Mixed connective tissue disease

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Shaghayegh Habibi, M.D.[2]

MCTD was first defined by Gordon C.Sharp et al., in 1972. MCTD is a systemic autoimmune disease that is characterized by overlapping symptoms of two or more systemic autoimmune diseases (SLE, RA, DM, polymyositis, and scleroderma) and the presence of antibodies against U1snRNP. Primary pathogenesis in MCTD include vasculopathy leading to tissue ischemia, immunological and inflammatory processes and fibrosis caused by excessive synthesis of collagen and other proteins of matrix. In MCTD associated conditions include secondary Sjogren’s syndrome and trigeminal neuralgia. A significant association between U1RNP disease and HLA-DR4 and DR154-61 is detected It is an autoimmune disease and the exact cause is unknown. MCTD has to be differentiated from other conditions with similar presentation of arthritis and rash like systemic lupus erythematosus, rheumatoid arthritis, undifferentiated connective tissue disease, systemic sclerosis, Sjogren’s syndrome, vasculitis, Behcet’s syndrome, serum sickness, psoriatic arthritis and human parvovirus B19 infection. The incidence of MCTD is approximately 2.7 per 100,000 individuals per year and the mortality rate is nearly 10.4% over the period of 13-15 years. The female to male ratio is approximately 10 to 1. If the patients with MCTD left untreated, approximately 35% of patients may progress to develop lung fibrosis. Common complications of MCTD include polyarthritis, Raynaud’s phenomenon, interstitial lung disease, esophageal dysmotility, sclerodactyly, polymyositis, and pulmonary hypertension. Major causes of morbidity in long-term MCTD patients include sclerodactyly, diffuse sclerosis, pulmonary arterial hypertension, and nervous system disease. Patients with MCTD may have a positive history of Raynaud’s phenomenon, arthralgia, gastroesophageal reflux, myalgia and dyspnea and common symptoms of MCTD include swollen fingers, diffuse swelling of hands, and dry cough. Physical examination is usually include tachycardia, tachypnea, periungual telangiectasia, sclerodactyly, jugular vein distention, rhonchi and wheezing, joint swelling and tenderness, and joints erythema and effusion. Laboratory findings consistent with the diagnosis of MCTD include antibodies against the U1RNP, rheumatoid factor (RF), high CRP levels, hypergammaglobulinemia, anemia, leucopenia, circulating immune complexes, and hypocomplementemia. An x-ray may be helpful in the diagnosis of complications of MCTD, which include features characteristic of polyarthritis and esophageal dilatation. The treatment of patients with MCTD depends on type of internal organ involvement, phase of the disease, and rate of disease progression. Treatment strategies must follow conventional treatments that are used for similar problems in other rheumatic diseases. Usually the treatment of patients with MCTD include low doses of steroids, NSAIDs, immunosuppressive drugs, and biologic agents. The treatment options in refractory cases or in severe clinical conditions include immunoglobulins, cytotoxic agents, and biologic drugs.

MCTD was first defined by Gordon C.Sharp et al., in 1972. It has been the first rheumatic disease syndrome defined by a serologic test. In 1976, Alarcon-Segovia proposed criteria for classifying MCTD among all types of connective tissue diseases. It demonstrates the close association between MCTD and Sjogren’s syndrome.

There is no established system for the classification of mixed connective tissue disease.

MCTD is a systemic autoimmune disease that is characterized by overlapping symptoms of two or more systemic autoimmune diseases (SLE, RA, DM, polymyositis, and scleroderma) and the presence of antibodies against U1snRNP. Primary pathogenesis in MCTD include vasculopathy leading to tissue ischemia, immunological and inflammatory processes and fibrosis caused by excessive synthesis of collagen and other proteins of matrix. In MCTD associated conditions include secondary Sjogren’s syndrome and trigeminal neuralgia. A significant association between U1RNP disease and HLA-DR4 and DR154-61 is detected. Gross pathology of skin may include photo-distributed erythematosus annular lesions, papulosquamous lesions, telangiectasia, and sclerodactyly and the skin histopathological findings include poor and lichenoid interface dermatitis and suprabasilar exocytosis around necrotic keratinocytes.

Mixed connective tissue disease is an autoimmune disease and the exact cause is unknown.

MCTD has to be differentiated from other conditions with similar presentation of arthritis and rash like systemic lupus erythematosus, rheumatoid arthritis, rhupus, undifferentiated connective tissue disease, systemic sclerosis, Sjogren’s syndrome, vasculitis, Behcet’s syndrome, Kikuchi’s disease, serum sickness, psoriatic arthritis and human parvovirus B19 infection.

The incidence of mixed connective tissue disease is approximately 2.7 per 100,000 individuals per year. A nationwide study on MCTD showed the prevalence of mixed connective tissue disease was 2.7 per 100,000 individuals in Japan and 3.8 per 100,000 individuals in Norway. In MCTD, the mortality rate is nearly 10.4% over the period of 13-15 years. It is usually diagnosed during childhood and is more frequent among black and Asian population. The female to male ratio is approximately 10 to 1.

There are no established risk factors for mixed connective tissue diease.

There is insufficient evidence to recommend routine screening for mixed connective tissue disease.

If the patients with mixed connective tissue disease left untreated, approximately 35% of patients may progress to develop lung fibrosis. Common complications of MCTD include polyarthritis, Raynaud’s phenomenon, interstitial lung disease, esophageal dysmotility, sclerodactyly, polymyositis, and pulmonary hypertension. Major causes of morbidity in long-term MCTD patients include sclerodactyly, diffuse sclerosis, pulmonary arterial hypertension, and nervous system disease. The presence of pulmonary involvement is associated with worst prognosis and high mortality rate.

The diagnostic criteria of Kasukawa include symptoms common to all the diseases involved, presence of antibodies against the U1snRNP, and selected symptoms typical of each of the particular component diseases separately (systemic lupus erythematosus, systemic sclerosis, polymyositis). The MCTD can be confirmed when there is at least one common symptom, positive antibodies reacting with U1RNP, and at least one symptom from each of the component diseases.

Patients with MCTD may have a positive history of Raynaud’s phenomenon, arthralgia, gastroesophageal reflux, myalgia and dyspnea. Common symptoms of MCTD include swollen fingers (“sausage digits”), diffuse swelling of hands, and dry cough. Less common symptoms include rashes, alopecia, mild fever, fatigue.

Physical examination of patients with MCTD is usually remarkable by clinical features seen in systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), dermatomyositis (DM), polymyositis, and scleroderma. Physical examination in patients with MCTD include tachycardia, tachypnea, periungual telangiectasia, sclerodactyly, jugular vein distention, rhonchi and wheezing, joint swelling and tenderness, and joints erythema and effusion.

Laboratory findings consistent with the diagnosis of MCTD include antibodies against the U1RNP, rheumatoid factor (RF), high CRP levels, hypergammaglobulinemia, anemia, leucopenia, circulating immune complexes, and hypocomplementemia.

There are no ECG findings associated with MCTD.

An x-ray may be helpful in the diagnosis of complications of mixed connective tissue disease, which include features characteristic of polyarthritis (soft tissue atrophy, calcifications, distal interphalangeal joint erosions, juxta-articular osteoporosis, joint space narrowing, marginal erosions, joint deformities without erosions, and osteonecrosis) and interstitial lung disease (ground−glass opacities, peripheral reticular infiltrates, and small irregular opacities).

There are no ultrasound findings associated with mixed connective tissue disease.

In MCTD, the tomographic images may show radiographic abnormalities related to interstitial lung disease and the presence of esophageal dilatation. Chest CT scan findings include ground glass opacities, irregularity of the interfaces between the peripheral pleura and aerated lung parenchyma, septal and non-septal lines, intralobular reticular opacities, bronchiolectasis or traction bronchiectasis, areas of cystic spaces (honeycombing), areas of decreased attenuation and air trapping on expiratory computed tomography.

Musculoskeletal MRI can identify and characterize subclinical synovial inflammation and joint damage with a greater precision than X-rays. Also cardiac MRI is complementary for diagnosing pulmonary arterial hypertension.

There are no other imaging findings associated with mixed connective tissue disease.

Pulmonary function test may be helpful in the diagnosis of interstitial lung disease as a complication of MCTD. Findings suggestive of interstitial lung disease include significantly lower DLCO values in the active pulmonary stage and restrictive ventilatory defect (reduction of FEV1 and total lung capacity).

The treatment of patients with MCTD depends on type of internal organ involvement, phase of the disease, and rate of disease progression. Treatment strategies must follow conventional treatments that are used for similar problems in other rheumatic diseases (SLE, scleroderma, polymyositis). Usually the treatment of patients with MCTD include low doses of steroids, NSAIDs, immunosuppressive drugs, and biologic agents. The treatment options in refractory cases or in severe clinical conditions include immunoglobulins, cytotoxic agents, and biologic drugs.

In MCTD, surgical options are the alternative for the patients who continue to progress in the disease related complications despite aggressive therapy. The surgical options include procedures like atrial septostomy and lung transplantation.

There are no established measures for the primary prevention of MCTD.

In MCTD effective measures for the secondary prevention of Raynaud’s disease include vasodilator therapies (such as calcium channel blockers), preventive approaches like avoidance of cold temperatures, smoking, and sympathomimetic agents and use of warm and protection techniques of fingers. Current strategies include Bosentan (endothelin receptor antagonist) as the recommended medication for the prevention of new digital ulcers.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Shaghayegh Habibi, M.D.[2]

In 1972, Gordon C.Sharp was the first physician who defined MCTD. It has been the first rheumatic disease syndrome that has represented by a serologic test. In 1976, Alarcon-Segovia proposed criteria for MCTD classifying between all types of connective tissue diseases. It represents the close association between MCTD and Sjogren’s syndrome.

• In 1972, Gordon C.Sharp was the first physician who defined MCTD.
• MCTD has been the first rheumatic disease syndrome that has represented by a serologic test (positive U1RNP).^[1][2]
• In 1976, Alarcon-Segovia proposed criteria for MCTD classifying between all types of connective tissue diseases. It represents the close association between MCTD and Sjogren’s syndrome.
• In 1987, Sharp, Alarcon-Segovia and The Research Committee of Japanese Ministry of Health and Welfare for MCTD (JMHW) suggested three groups of criteria for diagnosing MCTD.^[3]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Shaghayegh Habibi, M.D.[2]

There is no established system for the classification of mixed connective tissue disease.

There is no established system for the classification of mixed connective tissue disease.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Shaghayegh Habibi, M.D.[2]

MCTD is a systemic autoimmune disease that is characterized by overlapping symptoms of two or more systemic autoimmune diseases (SLE, RA, DM, polymyositis, and scleroderma) and the presence of antibodies against U1snRNP. Primary pathogenesis in MCTD include vasculopathy leading to tissue ischemia, immunological and inflammatory processes and fibrosis caused by excessive synthesis of collagen and other proteins of matrix. In MCTD associated conditions include secondary Sjogren’s syndrome and trigeminal neuralgia. A significant association between U1RNP disease and HLA-DR4 and DR154-61 is detected. Gross pathology of skin may include photo-distributed erythematosus annular lesions, papulosquamous lesions, Telangiectasia, and Sclerodactyly and the skin histopathological findings include poor and lichenoid interface dermatitis and suprabasilar exocytosis around necrotic keratinocytes.

The pathogenesis of mixed connective tissue disease is as follows:^[1][2][3][4]

• MCTD is a systemic autoimmune disease that is characterized by:
  • Overlapping symptoms of two or more systemic autoimmune diseases
  • Presence of antibodies against the U1 small nuclear ribonucleoprotein autoantigen (U1snRNP)
• MCTD is characterized by clinical symptoms seen in systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), dermatomyositis (DM), polymyositis, and scleroderma.
• Primary pathogenesis in MCTD include:
  • Vasculopathy leading to tissue ischemia
  • Autoimmunity causes immunological and inflammatory
  • fibrosis caused by excessive synthesis of collagen and other proteins of matrix
• In MCTD, U1-snRNP components play an important role for triggering immune responses.
• Two complications of pulmonary hypertension and interstitial lung disease are the most frequent causes of death.

• In MCTD, the frequency of HLA-DR4 is increased compared with healthy individuals in worldwide studies.^[4]
• A significant association between U1RNP disease and HLA-DR4 and DR154-61 is detected.

In MCTD associated conditions include:^[3]

• Secondary Sjogren’s syndrome
• Trigeminal neuralgia

• In MCTD, gross pathology of skin may include:^[5][6]
  • Photo-distributed erythematosus annular lesions
  • Papulosquamous lesions
  • Telangiectasia
  • Sclerodactyly

• In MCTD, histopathological features of interstitial lung disease are similar to idiopathic pulmonary fibrosis (IPF). The findings including:^[7]
  • Infiltration of lymphocytes and plasma cells in alveolar septum
  • Deposition of type III collagen
• In MCTD, skin histopathological characteristics are similar to subacute cutaneous lupus erythematosus (SCLE). The findings include:^[5]
  • Poor and lichenoid interface dermatitis
  • Suprabasilar exocytosis around necrotic keratinocytes

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Shaghayegh Habibi, M.D.[2]

Mixed connective tissue disease is an autoimmune disease and the exact cause is unknown.

Mixed connective tissue disease is an autoimmune disease and the exact cause is unknown.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mahshid Mir, M.D. [2] Shaghayegh Habibi, M.D.[3]

Mixed connective tissue disease has to be differentiated from other conditions with similar presentation of arthritis and rash like systemic lupus erythematosus, rheumatoid arthritis, rhupus, undifferentiated connective tissue disease, systemic sclerosis, Sjogren’s syndrome, vasculitis, Behcet’s syndrome, Kikuchi’s disease, serum sickness, psoriatic arthritis and human parvovirus B19 infection.

Abbreviations: ANA: Antinuclear antibody, RF: Rheumatoid factor, Anti-CCp: Anti-cyclic citrullinated protein antibody, Anti U1RNP: Anti-U1 ribonucleoprotein antibodies , Anti Sm : Anti-Sm antibodies, Anti Ro: Anti Ro antibody also called anti-Sjögren’s-syndrome-related antigen A antibody, Anti-dsDNA: Anti-double stranded DNA.

Disease		Arthritis					Auto-antibodies							Raynaud phenomenon	Rash pattern	Distinguishing/specific features
		Polyarthritis	Tenderness	Edema	Deformity /Erosion	Pattern	ANA	RF	Anti-CCp	Anti U1RNP	Anti Sm	Anti Ro	Anti-dsDNA
Mixed connective tissue disease (MCTD)[1]		–	–	–	+	Small and large joints	–	↑↑	↑	–	–	–	–	+	Cutaneous eruptions, gottron’s papules, photodistributed erythema, poikiloderma, and calcinosis cutis	Overlapping features of SLE, systemic sclerosis (SSc), and polymyositis (PM) that lead to more than one diagnosis
Systemic lupus erythematosus[2]		+	+	+	–	Small joints	↑	–	–	–	↑	↑	–	+	Malar rash and photosensitivity
Rheumatoid arthritis (RA)[3]		+	+	+	+	Small and large joints	–	↑↑	↑↑	–	–	–	–	+	Subcutaneous nodules	Erosive arthropathy
Rhupus[4]		+	+	+	+	Small and large joints	↑	↑	↑	↑	↑	–	↑	+	Malar rash and photosensitivity	Erosive arthropathy
Undifferentiated connective tissue disease (UCTD)[5]		+	–	–	–	Lower extremity	↑	↑	–	–	↑	–	–	+	Erythematous macules, patches, or papules with delicate scale	Multiple connective tissue diseases with no enough criteria for a single diagnosis
Systemic sclerosis (SSc)[6]		+/-	+	+	+/-	Lower extremity	↑↑	–	–	–	↑	–	↑	+	Hyperkeratosis, edema, and erythema	Sclerodactyly, Telangiectasias, Calcinosis, Malignant hypertension, acute renal failure
Sjögren’s syndrome[7]		+/-	+/-	–	–	Lower extremity, axiallary creases	↑	–	–	–	↑	↑	–	–	Xerosis, scaly skin, annular erythema	Keratoconjunctivitis sicca
Vasculitis	Giant cell[8]	–	+	+	–	Distal extremity	–	–	–	–	–	–	–	–	Rare	Involvement of cranial branches of arteries, visual loss
	Takayasu[9]	–	+/-	+/-	–	Transient extremity	–	–	–	–	–	–	–		Erythema nodosum, pyoderma gangrenosum	Absent or weak peripheral pulse
	Poly-arteritis nodosa[10]	–	+/-	–	–	General and mild	–	–	–	–	–	–	–		Tender erythematous nodules, purpura, livedo reticularis, bullous or vesicular eruption	Testicular pain or tenderness and neuropathies
Behçet’s syndrome[11]		+/-	+/-	+/-	–	medium and large joints	–	–	–	–	–	–	–	–	Recurrent and usually painful mucocutaneous ulcers, acneiform lesions, papulo-vesiculo-pustular eruptions, superficial thrombophlebitis	Male dominancy
Kikuchi’s disease[12]		–	+/-	–	–	medium and large joints	↑/↓	–	–	–	–	–	–	–	Transient skin rashes, malar rash, erythematous macules, patches, papules, or plaques	May be associated with SLE
Serum sickness[13]		+	+	+/-	–	General	–	–	–	–	–	–	–	–	Pruritic rash, urticaria and/or serpiginous macular rash	Self-limited
Psoriatic arthritis[14]		–	–	–	–	Small and large joints	–	–	–	–	–	–	–	–	Psoriasis and onychodystrophy	Dactylitis (sausage digits)
Human parvovirus B19 infection[15]		+	+	–	–	Small joints	–	–	–	–	–	–	–	–	Erythematous rashes	Rare in adults, fifth’s disease in children

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Shaghayegh Habibi, M.D.[2]

The incidence of mixed connective tissue disease is approximately 2.7 per 100,000 individuals per year. A nationwide study on MCTD showed the prevalence of mixed connective tissue disease was 2.7 per 100,000 individuals in Japan and 3.8 per 100,000 individuals in Norway. In MCTD, the mortality rate is nearly 10.4% over the period of 13-15 years. It is usually diagnosed during childhood and is more frequent among black and Asian population. The female to male ratio is approximately 10 to 1.

• The incidence of mixed connective tissue disease is approximately 2.7 per 100,000 individuals per year.^[1]

• A population-based epidemiology study in Norway demonstrates the prevalence of adult-onset MCTD is 3.8 per 100,000 individuals.^[2]
• A nationwide study on MCTD in Japan showed the prevalence of mixed connective tissue disease was 2.7 per 100,000.^[3]

• In MCTD, the mortality rate is nearly 10.4% over the period of 13-15 years.^[4]

• Mixed connective tissue disease is usually diagnosed during childhood. It usually starts between 2 and 16 years of age (mean age is 11 years old).^[1]

• MCTD is more frequent among black and Asian population.^[5]

• Female are more frequently affected by MCTD than male. The female to male ratio is approximately 10 to 1.^[6]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Shaghayegh Habibi, M.D.[2]

There are no established risk factors for mixed connective tissue diease.

There are no established risk factors for mixed connective tissue diease.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Shaghayegh Habibi, M.D.[2]

There is insufficient evidence to recommend routine screening for mixed connective tissue disease.

There is insufficient evidence to recommend routine screening for mixed connective tissue disease.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Shaghayegh Habibi, M.D.[2]

If the patients with mixed connective tissue disease left untreated, approximately 35% of patients may progress to develop lung fibrosis. Common complications of MCTD include polyarthritis, Raynaud’s phenomenon, interstitial lung disease, esophageal dysmotility, sclerodactyly, polymyositis, and pulmonary hypertension. Major causes of morbidity in long-term MCTD patients include sclerodactyly, diffuse sclerosis, pulmonary arterial hypertension, and nervous system disease. The presence of pulmonary involvement is associated with worst prognosis and high mortality rate.

• The symptoms of mixed connective tissue disease usually develop in the first decades of life, and presents with symptoms of other rheumatologic diseases such as SLE, systemic sclerosis, polymyositis, or rheumatoid arthritis.^[1]

• If left untreated, approximately 35% of patients with mixed connective tissue disease may progress to develop lung fibrosis.^[2]

• Common complications of MCTD include:^[3][4][5]
  • Polyarthritis
  • Raynaud’s phenomenon
  • Puffy fingers (sausage digits)
  • Interstitial lung disease
  • Esophageal dysmotility
  • Sclerodactyly
  • Polymyositis
  • Pulmonary hypertension

• In patients with MCTD the prognosis is relatively good.^[6]
• In MCTD, prognosis depends on the type of organ involvement.^[7]
• Major causes of morbidity in long-term MCTD patients include:^[8]
  • Sclerodactyly
  • Diffuse sclerosis
  • Pulmonary arterial hypertension
  • Nervous system disease
• The presence of pulmonary involvement is associated with worst prognosis and high mortality rate.^[9]

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