What Is Undifferentiated Connective Tissue Disease?
Undifferentiated connective tissue disease (UCTD) is an autoimmune connective tissue disorder that is diagnostically exclusive and has similar serological and clinical manifestations to systemic autoimmune disease but does not fulfill the diagnostic criteria of a defined connective tissue disorder. The clinical manifestations are similar to any of the other connective tissue diseases, so the clinical presentation can vary widely among patients.
Who Is Susceptible to UCTD?
UCTD is observed 90 percent of the time in females between the ages of 33 and 44. Most of the time, the condition does not progress into a definitive connective tissue disorder. Up to 50 percent of patients with a defined connective tissue disorder have UCTD. The white population is 70 percent more prone to UCTD than any other race.
What Causes UCTD?
UCTD is an autoimmune disorder, so the condition follows the common etiology of any other autoimmune disease. UCTD is caused when the body’s immune system fails to differentiate between its own cells and foreign cells, ending up attacking the former.
There is a significant rise in the activity of the immune system, which may result in the formation of autoantibodies or by activation of antigen-specific T-cells and can target autoantigens present within different connective tissues.
The initial presentation of the disorder might be vague and slow or rapid and then may or may not progress into a definitive connective tissue disorder.
UCTD can be triggered in the presence of environmental factors like cigarette smoke, pollutants, and ultraviolet light. In the presence of these factors, there is a decline in the T-regulatory cell population which triggers the development of UCTD. Further decline in the T-regulatory cell population worsens the symptoms, ultimately transforming into a definitive connective tissue disorder.
What Is the Pathophysiology of UCTD?
The occurrence of UCTD, like other autoimmune connective tissue disorders, is multiphasic.
In the initial stages of UCTD, the diagnosis can not be established as there is no serological evidence or signs and symptoms. The patient may even be unaware of the presence of any disease.
In the next stage, autoantibodies can be detected in the serum with an absence of clinical manifestations. This might be a gap phase between detecting autoantibodies and the onset of significant signs or symptoms. The nature and duration of the phase can be significantly variable among patients.
In the final stage of pathogenesis, clear signs and symptoms, along with antinuclear antibodies in the serum can be detected. The patient may continue to exhibit the same phase or may worsen with time which might indicate the progression of the disease into a definitive connective tissue disorder.
There are various serological markers used to diagnose or detect an autoimmune disorder. Anti-Ro or Anti-SSA and anti-U1-RNP are usually detected in serological studies specific to UCTD.
The absolute and relative number of the natural regulatory T-cells was found to be decreased in patients with UCTD, which is associated with the progression to a differentiated connective tissue disease. There is an association between the degree of variation of declining natural regulatory T-cells with the nature of the definitive connective tissue disorder it progresses to.
Vitamin D deficiency can result in pathological changes in the function and number of the CD4+ T-helper cells in UCTD and vitamin D supplementation shows an improvement in the balance of anti and pro-inflammatory processes in the disease.
What Are the Signs and Symptoms of UCTD?
The signs and symptoms of UCTD can mimic any of the differentiated connective tissue disorders and may or may not progress towards the same. The presence of such symptoms without fulfilling the diagnostic criteria of any known differentiated connective tissue disorder is an evident criterion to diagnose UCTD.
Some of the symptoms of UCTD include:
Skin: Sclerodactyly (skin tightening), calcinosis (calcium salt deposition in the skin), discoid rash (round sores), erythema nodosum (tender round bumps on shins), periungual erythema (redness around a fingernail), heliotrope rash (reddish-purple rash around the eyes), dilated or irregular nail fold capillaries, subcutaneous nodules, livedo (netlike pattern of reddish-blue skin), purpura (bleeding under the skin), acrocyanosis (blue discoloration of digits), telangiectasias (dilated small superficial blood vessels), urticaria (raised itchy rash), and Raynaud's phenomenon (numbness in digits due to cold temperature).
Eyes: Iritis (inflammation of the iris), uveitis (inflammation of the middle layer of the eye wall), scleral-episcleral disease (inflammation of the sclera and episclera of the eye), or conjunctivitis.
Lungs: Rales (rattling sounds when inhaling), pleural effusion (fluid accumulation between the layers of the lung covering), pleurisy (inflammation of the pleura), wheezing (high-pitched noise while breathing), pleural rub (sound heard due to rubbing of the pleural layers), and interstitial pneumonia (scarring lung disease).
Heart: Cardiomegaly (increased size of the heart), heart murmur (sound caused due to abnormal blood flow through the heart), pericardial rub (sound produced due to an inflamed pericardium), pericarditis (inflammation of the pericardium-sac enclosing the heart), irregular heartbeat, edema, or irregular P2 heart sound.
Muscles: Proximal muscle weakness (weakness in the muscles close to the center of the body), muscle tenderness (painful muscles), tendon friction rubs, or muscle atrophy (thinning of muscle mass).
Additional Signs: Leukopenia (lack of sufficient leukocytes), anemia (lack of sufficient red blood cells), thrombocytopenia (low platelet count), and abnormal nerve sensations in limbs.
How to Diagnose UCTD?
UCTD cannot be diagnosed in the early stages. Serological tests in the gap phase and clinical manifestation in the final stages aid in the diagnosis of the disease.
The diagnostic criteria of UCTD largely depend on the presence or absence of a differentiated connective tissue disorder.
These criteria include:
Clinical symptoms are similar but do not match the diagnostic criteria of a differentiated connective tissue disorder.
Presence of serological markers, including positive antinuclear antibody markers, on at least two serological investigations.
More than three years of symptom presentation.
Positive serological evidence includes the presence of anti-Ro or anti-SSA and anti-U1-RNP in the serum. Supplemental tests covering complete blood count, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), serum creatinine, urinalysis with microscopic analysis, rheumatoid factor (RF), and antinuclear antibodies (ANA) can be done to help in diagnosis.
Additionally, complement components (C3, C4, Ch50), creatine kinase, aldolase, anti-cyclic citrullinated peptide (CCP), anti-La or anti-SSB, thyroid-stimulating hormone, anti-jo1, anti-smith, anti-mi 2, anticardiolipin, lupus anticoagulant, anti-beta-2 glycoprotein 1, anti-Ku, rapid plasma reagin (RPR), anti-scl 70 (topoisomerase antibody), anti-chromatin, anti-histone, and vitamin D studies can be done.
Chest radiographs may be normal or display signs of pleural or pericardial effusion, longstanding pulmonary hypertension, cardiomegaly, or interstitial lung disease.
Chest CT (computed tomography scan) might be required to assess the extent and severity of interstitial lung disease, followed by ultrasonography of the salivary glands to differentiate between UCTD and Sjögren syndrome.
Other pulmonary and cardiac tests can be performed to diagnose any involvement of the lungs and heart. Pulmonary function tests like lung volumes, spirometry, carbon monoxide-diffusing capacity, and an ECG (electrocardiogram) can be performed to rule out ischemic changes, chamber enlargement, or axis deviation of the heart.
How To Treat UCTD?
UCTD has a mild pathological course and can be managed without hospitalization. Drugs used for autoimmune disorders are relevant in the treatment of UCTD, including nonsteroidal anti-inflammatory drugs, corticosteroids, calcium channel blockers, and Hydroxychloroquine.
NSAIDs (non-steroidal anti-inflammatory drugs), like Naproxen, are prescribed for their antipyretic, analgesic, and anti-inflammatory effects. In the presence of any side effects, COX-2 selective medications, like Celecoxib, are prescribed.
Systemic corticosteroids, like Prednisone, are prescribed to manage any flare-ups and to induce remission. Although generally exhibiting mild symptoms, some untameable symptoms can be treated with immunosuppressants like Methotrexate and Azathioprine.
Apart from using sunblock lotions and protective clothes, antimalarial-Hydroxychloroquine is used to treat any photosensitive rashes and is used in combination with NSAIDs to counter other articular, mucocutaneous, and constitutional symptoms. Calcium channel blockers, like Nifedipine and Diltiazem, are used to manage Raynaud's phenomenon.
What Is the Prognosis of UCTD?
The prognosis of UCTD depends upon the progression of the condition into a definitive connective tissue disorder or lack thereof. The progression of around 60 percent of UCTD cases will stall at the undifferentiated level and never proceed, out of which symptoms of 10 to 20 percent of the cases might subside and remit. The probability of progression into a definitive stage is highest in the initial five years of onset, and the probability decreases with time. Late progression leads to a much milder variant of a definitive connective tissue disorder. The mortality of such patients is comparable to that of SLE and RA.
What Is the Differential Diagnosis of UCTD?
Dermatomyositis (an inflammatory disease with muscle weakness and skin rashes).
Antiphospholipid syndrome (the immune system attacks the body’s proteins and forms clots within vessels and organs).
Fibromyalgia (widespread muscle pain and tenderness).
Linear scleroderma (loss of subcutaneous fat with pigment changes).
Regional fibrosis (excess synthesis and decreased degeneration of collagen).
Systemic lupus erythematosus (SLE-immune system attacks the body’s own cells in multiple organs).
Overlap syndrome (inflammatory rheumatic diseases with manifestations resembling multiple immune diseases).
Mixed connective tissue disease (MCTD-primarily lupus, scleroderma, and polymyositis).
Raynaud phenomenon (decreased blood flow to the fingers).
Polymyositis (inflammatory disease that causes muscle weakness).
Sjögren syndrome (rheumatoid arthritis, dry eyes, and dry mouth).
Systemic sclerosis (hardening and tightening of the skin).
Rheumatoid arthritis (RA-immune mediated joint damage).
What Are the Complications of UCTD?
The complications of non-progressive UCTD are:
Interstitial lung disease.
Lung fibrosis (damage and scarring of the lung tissue).
Cardiomegaly (enlarged heart).
There is a 40 percent chance of progression into severe forms of connective tissue disorders like SLE, RA, scleroderma, MCTD, etc.
Early recognition of the signs and symptoms, awareness, and implementation of management protocol can stop the disease progression at a nascent stage. The patient should be educated about the triggering factors and about the management protocol. It is also of utmost importance to establish a support system consisting of family members and specialists from various departments, including but not limited to cardiothoracic, nephrology, endocrinology, rheumatology, and psychiatry. A collective effort can bring down the probability of any complications and help the patient lead a normal life.