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Mixed Connective Tissue Disease

Syndrome Sharp


Presentation

Most of the clinical features of MCTD during the initial stages are very non-specific and hence difficult to confirm. Presence of Raynaud’s phenomenon and high levels of serum ANA are useful predictors during this period. The distinctive, overlapping features of the other three connective tissue disorders including SLE, scleroderma and myositis may appear only after a period of disease progression.

The most common sets of clinical manifestations include Raynaud phenomenon and swollen hands/digits, severe form of arthritis and pulmonary hypertension, and high serum titres of anti-U1SnRNPs [12]. Many organs including skin, joints, muscles, heart, lungs, gastrointestinal tract, kidneys, central nervous system, and vascular system are involved in MCTD during various stages of the disease progression. Skin manifestations include Raynaud’s phenomenon, sclerodactyly, swollen digits and calcinosis curtis. Joint involvement is also severe and common in MCTD. Most of the patients develop rheumatoid arthritis, often with in deformities as in boutonniere deformities and swan neck changes. Muscle involvement is in the form of inflammatory myopathy that resemble polymyositis, both clinically and histologically.

Abnormal electrocardiogram is also observed frequently. Right ventricular hypertrophy, right atrial enlargement and abnormality in conduction of signals are commonly reported. About 75% of the patients have pulmonary involvement with a wide variety of problems including pulmonary hypertension, pleural effusions, obstructive airways disease, and pleuritic pain. Also seen are gastrointestinal disorders of different kinds as an overlapping symptom of scleroderma. Low-grade anemia is noted in majority of patients.

Fever
  • In this report, we describe the case of a 73-year-old Japanese woman with MCTD who developed fever, thrombocytopenia, and microangiopathic hemolytic anemia and was diagnosed with MCTD together with TTP.[ncbi.nlm.nih.gov]
  • Herein, we present the case of a 25-year-old female who initially presented for evaluation of persistent fevers and fatigue. She was found to have splenomegaly, generalized lymphadenopathy, pancytopenia, and acute hepatic failure.[ncbi.nlm.nih.gov]
  • Low-grade fever. Raynaud phenomenon (reduced blood flow to the fingers, toes, ears, and nose, causing sensitivity, numbness, and loss of color in these areas).[my.clevelandclinic.org]
  • At least one of these areas must show severe symptoms; additionally, you must show at least two symptoms of severe illness (fever, loss of weight, severe weakness,etc.).[disability-benefits-help.org]
Edema of the Hand
  • Three months later, she developed edema of the hands, synovitis and acrosclerosis. The patient was finally diagnosed as having MCTD. We emphasized MCTD as a rare cause of "treatable dementia".[ncbi.nlm.nih.gov]
  • The physical examination revealed unremarkable findings, except for the presence of indurated edema of the hands with sclerodactyly.[oatext.com]
  • The association of edema of hands, Raynaud's phenomenon, and acrosclerosis in any combination requires at least one of the other two clinical features, that is, synovitis or myositis to be present.[e-ijd.org]
Rapidly Progressive Glomerulonephritis
  • We report the case of an elderly female patient with MCTD who developed autoimmune pleurisy and rapidly progressive glomerulonephritis. Myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA) was positive with a titer of 59.0 EU.[ncbi.nlm.nih.gov]
  • The complication of ANCA-associated glomerulonephritis should not be overlooked when abnormal urinalysis findings appear in the course of connective tissue disease, irrespective of the presence of rapidly progressive glomerulonephritis.[ncbi.nlm.nih.gov]
Splenectomy
  • However, portal vein thrombosis developed after splenectomy. This was a rare case of severe complications of IPH accompanying MCTD and protein C deficiency.[ncbi.nlm.nih.gov]
Mitral Valve Prolapse
  • These abnormalities included conduction abnormalities, pericardial effusion and mitral valve prolapse. Diastolic dysfunction and accelerated atherosclerosis were well-documented in a case-control study.[ncbi.nlm.nih.gov]
  • Acute pericarditis and/or pericardial effusion was detected in 11 patients (29%) and mitral valve prolapse was identified in 10 patients (26%).[circ.ahajournals.org]
  • Pericarditis is the most common cardiac diagnosis. [ 8 ] Other abnormalities include conduction abnormalities, pericardial effusion and mitral valve prolapse.[patient.info]
  • Other cardiac abnormalities include conduction abnormalities, pericardial effusion, mitral valve prolapse, diastolic dysfunction, and accelerated atherosclerosis.[emedicine.medscape.com]
Arthritis
  • Fifty-two patients had continuous JMCTD; the most common manifestations were: Raynaud (100%), arthritis (94%), puffy hands (77%) and pulmonary manifestations (58%).[ncbi.nlm.nih.gov]
  • Swelling and pain in the joints, typical of arthritis, are also common. Some patients may have joint deformities as in the case of rheumatoid arthritis.[symptoma.com]
  • The study identified male gender, elevated anti-RNP titre, presence of anti-ro52 antibodies and absence of arthritis as the strongest predictors of ILD progression.[ncbi.nlm.nih.gov]
  • Arthritis and Rheumatism . 62 (12): 3730–40. doi : 10.1002/art.27700 . PMID 20722023 .[en.wikipedia.org]
  • The most common systemic rheumatologic conditions are connective tissue diseases (including rheumatoid arthritis [RA]) followed by spondyloarthropathy.[ncbi.nlm.nih.gov]
Proximal Muscle Weakness
  • We present the case of a 50-year-old black woman whose inaugural presentation of MCDT was oropharyngeal dysphagia, symmetrical proximal muscle weakness, tongue atrophy and skin sclerosis.[ncbi.nlm.nih.gov]
  • muscle weakness Primary pulmonary hypertension- elevated pulmonary artery pressure with no known cause, if left untreated will lead to right-sided heart failure Raynaud phenomenon- recurrent vasospasms of the fingers or toes which usually occurs as a[physio-pedia.com]
  • The patient being reported is a 21-year-old male who presented in the Immunology Outpatient Department in February 2010 with complaints of arthritis involving small as well as large joints, low-grade fever, on and off, puffy fingers and proximal muscle[sjkdt.org]
  • The myositis-like subgroup was defined by proximal muscle weakness, elevated creatinine kinase, pathological electromyography and/or myositis verified by muscle biopsy.[doi.org]
Suicidal Ideation
  • Depression symptoms were present in 23%, suicidal ideation in 15%, and anxiety in 27% of participants.[ncbi.nlm.nih.gov]
  • Suicidal ideation was present in 7 (14%) SLE/MCTD and 2 (4%) healthy subjects, which was a statistically significant difference (OR   5.4, 95% CI 1.02-28.3, p   0.047).[ncbi.nlm.nih.gov]

Workup

Laboratory tests show high serum levels of anti-U1RNP antibodies. Elevated levels of ANA can be observed as speckled pattern in fluorescent antinuclear antibody test. Patients with pulmonary hypertension show antiphospholipid antibodies. More than 60% of the patients are positive to rheumatoid factor. Other immunodiagnostic tests including anti-U1RNA and antibodies against snRNP polyeptides 68kd may also be useful.

Cardiomegaly, effusion, pulmonary hypertension and valvular diseases can be assessed using chest X-ray and echocardiography. CT scan or ultrasonography reveal the presence of visceral perforations, pancreatitis or serositis. Reduced diffusion capacity of lung for carbon monoxide (DLCO) in a pulmonary function test indicate the presence of pulmonary hypertension. Cardiac problems including myocardial ischemia and myocarditis is assessed using ECG. Presence of neuropsychiatric symptoms is monitored through cerebrospinal fluid analysis.

X-Ray Abnormal
  • Sullivan et al . described chest X-ray abnormalities in 10/34 MCTD patients [ 29 ]. Small irregular opacities were found predominantly in the lower and midlung fields during a 1 to 18 yr follow-up period.[academic.oup.com]
Chest X-Ray Abnormal
  • Sullivan et al . described chest X-ray abnormalities in 10/34 MCTD patients [ 29 ]. Small irregular opacities were found predominantly in the lower and midlung fields during a 1 to 18 yr follow-up period.[academic.oup.com]
Esophageal Motility Disorder
  • PM: Polymyositis DM: Dermatomyositis RA: Rheumatoid Arthritis CREST: Calcinosis, Raynaud disease, Esophageal motility disorder, Sclerodactyly, and Telangiectasia SLE: Systemic Lupus Erythematosus MCTD: Mixed Connective Tissue Disease *The figure is developed[vibrant-america.com]
Elevated Sedimentation Rate
  • These may include: Elevated sedimentation rate (also known as erythrocyte sedimentation rate or ESR), an indicator of inflammation. Antiphospholipid antibodies (which can affect blood clotting and may increase your risk of miscarriage).[hss.edu]
Insulin Decreased

Treatment

Treatment of MCTD is often based on the organ involved and the progression of the disease. Priority is given to control the symptoms and prevent the development of complications associated with the disorder. Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used to control the symptoms in case of mild MCTD. For those patients who present refractory synovitis, low doses of corticosteroids are recommended. NSAIDs along with hydroxychloroquine is used for symptomatic relief of arthritis. Corticosteroids are suggested in severe forms of MCTD, with the dose depending on the severity and the organ involved.

Calcium channel blockers have vasodilatory effect which is useful in controlling Raynaud’s phenomenon. Phosphodiesterase inhibitors may also be used in Raynaud’s disease and is also helpful in controlling pulmonary hypertension. Pulmonary hypertension, if present, should be the focus of any treatment, as it increases morbidity and mortality. Endothelin receptor antagonists are found to be useful in improving pulmonary hypertension [13], but has the risk of liver toxicity. Steroid pulse therapy can prevent complications like vascular lesions in patients with pulmonary hypertension [14]. Prostaglandins are also considered to be useful in the management of pulmonary hypertension and the dosage and administration should be done by experts. Immunosuppression using cytotoxic agents along with corticosteroids is suggested in case of organ involvement.

Prognosis

Prognosis is variable in MCTD. Most of the clinical features associated with MCTD develop over a period of time while some like esophageal hypomotility and Raynaud’s phenomenon reduce. In some of the patients the symptoms may enter long-term remission, but in some others it will show severe progression.

A study conducted on a cohort of patients with MCTD showed that features like pulmonary hypertension and pulmonary dysfunction tend to persist even after a period of treatment [11]. This study also reported that most of the patients had a favorable outcome. The most common cause of mortality associated with this disorder is pulmonary hypertension. Morbidity is caused by arthritis, fatigue and dyspnea associated with exertion.

Etiology

Pathogenesis of this autoimmune disorder is not fully known yet. One of the most characteristic feature of the disease is the presence of high titre of antibodies to U1RNPs. Induction of these antibodies along with alterations of self-antigens and antigenic changes during cell apoptosis are hypothesized to trigger an immune process that result in abnormal activation and responses of B- and T-lymphocytes which in turn lead to clinical manifestations of the disorder [4].

Some of the hypothesized mechanisms that lead to U1SnRNP induction include spreading of epitopes, modifications during cell apoptosis and activation of toll-like receptor (TLR) [5].

Epidemiology

Prevalence of this disorder remains unknown in different parts of the world. In Japan, MCTD is estimated to affect one in 37,000 people. A multicenter survey conducted in Norway showed a prevalence of 3.8 per 100,000 adults [6]. Females were found to be more affected than males and incidence of MCTD was lower when compared to other connective tissue disorders including SLE, polymyositis and systemic sclerosis.

Sex distribution
Age distribution

Pathophysiology

One of the distinctive features of this disease is the presence of increased levels of U1RNP and U1-70 kd antibodies. Levels of human leucocyte antigens HLA-DR4 and HLA-DRw53 were found to be more in patients with this connective tissue disorder [7].

MCTD patients have an increased frequency of the allele MICA 129 when compared to patients with other forms of connective tissue diseases [8]. Majority of the patients with MCTD also showed the presence of increased levels of anti-endothelial cell antibodies (AECA) and these were associated with disease activity and vasculitic manifestations [9]. Elevated levels of AECA correlate with increased levels of plasma immunoreactive endothelin-1 [10].

Prevention

There is no guideline for the prevention of MCTD.

Summary

Mixed connective tissue disease or MCTD is an autoimmune disorder, first identified in patients presenting features of three different connective tissue diseases – systemic lupus erythematosus (SLE), scleroderma and myositis [1]. The differentiating feature of MCTD is the presence of high amounts of antinuclear antibodies (ANAs) and antibodies against U1 small nuclear ribonucleoprotein (SnRNP).

MCTD was considered as a separate disease entity after years of controversies but is now fully characterized as having increased frequency of features including Raynaud’s syndrome, sclerodactyly, myositis, esophageal dysmotility, arthritis, and polymyositis [2] [3]. As the disease progresses, a subgroup of patients may evolve into having other connective tissue disorders.

Patient Information

MCTD is a rare form of autoimmune disorder characterized by the presence of ‘overlapping’ symptoms of three different connective tissue diseases including SLE (or lupus as it is commonly known as), scleroderma and myositis. As the disease progresses, the symptoms may gradually evolve and become dominated by one of the above-mentioned diseases. The actual cause of the disease is not yet known. MCTD may occur at any age but is more common among women under 30 years of age.

Patients with this disease have high serum levels of anti-U1snRNP antibodies that trigger an abnormal immune response in which the immune system attacks the body’s own tissues. Symptoms of MCTD are varied and may differ from person to person. During the early stages of the disease, non-specific symptoms like fever and fatigue exist. Raynaud’s phenomenon is a common feature of this disease in which the fingers may become cold and numb during stress or in cold conditions. Constriction of blood vessels may cause the fingers to turn pale and then purple. Swelling in the fingers or hands is yet another symptom of MCTD. Swelling and pain in the joints, typical of arthritis, are also common. Some patients may have joint deformities as in the case of rheumatoid arthritis. MCTD may lead to complications including pulmonary hypertension, in which the high blood pressure may affect the blood vessels of the lungs. MCTD may affect many organs. It may also lead to kidney problems and cardiac abnormalities. Some people may develop gangrene, acute arthritis, meningitis, neuropathy, high fever or abdominal pain depending on the organ affected.

Clinical examination and laboratory tests are used to diagnose MCTD. Presence of ‘overlapping’ symptoms along with high serum levels of ANA and anti-U1RNP antibodies are the most important indicators of MCTD. These antibodies are different from the ones present in SLE or scleroderma and thus help in distinguishing MCTD from other common connective tissue disorders.

Treatment of MCTD depends on the symptoms and the type and severity of organ affected. People with mild MCTD may be prescribed NSAIDs for symptomatic relief. Antihypertensive medications are recommended for those who have pulmonary hypertension. Treatment of pulmonary hypertension is very important as it is most important cause of death associated with MCTD. In moderate to severe form of the disease, corticosteroids and immunosuppressants are recommended. For controlling arthritic inflammation, low doses of corticosteroids are used. Patients should regularly monitor their heart condition to prevent cardiac problems. The outcome of MCTD is favorable in most of the cases and timely treatment of the different conditions will help in reducing morbidity associated with connective tissue disorders.

References

Article

  1. Sharp GC, Irvin WS, Tan EM, Gould RG, Holman HR. Mixed connective tissue disease--an apparently distinct rheumatic disease syndrome associated with a specific antibody to an extractable nuclear antigen (ENA). Am J Med. 1972; 52(2): 148-59.
  2. Cappelli S, Bellando randone S, Martinović D, et al. "To be or not to be," ten years after: evidence for mixed connective tissue disease as a distinct entity. Semin Arthritis Rheum. 2012; 41(4): 589-98.
  3. Venables PJ. Mixed connective tissue disease. Lupus. 2006; 15(3): 132-137.
  4. Hoffman TW, Maldonado ME. Immune pathogenesis of mixed connective tissue disease: a short analytical review. Clin Immun. 2008; 128(1): 8-17.
  5. Kattah NH, Kattah MG, Utz PJ. The U1-snRNP complex: structural properties relating to autoimmune pathogenesis in rheumatic diseases. Immunol Rev. 2010; 233(1): 126-145. 
  6. Gunnarsson R, Molberg O, Gilboe IM, et al. The prevalence and incidence of mixed connective tissue disease: a national multicenter survey of Norwegian patients. Ann Rheum Dis. 2011; 70(6): 1047-51.
  7. Hoffman RW, Rettenmaier LJ, Takeda Y, et al. Human autoantibodies against the 70-kd polypeptide of U1 small nuclear RNP are associated with HLA-DR4 among connective tissue disease patients. Arthritis Rheum. 1990; 33(5): 666-673.
  8. Yoshida K, Inoue H, Komai K, et al. Mixed connective tissue disease is distinct from systemic lupus erythematosus: study of major histocompatibility complex class I polypeptide-related sequence A and HLA gene polymorphisms. Tissue Antigens. 2013; 81(1): 44-5.
  9. Lage LV, de Carvalho JF, Caleiro MT, et al. Fluctuation of anti-endothelial cell antibody titers in mixed connective tissue disease. Isr Med Assoc J. 2012; 14(2): 84-87. 
  10. Janos GF, Edit B, Sandor S, et al. Plasma Endothelin Correlates With Antiendothelial Antibodies in Patients With Mixed Connective Tissue Disease. Circulation. 1995; 92: 2969-2974. 
  11. Burdt MA, Hoffman RW, Deutscher SL, et al. Long-term outcome in mixed connective tissue disease: Longitudinal clinical and serologic findings. Arthritis Rheum. 1999; 42(5): 899-909. 
  12. Bennet RM. Clinical manifestations of mixed connective tissue. UpToDate 
  13. Girgis RE, Frost AE, Hill NS, et al. Selective endothelinA receptor antagonism with sitaxsentan for pulmonary arterial hypertension associated with connective tissue disease. Ann Rheum Dis. 2007; 66: 1467-1472. 
  14. Kamata Y, Nara H, Sato H, Masuyama JI, Minota S, Yoshio T. Effect of steroid pulse therapy on mixed connective tissue disease with pulmonary arterial hypertension. Ann Rheum Dis. 2005; 64:1236-1237. 

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Last updated: 2018-06-21 18:29