OVERVIEW
A disease characterized by a mixture of clinical manifestations of various connective tissue diseases and the presence of high titers of anti-U1-RNP antibodies. Common symptoms include polyarthritis, Raynaud’s phenomenon, finger swelling, myositis, and esophageal dysfunction. The cause of the disease is unclear, and it may be related to immune, genetic, environmental, and other factors. Treatment is based on pharmacological therapy.
Definition
Mixed connective tissue disease is a connective tissue disease characterized by having mixed clinical manifestations of multiple connective tissue diseases (systemic lupus erythematosus, scleroderma, dermatomyositis/multiple myositis, or rheumatoid arthritis, etc.), often with high titers of spotty antinuclear antibodies and high titers of anti-U1RNP antibodies in the blood, which do not yet meet the current diagnostic criteria of a particular rheumatologic disease [1].
Clinically, it presents with symptoms in the skin, joints, and muscles, as well as damage to organs. Common symptoms include arthritis, Raynaud’s phenomenon, finger swelling, and myositis.
Morbidity
The age of onset ranges from 4 to 80 years, with a mean age of 37 years, but the disease can also affect children and the elderly [2].
The prevalence is higher in females in the population, about 80% [1-2].
Etiology
Causes
The cause of mixed connective tissue disease is currently unknown, and studies have found the disease to be somewhat hereditary. It is believed that its etiology may be related to immune, genetic and environmental factors.
Under conditions of genetic susceptibility, when external factors such as infections and environmental interventions are present, the highly activated response of B lymphocytes, the abnormal activation of T cells, and the abnormalities of self-antigens can lead to a disruption of the immune system functioning and an attack on the body’s normal connective tissues, which can lead to the corresponding symptoms.
High risk factors
People with a family history of rheumatic diseases such as systemic lupus erythematosus, systemic sclerosis, polymyositis, rheumatoid arthritis, and abnormalities of the immune system are at high risk for mixed connective tissue disease.
Symptoms
Mixed connective tissue disease combines the clinical symptoms of many connective tissue diseases. These symptoms do not appear at the same time, but may appear successively, and the manifestations vary from patient to patient. Typical clinical manifestations are Raynaud’s phenomenon, waxing and waning fingers, arthritis/arthralgia, sclerosis of the extremities, delayed esophageal loss, myositis, and pulmonary hypertension [3].
Main Symptoms
Skin manifestations
Swelling of the hands or fingers is a characteristic manifestation of the disease.
Other symptoms such as purplish papules of the metacarpophalangeal and interphalangeal joints and non-scarring baldness, photosensitivity, oral and genital ulcers, reticular cyanosis, and erythema nodosum may also be present.
Muscles and Joints
Almost all patients may present with pain and stiffness in multiple joints [2-3].
About 75% of patients have significant arthritis, which is mostly a transient condition, and a small percentage may have joint deformities similar to rheumatoid arthritis [2].
Pulmonary manifestations
Lung lesions account for approximately 70% of cases [2] and may present as pleurisy or interstitial pneumonia.
Specifically, there may be dyspnea, chest pain, and dry cough.
It may be accompanied by malaise, fatigue, weight loss, pestle finger, etc. When combined with infection, it may be accompanied by fever and cough. Some patients may also develop pulmonary hypertension, suggesting a poor prognosis.
Cardiac manifestations
The incidence of cardiac damage is 11% to 85% [2]. The whole layer of the heart can be involved, commonly pericarditis, but also myocardial and coronary artery involvement and pulmonary hypertension.
Specific manifestations may include precordial pain, radiating pain, dyspnea, and edema.
The predisposing aggravating factors are infection, physical activity, etc..
It may be accompanied by fever, malaise and other symptoms.
Digestive tract manifestations
About 70% of patients can be involved [2], the most common is reflux esophagitis.
Specifically, it can be manifested as reflux, heartburn, abdominal distension, and even dysphagia.
After meals, it can be aggravated by lying down, bending over or increased intra-abdominal pressure [2].
Accompanied by chest pain, pharyngitis, cough and other symptoms.
Neurological manifestations
Involvement is found in about 15% of cases [2]. The most common manifestations are trigeminal neuropathy and headache.
Specifically, it may manifest as trigeminal neuralgia or numbness at the end of the extremities; other occasional symptoms include seizures, transverse myelitis, cauda equina syndrome, episodic vascular headache, or psychiatric symptoms.
It is accompanied by fever, dizziness and vomiting.
Renal manifestations
The incidence of nephropathy is only 5% [2]. It usually presents as membranous glomerulonephritis.
It may present as proteinuria, hematuria, edema and other symptoms.
Renal crisis may occur in a few patients.
Hematologic manifestations
75% of patients may have anemia [3].
This is manifested by symptoms such as anemia, hemolysis, leukopenia or thrombocytopenia.
Vascular manifestations
Raynaud’s phenomenon is an early clinical sign in almost all patients [3].
It is specifically manifested in the appearance of pale, bruise and other color changes in areas such as fingertips or toe tips.
It can be induced by cold stimulation, emotional excitement and other factors.
Accompanied by pain, sensory abnormalities and other symptoms.
Other symptoms
Patients may combine with dry syndrome, chronic lymphocytic thyroiditis (Hashimoto’s thyroiditis) and persistent hoarseness.
About 1/3 of patients have fever, generalized lymph node enlargement and hepatosplenomegaly.
Consultation
Department of Medicine
Rheumatology
If multi-system symptoms such as Raynaud’s phenomenon, finger swelling, joint pain and stiffness occur, or if high titers of spotted antinuclear antibody (ANA) or high potency anti-U1-RNP antibody are detected on physical examination, it is recommended that patients consult the Department of Rheumatology and Immunology in a timely manner.
Nephrology
If symptoms such as proteinuria, hematuria, edema, etc. appear, it is recommended to consult the Nephrology Department first.
Dermatology
When symptoms such as multiple skin lesions, papules, erythema, and alopecia are present, it is recommended to visit the Department of Dermatology first.
Preparation for medical treatment
Preparing for the consultation: registration, preparation of documents, common problems
Tips for medical treatment
Patients with joint pain and difficulty in walking are recommended to be accompanied by their family members.
Avoid self-medication before consultation to avoid masking the condition.
If there is skin damage on the face, do not wear make-up before the consultation.
Preparation List
Symptom list
Pay particular attention to the time of onset of symptoms, special manifestations, etc.
Are there any signs that the ends of the fingers have turned white and purple or are painful and numb when cold?
Is there any swelling of the fingers?
Are there purplish-red papules on the interphalangeal joints, oral and genital ulcers?
Are there any joint problems such as joint pain, joint swelling and morning stiffness?
Is there dyspnea, chest pain, and dry cough along with malaise, fatigue, weight loss, and fever?
Are there symptoms such as hematuria and edema?
Are there any symptoms of anemia such as pallor and weakness or hematologic symptoms such as skin bruising and bleeding that does not stop easily?
List of medical history
Is there a family history of rheumatic diseases such as systemic lupus erythematosus, systemic sclerosis, polymyositis, rheumatoid arthritis, etc.?
Any recent abnormalities in immune system function (e.g., infectious diseases)?
Checklist
Test results in the last six months, which can be brought to the doctor’s office
General laboratory tests: blood routine, urine test, blood biochemistry (including liver and kidney function, cardiac enzyme profile, blood sedimentation, C-reactive protein, immunoglobulin and complement, etc.).
Specialized laboratory tests: autoantibody tests (including anti-nuclear antibody, anti-U1RNP antibody, anti-Sm antibody, anti-dsDNA antibody, anti-rRNP antibody, anti-SSA antibody, anti-SSB antibody, anti-cardiolipin antibody, anti-B2 glycoprotein 1 antibody, lupus anticoagulant, etc.).
Imaging tests: cardiac ultrasound, X-ray, CT of chest and abdomen.
Other tests: pathologic examination, such as renal puncture biopsy pathology, muscle biopsy pathology, etc.
Medication list
Medication used in the last 3 months, if available in boxes or packages, carry with you to the doctor’s office
NSAIDs: acetaminophen, indomethacin, ibuprofen, etc.
Glucocorticoids: prednisone, methylprednisolone, etc.
Immunosuppressants: methotrexate, hydroxychloroquine, leflunomide, cyclophosphamide, mertiomacrolide, etc.
Calcium channel blockers: nifedipine, amlodipine, etc.
Diagnosis
Diagnosis is based on
Medical history
Medical history is not necessary for the diagnosis of the disease, but the presence of the following medical history may provide some reference for the diagnosis of the disease.
Family history of rheumatic diseases such as systemic lupus erythematosus, systemic sclerosis, polymyositis, rheumatoid arthritis.
Recent infectious diseases.
Clinical manifestations
Symptoms
The clinical symptoms of mixed connective tissue disease are complex and may show clinical symptoms of various connective tissue diseases (systemic lupus erythematosus, systemic sclerosis, multiple myositis, dermatomyositis, rheumatoid arthritis, etc.), which do not have characteristic changes and vary from patient to patient.
The typical clinical manifestations are Raynaud’s phenomenon, arthritis/arthralgia, sclerosis of the extremities, delayed esophageal loss, myositis, and pulmonary hypertension.
Physical signs
Some patients may present with decreased finger tip temperature, finger swelling, joint swelling and tenderness, and sclerosis of the extremities.
In interstitial lung disease, small Velcro rales at the end of inhalation are detected at the base of both lungs.
In pericarditis, pericardial friction may be heard in the 3rd-4th intercostal space at the left border of the sternum.
General Laboratory Tests
Routine blood tests
Determine whether hematologic damage has occurred.
An increase in leukocytes and neutrophil ratio suggests a possible bacterial infection; a decrease in leukocytes, erythrocytes, and platelets suggests possible hematologic damage and may assist in the diagnosis of mixed connective tissue disease.
Urinalysis
It can help to determine whether there is kidney disease.
If there are more red blood cells and proteins in the urine, it suggests that there may be kidney disease. 24-hour urine protein quantification can help to determine the activity of the disease and the severity of kidney disease.
Blood biochemistry
It mainly includes liver and kidney function, cardiac enzyme profile, blood sedimentation, C-reactive protein, immunoglobulin and complement.
Find out whether the patient has inflammation, muscle lesions, liver damage, kidney injury.
Elevated serum aminotransferase may indicate liver damage; elevated creatinine may indicate renal disease; elevated serum myosin may indicate myocardial or skeletal muscle disease.
All of these indicators are important in the diagnosis of mixed connective tissue disease.
Specialized Laboratory Tests
Mixed connective tissue disease usually presents with high titers of spot ANA antibodies, often greater than 1:1000, sometimes greater than 1:10,000, and should be immediately tested for anti-Ul-RNP, Sm, anti-SSA, anti-SSB, and anti-double-stranded DNA antibodies.
If anti-dsDNA or anti-Sm is positive, it should be clinically differentiated from systemic lupus erythematosus (SLE). Anti-cardiolipin antibody, anti-B2 glycoprotein 1 antibody, lupus anticoagulant, etc. are also needed to help diagnosis and differential diagnosis.
Imaging
Nailfold microcirculation examination
Most patients with mixed connective tissue disease (MCTD) show abnormal results, with dilated and absent capillaries.
Ultrasound of the heart
The main objective is to observe the presence of cardiac lesions.
If the diagnosis suggests reduced ejection fraction, valvular dysfunction, pulmonary hypertension, etc., it may indicate the presence of cardiac pathology. It has some diagnostic significance for mixed connective tissue disease important organ lesions.
X-ray
Used to observe the presence of joint damage.
If the diagnosis suggests cortical erosion, phalangeal erosion, periarticular calcification, etc., it may suggest the presence of joint bone damage, which needs to be differentiated from rheumatoid arthritis.
CT
CT can be used to visualize the extent of lung disease.
If the diagnosis suggests lattice-like changes and honeycomb changes in the basal portion of the lungs without bronchodilation, it may suggest the presence of fibrotic lesions in the lungs.
Pathologic examination
Renal puncture biopsy pathology helps to define the type (glomerulonephritis, interstitial tubulopathy, renal microangiopathy), activity and severity of renal damage.
Muscle biopsy pathology determines the presence of muscle lesions and helps in the diagnosis and differential diagnosis of inflammatory myopathies. If the results show the presence of lymphocytes and macrophages at the visible lesions, it can suggest the presence of muscle showing inflammatory myositis.
Diagnostic criteria
There are no uniform diagnostic criteria for the classification of mixed connective tissue disease (MCTD). The Sharp, Alarcon-Segovia, and Kahn criteria are more representative [1]. The Alarcon-Segovia and Kahn criteria are commonly used.
Alarcon-Segovia criteria
Serologic criteria
Anti-U1-RNP titer ≥ 1:1600.
Clinical criteria
Swelling of the hand.
Synovitis.
Myositis.
Raynaud’s phenomenon.
Sclerosis of the extremities.
MCTD is diagnosed if serologic criteria are accompanied by 3 or more clinical criteria, which must include synovitis or myositis.
Kahn criteria
Serologic criteria
High titer anti-U1-RNP with a corresponding spotted ANA titer ≥ 1:1200.
Clinical criteria
Swelling of the hands.
Synovitis.
Myositis.
Raynaud’s phenomenon.
MCTD is diagnosed if serologic criteria are accompanied by Raynaud’s phenomenon and at least 2 of the 3 clinical criteria.
Differential Diagnosis
Mixed connective tissue disease needs to be differentiated from systemic sclerosis, systemic lupus erythematosus, and dermatomyositis/multiple myositis.
Systemic sclerosis
Similarities: Both can present with Raynaud’s phenomenon, skin symptoms, muscle and joint lesions, gastrointestinal symptoms, and other symptoms.
Differences: Systemic sclerosis has prominent cutaneous sclerosis, and some patients are positive for anti-topoisomerase I antibody. Mixed connective tissue disease is not positive for this antibody, but there are high titer speckled ANA and high potency anti-U1-RNP antibody.
Systemic lupus erythematosus
Similarities: Both can present with skin symptoms, muscle and joint lesions, cardiovascular manifestations, pulmonary manifestations, gastrointestinal manifestations and other symptoms.
Differences: SLE patients may present with typical pteronyssinus erythematosus, and some patients may be positive for dsDNA-specific antibodies or anti-Sm antibodies; mixed connective tissue disease is rarely positive for anti-ds-DNA antibodies and negative for anti-Sm antibodies, but spotted ANA is high titer, and anti-U1-RNP antibodies are highly potent.
Dermatomyositis/Polymyositis
Similarities: both may present with cutaneous symptoms, musculoarticular lesions, and pulmonary manifestations.
Differences: Inflammatory myopathies have more pronounced myalgia and muscle weakness; mixed connective tissue diseases such as Raynaud’s and swollen hands are more prominent, and high-titer ANA and RNP antibodies are helpful in differentiating them.
Treatment
Treatment objective: to relieve the patient’s symptoms and reduce the occurrence of complications.
Treatment principle: to choose the appropriate drugs for symptomatic treatment.
Drug therapy
Non-steroidal anti-inflammatory drugs
Suitable for patients with only fever, arthritis, mild skin lesions and insignificant systemic damage.
Common medications include acetaminophen, indomethacin, and ibuprofen.
Patients’ symptoms can be controlled, and adverse reactions such as rash, nausea and vomiting may occur during the medication. Patients with hepatic or renal dysfunction should inform the doctor in advance and follow the doctor’s instructions.
Glucocorticoid
Glucocorticosteroids are suitable for patients with severe organ damage, such as those with interstitial lung lesions, vasculitis, nephropathy, severe myositis, and severe thrombocytopenic purpura.
Common drugs include prednisone, methylprednisone, betamethasone and so on.
Its adverse reactions are more, can appear Cushing face (i.e., full moon face, buffalo back, centripetal obesity, and the appearance of purple lines in the skin of the face), hypertension, hyperlipidemia, hyperglycemia, reduce body resistance and secondary infection, cause aseptic osteonecrosis, osteoporosis, cataracts and so on.
Immunosuppressant
It is suitable for patients with poor efficacy of glucocorticosteroids, important organ involvement or rapid progression of the disease.
Common drugs include methotrexate, hydroxychloroquine, leflunomide, azathioprine, cyclophosphamide, and mertiomacrolide.
Adverse drug reactions include nausea, vomiting, rash, alopecia, diarrhea, bone marrow suppression, leukopenia, and liver damage. It is contraindicated in infected persons.
Calcium channel blockers
For patients with Raynaud’s phenomenon (i.e. whitening, purpling, flushing of fingers, toes, etc.) and patients with pulmonary hypertension.
Common drugs include nifedipine and amlodipine.
Common adverse effects may include swelling of the lower extremities, ankles, dorsum of the feet, and gingival hyperplasia.
Prognosis
Cure
Mixed connective tissue disease has relatively little damage to vital organs and is mild, so its prognosis is relatively good, and correct diagnosis and treatment and follow-up can make most patients’ conditions stable for a long time [2]. Some patients with mixed connective tissue disease may eventually turn into a specific diffuse connective tissue disease, which requires long-term follow-up and close observation.
Almost one-third of patients with mixed connective tissue disease will make a full recovery, while another third may develop life-threatening complications [4]. When complications such as pulmonary hypertension and heart disease progress, the prognosis is generally poor [3].
Prognosis depends on the organs affected, the degree of inflammation and the rate of disease progression. Mortality varies between 8% and 36% [4].
Prognostic factors
Mixed connective tissue disease has a better prognosis when diagnosed by early screening and treated early.
Milder disease without lesions in organs such as myocarditis, pulmonary hypertension, or cerebral hemorrhage generally has a better prognosis.
Hazards
Mixed connective tissue disease has a long course, and patients are prone to depression, worry, irritability and other adverse emotions.
If the symptoms of joint pain and stiffness exist for a long time, it may affect daily life and work.
Daily
Daily Management
Dietary management
Eat more fresh vegetables and fruits, such as broccoli, apples and dragon fruits.
Ensure your body has sufficient water intake every day.
Take appropriate supplement of protein-rich food, such as lean meat, fish, eggs, etc., to enhance nutrition so as to improve the nutritional status of the whole body.
Life Management
Ensure sufficient sleep time in daily life and less staying up late.
Avoid skin sun exposure or freezing in daily life to reduce the damage to muscles and skin.
Exercise appropriately, such as walking, brisk walking, etc., to maintain good health and enhance the resistance of the body.
Psychological support
Patients with mixed connective tissue disease may have bad moods such as irritability, anxiety and uneasiness. Relatives should strengthen communication with patients and encourage them to maintain an optimistic mindset.
Follow-up
Mixed connective tissue disease requires regular follow-up, which allows the doctor to dynamically assess the patient’s condition and prevent complications.
The follow-up schedule should be set by the specialist according to the patient’s specific condition or follow the doctor’s instruction to conduct regular review, and those with stable conditions can be reviewed once every 3 months.
The follow-up may include blood tests, urine tests, liver and kidney functions, C-reactive protein, autoantibody tests, and other tests.
Prevention
There are no specific preventive measures for mixed connective tissue disease. However, early intervention to address the factors associated with it may play a positive role in preventing the development of the disease.
People with a family history of the disease should pay attention to regular medical checkups, learn about the disease, and consult a doctor when symptoms are suspected.
Pay attention to diet and environmental hygiene.