on leaning forward position. He has a history of mixed connective tissue disease (MCTD). He takes NSAIDs for his arthralgia as needed. On physical examination, his weight is 98 kg, and BMI is 22. Vital signs are normal. Heart sounds are normal with no murmur, but a friction rub is heard. The chest is clear to auscultation bilaterally. The abdomen is benign and neurological examination did not show any focal deficits. Tenderness and swelling are obvious over bilateral first and second metacarpophalangeal joints. Laboratory tests show normal complete blood count and basic metabolic panel, CPK is 590 IU and anti-U1 RNP is positive. EKG showed diffuse ST elevations. An echocardiogram shows pericardial thickening with no effusion, normal right and left ventricular size and function. What is the most appropriate next step in the management of this patient?



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A 30-year-old female is being evaluated for a 2-year history of pain and swelling of her entire bilateral hands. She also reports bluish discoloration of her fingers on exposure to cold. She has a six months history of pain over bilateral wrists and knees. On physical examination, diffuse edematous, sausage-shaped fingers are noted bilaterally, tenderness is present over the bilateral wrist. Skin examination shows discoid plaques over the posterior neck. A laboratory study shows hemoglobin 11 g/dl, positive ANA (1:320), positive rheumatoid factor and anti-U1 RNP antibody (1:1600). C3, C4, anti-ds DNA antibody, anti-Scl 70 antibody, anti-Ro, and anti-La antibodies are negative. What is the most likely diagnosis?



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A 38-year-old female was evaluated for arthralgias of her hands and feet. She also had malaise, low-grade fever, decreased appetite, and a rash over elbows. Biopsy of the rash showed discoid lupus. Prednisone was prescribed after which symptoms were controlled. Two years later she presented with shortness of breath on exertion for one month. She also reported pain and bluish discoloration of fingers on exposure to cold. She denied any cough, chest pain, orthopnea, and leg swelling. On physical examination, systolic pulsation over the left sternal border and an accentuated second heart sound were appreciated. Lungs were clear to auscultation. Laboratory tests were significant for positive ANA, anti-U1 ribonucleoprotein (RNP) antibody, and antiphospholipid antibody. Anti-DS DNA antibody, rheumatoid arthritis factor, and anti-cyclic citrullinated peptide (anti-CCP) antibody were negative. Chest x-ray showed a dilated pulmonary artery. Echocardiogram showed enlarged right ventricle. What is the next step in the management of this patient?



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A 40-year-old male presented with gradually worsening shortness of breath for the last six months. He has also noted pain and swelling over wrists and metacarpophalangeal (MCP) joints bilaterally. Recently he has noticed generalized myalgia and symptoms of Raynaud phenomenon. His medical problems include hypertension for which he takes amlodipine 10 mg/day. He has a seasonal allergy to pollens. He is an active smoker and smokes one pack per day for the last 20 years. He worked as a stone crusher for the previous ten years. On physical examination, the patient appears pale, has sclerodactyly over bilateral hands, tenderness over bilateral wrists and MCP joints. Fine crepitations are heard over bilateral lower lungs on auscultation. Labs showed hemoglobin 10 gm/dl, ESR 65 mm/hr, CPK 1200 mcg/L, positive ANA, and positive anti-U1 ribonucleic protein (RNP). Chest x-ray showed bibasilar infiltrates. CT chest showed ground-glass opacities and centrilobular nodules over bilateral lower lobes. Transbronchial biopsy of the lung showed findings typical for silicosis. Based on positive anti-U1 RNP, Raynaud phenomenon, arthritis, sclerodactyly, and myositis, a diagnosis of mixed connective tissue disease (MCTD) was made. He was started on prednisone 20mg daily and methotrexate 25 mg weekly. During a follow up at one month he showed significant improvement in his respiratory and joint symptoms. Which of the following mechanism is likely responsible for the pathogenesis of MCTD in this patient?



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Mixed Connective Tissue Disease - References

References

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