Mixed connective tissue disease (MCTD) is a clinical syndrome characterized by overlapping symptoms of SLE, SSc, PM/DM and RA. It is characterized by high titers of speckled antinuclear antibodies (ANA) and anti-u1RNP antibodies.
The etiology and pathogenesis of MCTD is unclear, as it is an immune disorder characterized by suppressive T-cell deficiency, autoantibodies, hyperglobulinemia, the presence of circulating immune complexes and tissue infiltration with lymphocytes and plasma cells. There is still controversy as to whether MCTD is a separate connective tissue disease or whether it is classified as an overlapping syndrome. Evidence supporting MCTD as an independent disease: the disease has overlapping symptoms of multiple connective tissue diseases but cannot be diagnosed as a specific connective tissue disease by traditional classification criteria, and Raynaud’s sign of the finger and salpingitis are most common; MCTD has very high titers of ANA and anti-u1RNP antibodies, while other antibody titers are not high or negative; compared with SLE, the reticuloendothelial system of the disease The ability of the reticuloendothelial system to clear immune complexes is normal in this disease compared to SLE; the patient has an abnormal developmental process of immunomodulatory T cells, unlike other connective tissue diseases; the pathological changes of the vessels in this disease, like SSc, show extensive intimal and/or mesangial proliferative damage, leading to stenosis of the large vessels and many small vessels of the organs; there is often proliferative vasculopathy with pulmonary hypertension with mild fibrosis. However, follow-up reveals that some patients with MCTD eventually turn into typical SSc and SLE, so it is thought that this disease is not an independent disease.
The age of onset of MCTD ranges from 4 to 80 years, and most patients develop symptoms around 30-40 years of age, with a mean age of 37 years. It is more common in women, accounting for about 80% of cases. The incidence in China is unknown, but not rare.
Clinical manifestations
Patients may exhibit any of the clinical symptoms of the various connective tissue diseases that make up the disease (SLE, SSc, PM/DM or RA). However, the multiple clinical manifestations of MCTD do not occur simultaneously, and overlapping features can occur sequentially and vary from patient to patient. Typical clinical manifestations are polyarthritis, Raynaud’s phenomenon, swelling or sclerosis of the fingers, inflammatory changes in the lungs, myopathy and muscle weakness, esophageal dysfunction, lymph node enlargement, hair loss, zygomatic rash, and plasmacytosis.
1.Joints
Almost all patients have joint pain and stiffness. 60% of patients have symptomatic arthritis with clinical features similar to RA, but usually without flexor tendon arthritis, swan neck deformity and ulnar deviation. The most commonly affected joint is the metacarpophalangeal joint. Radiological examination lacks severe bony erosive lesions, but joint edge erosion and joint destruction can be seen in some patients. 50-70% of patients are positive for rheumatoid factor (RF).
2.Skin mucosa
Most patients develop skin and mucosal lesions during the course of the disease. Raynaud’s phenomenon with swelling and thickening of the fingers and edema of the whole hand is sometimes the most common and earliest manifestation of MCTD patients. The skin of the fingers is distended and thickened, but no contracture occurs. In some patients, the skin lesions appear as a lupus-like rash, especially zygomatic erythema and discoid erythema. About 25% of patients have alopecia, sclerosis of the fingers and toes, hypopigmentation, photosensitivity, urticaria, and dilated capillaries on the face and around the nails. Scleroderma-like changes may be present on the facial skin, but a true scleroderma face is rare. A small number of patients with MCTD may have typical dermatomyositis skin changes such as purplish eyelids and erythema at the fingers, elbows and knees. Mucosal damage includes buccal mucosal ulcers, dry compound orogenital ulcers, and nasal septal perforations. Peritendinous and subcutaneous nodules may develop in the forearm flexors, hand and foot extensors, and Achilles tendons. There are no characteristic changes in skin histology, with an increased collagen component in the dermis, but rarely with true scleroderma-like changes. Some patients have immunoglobulin deposits at the epidermal-dermal junction.
3. Muscle lesions
Myalgia is a common symptom of MCTD, but most patients do not have definite muscle weakness, electromyographic abnormalities, or myoenzymatic changes. Patients with MCTD with definite inflammatory myopathy, sometimes with hyperthermia, have the same clinical and histological aspects as PM, such as elevated myoenzymes, typical inflammatory myopathy changes on EMG, degenerative changes of muscle fibers on muscle biopsy, and plasma cell and lymphocyte infiltration around blood vessels and in the interstitium.
4. Heart
The electrocardiogram is abnormal in 20% of patients, and the most common changes are arrhythmias, right ventricular hypertrophy, right atrial enlargement and interventricular conduction damage. 10-30% of patients present with pericarditis, the most common clinical manifestation of cardiac involvement, and pericardial tamponade is rare. Early detection of the presence or absence of pulmonary hypertension facilitates early treatment. Ultrasound multispectral estimation of right ventricular systolic pressure can detect subclinical pulmonary hypertension. Pulmonary hypertension is diagnosed if four or more of the following six criteria are present: (1) exertional dyspnea, (2) systolic pulsation at the left border of the sternum, (3) increased second heart sound in the pulmonary artery region, (4) widening of the pulmonary artery on chest radiograph, (5) right ventricular hypertrophy on electrocardiogram, and (6) right ventricular enlargement on echocardiogram. The conduction disturbances include bundle branch conduction block and total heart block.
5. Lung
Eighty-five percent of patients with MCTD have evidence of pulmonary involvement, but most are asymptomatic. Early lung dysfunction is not easily detected without detailed examination. Symptoms include dyspnea, chest pain and cough. Chest radiographic abnormalities include interstitial changes, pleural exudates, pulmonary infiltrates and pleural thickening. The most discriminatory pulmonary function test is the diffusion function of primary respiratory CO Interstitial lung disease usually shows progressive exacerbation with reduced effective volume and alveolar gas exchange. Pulmonary hemorrhage has also been reported occasionally.
6. Kidney
Renal damage is present in 25% of patients. High titers of anti-u1RNP antibodies are relatively protective against the progression of diffuse glomerulonephritis. Diffuse glomerulonephritis and parenchymal interstitial lesions are rare, usually membranous glomerulonephritis, and sometimes can cause nephrotic syndrome, but most patients are asymptomatic. Some patients develop renal vascular hypertensive crisis, similar to scleroderma renal crisis. Long-term renal lesions can cause amyloidosis and renal insufficiency.
7. Gastrointestinal tract
Gastrointestinal tract involvement is the main feature of MCTD patients with SSc manifestations. Most patients have symptoms of esophageal dysfunction and altered esophageal pressure, which is independent of the severity of skin injury. The main manifestations are decreased pressure in the upper and lower esophageal sphincter, decreased peristalsis in the distal 2/3 of the esophagus, and choking and dysphagia after eating. abdominal pain in MCTD may be due to decreased intestinal peristalsis, plagiocele, mesenteric vasculitis, colonic perforation, or pancreatitis. Other gastrointestinal damages are hypotonia, pseudocystic dilatation, and malabsorption.
8.Nervous system
Central nervous system lesions are not a significant clinical feature of the disease. The most common manifestation as in SSc is trigeminal neuropathy. Headache is a common symptom, and most patients may have vascular headache. Some patients have headache with fever, sometimes with myalgia, and some present like the sequelae of a viral infection. Some of these patients present with signs of meningeal irritation, and cerebrospinal fluid examination reveals aseptic meningitis. Aseptic meningitis may also be a hypersensitivity reaction to nonsteroidal anti-inflammatory drugs, particularly sulforaphane and ibuprofen. Other neurological involvement includes epileptiform seizures, organic psychiatric syndromes, multiple peripheral neuropathies, cerebral embolism and cerebral hemorrhage.
9.Vascular
Mild hyperplasia and mid-layer hypertrophy of the intima of small and medium-sized vessels are the characteristic vascular lesions of the disease, with histological changes similar to those seen in SSc. All patients have SSc-like capillary microscopic changes, and a “bushy pattern” pattern is seen in 73% of patients. Most patients had changes in the nail fold capillary loops such as dilated capillaries, which were the same as those seen in SSc. SSc-like changes in the nail fold capillary loops are the characteristic difference between MCTD and SLE. Elevated levels of anti-endothelial cell antibodies and serum factor VIII-related antigens support the presence of vascular endothelial cell injury in MCTD. Angiography revealed a higher incidence of medium-sized vessel occlusion in patients with MCTD.
10. Hematologic system
Anemia is present in 75% of patients. 60% of patients have a positive Coombs test, but hemolytic anemia is uncommon. As seen in SLE, 75% of patients have leukopenia, predominantly of the lymphocytic lineage, which is associated with disease activity. Thrombocytopenia, thrombotic thrombocytopenic purpura, and erythrocyte dysplasia are relatively uncommon. Most patients have hypogammaglobulinemia and 33% of IgG molecules have anti-u1 RNP specificity.
11.Other
Patients may have dry syndrome, chronic lymphocytic thyroiditis (Hashimoto’s thyroiditis) and persistent hoarseness. 1/3 of patients have fever, generalized lymph node enlargement and hepatosplenomegaly.
Diagnostic basis
In 1986, Sharp, Kasukawa and Segovia each proposed their own diagnostic criteria for the disease, and in recent years, the results were compared by Shen Nan and other examinations, and the diagnostic criteria of Sharp were considered to be more specific.
1, myositis (severe).
2, pulmonary damage: ① DLco <70%; ② b. pulmonary hypertension; ③ biopsy shows proliferative damage of pulmonary vessels.
3, Raynaud’s phenomenon or abnormal esophageal peristaltic function.
4, swollen hands or fingertip sclerosis.
5, anti-ENA antibody titer ≥ 1:10,000, and anti-U1RNP antibody (+), anti-Sm antibody (-). Confirmation of the diagnosis requires more than 4 indicators and exclusion of anti-Sm antibodies (+). However, clinically, even in cases that meet Sharp’s diagnosis, some cases are converted to other connective tissue diseases during subsequent follow-up.
Some scholars have suggested that it is difficult to diagnose which disease the patient belongs to based on the mixed symptoms of lupus erythematosus, dermatomyositis or polymyositis and scleroderma, among which the prominent ones are Raynaud’s phenomenon, hand or face swelling, tight skin thickening with poor elasticity but not sclerosis, salami-like or sclerotic fingers with arthralgia or arthritis, myositis, decreased esophageal motility, DLco <70%, mild or no renal involvement. With the addition of high potency anti-nRNP antibodies, the diagnosis can generally be made. Regular follow-up of these cases is required, and observation of their regression is essential.
Diseases that are easily misdiagnosed
1. Systemic lupus erythematosus: zygomatic pteroidal erythema, multiple and heavy renal involvement, positive anti-dsDNA and anti-Sm antibodies, high rate of positive LE cells, rare bushy nail wrinkle capillary abnormalities, rare swelling of the hand surface and finger sclerosis can be differentiated from mixed connective tissue disease.
2, scleroderma: this disease skin sclerosis is not only limited to the face, hands, arms, neck and trunk can also be involved, ANA fluorescence karyotype in addition to spots can also be seen in the mitotic type, anti-nRNP antibody positivity rate is low, and low potency, the effect on corticosteroids is also poor, can be distinguished.
3, dermatomyositis or polymyositis: mixed connective tissue disease also has a number of lupus erythematosus and scleroderma features in addition to dermatomyositis, high positive serum rate and high potency anti-nRNP antibodies can be distinguished.
4. Overlap syndrome: the symptoms of such cases need to meet the diagnostic criteria of more than two diseases at the same time, and there is no high-valent anti-nRNP antibody.
Treatment principles
Corticosteroids are effective against facial swelling, plasmacytitis, myositis, aseptic meningitis, early interstitial pneumonia, etc. The dose is 20-60 mg daily. For patients with combined myocarditis and severe renal vasculopathy, immunosuppressants such as azathioprine need to be added, and rhagamine preparations can also be applied. Intravenous drips of salvia and low molecular dextrose, or colchicine can soften the skin, and the latter is also effective for pulmonary arterial hypertension. Non-steroidal anti-inflammatory drugs can relieve joint symptoms, calcium channel blockers such as nifedipine are helpful for Raynaud’s phenomenon, and vasodilators such as tolazoline and niacinamide are also effective. It is also important to keep warm, prevent cold, and avoid overexertion.
Prognosis
In the past, it was thought that mixed connective tissue disease involving the kidneys and the central nervous system was less, and had a good prognosis with corticosteroids, but recently it was found that this was not the case in some cases, with a mortality rate of 4% to 7% in adults, and the causes of death were pulmonary hypertension, renal insufficiency, myocarditis, myocardial infarction, heart failure, cerebral embolism and pancytopenia, and perforation of the colon.
The relationship with pregnancy: the success of pregnancy is significantly reduced, fetal mortality is significantly higher, there are spontaneous abortions and stillbirths, and the activity of the patient’s disease can increase during pregnancy. Mixed connective tissue disease is more severe in children, with more central nervous system, cardiac, and renal involvement than in adults, and arthritis is common.