Undifferentiated connective tissue disease (UCTD), also known as unclassified connective tissue disease, is a condition in which the patient has the common symptoms of connective tissue disease, such as: polyarthritis, Raynaud’s phenomenon, myositis, vasculitis, pluritis, interstitial lung lesions, etc., as well as abnormal serum immunologic tests, such as: positive antinuclear antibodies and rheumatoid factor, and elevated immunoglobulins, but by today’s known diagnostic (or classification) criteria for connective tissue disease However, according to today’s known diagnostic (or classification) criteria and tests, it is difficult to assign to a specific connective tissue disease, and is a state before the connective tissue disease has progressed to a specific disease.
Epidemiology
Preliminary clinical studies with epidemiological investigation data show that UCTD is not uncommon and should be given due attention by clinicians, especially rheumatologists. Published clinical studies have shown that UCTD develops mostly at the age of 18 to 67 years, and is more common in women of childbearing age. Gender is associated with the onset of the disease, with a male to female ratio of 1:4 to 1:6. The disease can be seen in all races. Some foreign studies suggest that the incidence may be higher in white people.
Etiology
The etiology of UCTD is unknown, and there are few studies on it. However, some researchers believe that some UCTD may be an early stage of SLE or systemic sclerosis, and therefore its etiology should be the same as these two diseases. Studies suggest that the development of this disease may be the result of some environmental factors such as long-term exposure to chemical agents acting on susceptible individuals. Both environmental and genetic factors play an important role in its pathogenesis. The study by Lacey et al. further suggested that medical implants such as catheters, metal fixation brackets for artificial joints and orthopedic surgery may also increase the risk of developing UCTD.
Pathogenesis
As with most connective tissue diseases, there is a genetic basis for the development of UCTD. Changes in sex hormone levels or imbalances in the ratio of estrogen to progesterone are likely to be associated with the development of the disease.
Clinical presentation
The average time from the onset of clinical symptoms to the time of consultation is 2 to 3 years, with an average of 38 months. The clinical manifestations of undifferentiated connective tissue disease are often mild, and nonspecific symptoms such as malaise, hypothermia, and lymph node enlargement are common. Some larger clinical investigations have found that the most frequent symptoms are arthralgias, Raynaud’s phenomenon and skin mucosal damage, while involvement of vital organs such as the kidneys and central nervous system is rare. During the follow-up, it was found that the clinical symptoms of patients could fluctuate with the course of the disease and treatment, mostly showing a gradual remission trend, but overall the disease activity did not change much.
1. Skin mucosal lesions. Skin lesions are quite common, and the manifestation of rash type is diverse, and some patients have rash as the first symptom. Discoid erythema is more common than in SLE patients, appearing in about about 34% of patients. It can be found in all races and has a higher incidence in black patients. It presents as a red papule above the skin surface on exposed areas of the body, with the head and neck being the most common health search. The rash varies in size and shape, and the surface is often scaly, leaving scars and local skin atrophy after healing. The incidence of zygomatic erythema is about 10% for red papules on the cheeks, which can have a typical butterfly-like distribution, or irregular shape. The incidence of photosensitivity is between 13% and 24%. Dry mouth and dry eyes occur in about 18% of patients. The incidence of mucosal ulcers is lower than that of SLE, both in the range of 3% to 13%. Diffuse swelling of both hands and subcutaneous nodules have also been reported.
2, joint and muscle lesions. This lesion is more common. About 37% to 80% of patients may present with arthralgia or arthritis, with an average incidence of 55%, while the average incidence of arthritis is 42%. It is mostly non-invasive polyarthritis and rarely occurs in those with joint destruction and deformity. It can involve all joints of all sizes, including interphalangeal joints, metatarsophalangeal joints, and mandibular joints, but large arthritis is more common. Morning stiffness may be present, but is usually short-lived. Synovial fluid examination is mostly suggestive of inflammatory exudate, with low cell count, yellow color when protein content is high, and negative bacterial culture. Muscle involvement is mostly seen as myalgia and muscle weakness in the proximal muscle groups of the extremities. Individual reports may even show mild to moderate elevation of myoenzymes but no abnormal EMG or mild myogenic damage, and no significant abnormalities on muscle biopsy, which do not meet the diagnostic criteria for myositis or other connective tissue diseases.
3, vasculitis. Raynaud’s phenomenon is one of the most common clinical manifestations of UCTD, seen in about 50% of patients, and may persist for years as the only clinical symptom manifested as episodes of pale, blue and flushed extremities, with local pain or numbness before the onset of most of the triggers such as cold or emotional excitement, gradually relieved after a few minutes or tens of minutes small arterial spasm is its pathological basis. Long-term frequent attacks may show local soft tissue atrophy and necrosis and other dystrophic manifestations, and in severe cases, bone resorption at the extremities. In addition, about 5% of patients may develop hypertension, and imaging examination of local vascular wall hyperplasia or stenosis important organ vasculitis such as cardiac vasculitis, renal artery stenosis, arteriovenous embolism, etc.
4, lung and cardiac lesions. Plasmacytitis is the most common, but the incidence is slightly lower than that of SLE, about 11%, and can be manifested as pleural effusion, pericardial effusion or both. The severity of the disease varies from no obvious clinical manifestations in mild cases to even cardiac tamponade in severe cases. Plasmapheresis is often suggestive of leaking fluid and may be positive for antinuclear antibodies. Other pulmonary manifestations include interstitial fibrosis and interstitial pneumonia, and other rare manifestations such as endogenous lipoid pneumonia. Interstitial pulmonary fibrosis is insidious and presents with progressive dyspnea. X-ray examination reveals thickened lung texture and disorganized pulmonary function suggesting reduced diffusion. Exercise lung function and high-resolution CT of the chest are more sensitive and can assist in early diagnosis. Cardiac lesions can involve the whole heart, including pericarditis, myocarditis and endocarditis and other clinical symptoms such as chest tightness, palpitations and dyspnea, and electrocardiogram can have various arrhythmias and ST-T changes.
5. Hematologic lesions. About 20% of patients have this lesion can be manifested as leukocytes, thrombocytopenia and anemia to moderate reduction in white blood cells and non-hemolytic anemia is the most common health search. Thrombocytopenia occurs in about 7% of patients and can be quite severe. Individual cases have a pronounced bleeding tendency and even cause death. Hemolytic anemia is rare, mostly chronic disease anemia and iron deficiency anemia. Whole blood cytopenia is also seen.
6. Other neurological damage is rare and may manifest as psychiatric symptoms such as migraine, convulsive behavioral abnormalities and hallucinations or organic neurological disease manifestations, such as peripheral neuritis, headache, hemianopia, sensory and mobility disorders, etc.
Complications
1, Raynaud’s phenomenon of long-term frequent occurrence may appear local soft tissue atrophy necrosis and other dystrophy performance, serious cases appear limb bone resorption. Hypertension may occur in about 5% of patients, and important organ vasculitis such as cardiac vasculitis, renal artery stenosis and arterial embolism may also occur.
2.Pleural effusion, pericardial effusion or both are complicated.
3.Individual cases have obvious bleeding tendency and even cause death.
Laboratory tests
Patients with UCTD can have a variety of abnormal laboratory tests. However, for each individual, most UCTD patients have only one or two laboratory abnormalities. Positive ANA is the most common among serological tests, with a positive rate of 55% to 100% and an average of about 58%. The fluorescence karyotype is most common with the spotted type, and the homogeneous and perinuclear types are less common, while the titer is similar to that of SLE. A small percentage of patients may have positive rheumatoid factor, anti-RNP antibodies, and anti-SSA or SSB antibodies. The presence of anti-RNP antibodies is often associated with Raynaud’s phenomenon and arthritis, while anti-SSA antibody positivity is often associated with dry mouth. Anti-dsDNA antibody positivity, anti-Sm antibody positivity, false positive syphilis serologic test and complement reduction are rare.
Blood tests may show leukopenia, thrombocytopenia or anemia. Positive Coombs test may be seen in hemolytic anemia, and prolonged partial thromboplastin time in patients with autoimmune thrombocytopenia. Accelerated hematocrit and elevated gamma-globulin may be seen. Some patients present with elevated transaminases, often suggesting autoimmune liver damage.
Other ancillary tests include ultrasound, which may reveal enlarged liver and spleen lymph nodes, and ultrasound and x-ray, which may also reveal pericardial or pleural effusions. Pulmonary function abnormalities are rare.
Diagnostic criteria
There are no uniform diagnostic criteria for UCTD. Those who meet the clinical features of UCTD but have a short course may present with typical clinical manifestations or laboratory abnormalities of other connective tissue diseases within a certain period of time. For example, it is not uncommon that patients with Raynaud’s phenomenon with positive ANA may develop typical SLE or scleroderma manifestations within a year, or even several years after the diagnosis of UCTD. Therefore, the disease should not be easily diagnosed in patients with a disease duration of less than two years. Even in cases of longer duration with a clear diagnosis, close follow-up should be performed to watch for the possibility of progression to other connective tissue diseases.
Patients with diffuse connective tissue disease who have been treated with immunosuppressive drugs and glucocorticoids earlier may not show the clinical manifestations and laboratory abnormalities of other connective tissue diseases and may be eligible for the diagnosis of UCTD because their disease is partially controlled. This “setback” after treatment is itself a reflection of effective treatment, but it is also easy to neglect further examination and regular treatment of patients. Therefore, clinically, more systematic laboratory tests should still be conducted for such patients, such as muscle biopsy for those suspected of dermatomyositis, and anti-nuclear antibody and anti-ds-DNA antibody tests for those suspected of SLE, in order to make correct diagnosis and provide timely and regular treatment.
Clinically, care should be taken to distinguish undifferentiated connective tissue disease from overlapping syndrome and mixed connective tissue disease. Overlap syndrome refers to the simultaneous or sequential appearance of clinical manifestations of two connective tissue diseases that meet the respective diagnostic criteria. Mixed connective tissue disease has internationally recognized diagnostic criteria and may have clinical symptoms similar to those of SLE, polymyositis or progressive systemic sclerosis, but does not meet their diagnostic criteria and is characterized by Raynaud’s phenomenon, swelling hand lung involvement and high titers of nRNP antibodies.
Treatment
Patients with UCTD often have mild clinical manifestations and are generally treated symptomatically. The aim of treatment is to alleviate the clinical symptoms of patients, to bring about long-term remission and to prevent adverse regression treatment protocols and drug doses should pay attention to the principle of individualization, and to observe the adverse effects of drugs.
1.Symptomatic treatment
Weakness, fever, arthralgia or arthritis can be treated with non-steroidal anti-inflammatory drugs. Individual differences in the efficacy of NSAIDs are generally large. Generally speaking, those with severe symptoms prefer diclofenac and other anti-inflammatory drugs with better effects; those with mild symptoms or long-term medication can choose slow-release NSAIDs with small adverse effects and convenient administration, such as meloxicam and nabumetone; those with a history of upper gastrointestinal tract inflammation and ulcers should choose selective COX-2 inhibitors such as rofecoxib and celecoxib.
Patients with Raynaud’s phenomenon should be kept warm and treated with vasodilators such as calcium channel antagonists depending on the extent of the disease. In patients with severe symptoms or ulcers on the extremities, intravenous prostaglandins and regia can be given to improve circulation. Patients with photosensitivity should pay attention to avoid direct sunlight.
2.Glucocorticoids
For facial rash, topical hormonal ointment can be applied. Arthritis that is difficult to relieve can also be given local injections of betamethasone (Depo-Provera) and deferiprone acetate as anti-inflammatory treatment.
Systemic hormone therapy can be applied in cases of organ involvement such as pericarditis, thrombocytopenia or hemolytic anemia, but high doses of hormones should not be used. Except for special cases, generally prednisone 0.5mg/(kg・d) can improve the condition, and then it should be reduced to a small dose of less than 10mg/d as soon as possible to reduce the occurrence of hormone adverse reactions. The survey of the European League Against Rheumatism found that 38% of patients were treated with oral prednisone after the initial diagnosis, but the amount of hormone was ≤10mg/d. The ratio was 43% and 27% at the 1-year and 2-year follow-ups, respectively.
3. Antimalarials
Patients with fever, facial rash and arthritis can be treated with antimalarials, and can be combined with NSAIDs. The common dose of hydroxychloroquine is 200-400mg/d. At this dose, damage to the fundus of the eye rarely occurs. However, as a precaution, an ophthalmologic examination should be performed before and every 3-6 months after the administration of the drug to note changes in the visual field and the occurrence of lesions such as fundus.
A survey conducted by the European League Against Rheumatism in 2000 found that about 17% of 112 patients with UCTD were treated with antimalarials, but the proportion rose to about 32% after 2 years. The results suggest that patients have good compliance with antimalarial treatment, and the incidence of discontinuation due to adverse reactions is low enough for long-term application.
4.Immunosuppressants
Immunosuppressants can also be tried for patients whose conventional treatment is ineffective, and there are fewer reports on their clinical treatment experience. Generally, according to the clinical symptoms of different reference to the treatment of other connective tissue diseases to give different programs, but it is appropriate to use a small dose of short course of treatment program. Commonly used immunosuppressive agents include methotrexate, azathioprine, leflunomide, cyclophosphamide, and morte-macrolide.
Prognosis
Studies have shown that the incidence of visceral involvement such as interstitial lung fibrosis, renal damage and central nervous system damage is low and the prognosis is relatively good, with more than half of the patients in complete remission at long-term follow-up. Results of a 5-year follow-up study of 665 patients with UCTD found that 34% developed a definite connective tissue disease (rheumatoid arthritis 13.1%; dry syndrome 6.8%; systemic lupus erythematosus 4.2%; mixed connective tissue disease 4.0%; systemic sclerosis 2.8%; systemic vasculitis 3.3%; and polymyositis/dermatomyositis 0.5%).