Connective Tissue and Mixed Connective Tissue Disease.
PKGhatak, MD
Connective tissue is the most abundant tissue in the human body. It is present underneath the skin, in the lungs, in the mucus membranes of GI and GU tracts, and in the fatty tissue and in the coverings of the brain. The connective tissue fibers are made up of two proteins- Collagen and Elastin. Collagen is present in the tendons and elastin dominates in the lungs and skin. The connective tissue (CT) is a loose collection of cells in the middle of a water rich extracellular matrix. Blood, bones, cartilage, adipose and reticular tissues are special forms of connective tissues.
Embryology of CT.
CT is derived from the mesoderm. A sheet of cells in the developing fetus folds into two tubes ectoderm and endoderm and in between tubes the remaining cells from the mesoderm. The embryonic mesoderm is known as Mesenchyme. From the mesenchyme, the connective tissue, muscles, bones, cartilage, blood vessels and lymph tissues develop. The mesoderm cells undergo various stages of development, from the initial flat sheet of cells to tube formation and back to sheet form. CT cells migrate to the ectoderm and develop into the subcutaneous tissue of the skin; cells migrate to the endoderm and develop into the submucous tissue in the GI tract and interstitial cells in the lungs. The developing mesoderm receives cells from the yolk sack, these cells become Microglial cells of the brain. The end result is connective tissue containing blood and lymph vessels and nerve fibers.
This basic embryology is helpful to understand various manifestations of Connective Tissue Disease (CTD).
Connective tissue disease.
There are a number of Autoimmune CTDs are simply identified as Connective Tissue Diseases. These diseases are Systemic lupus erythematosus (SLE), Scleroderma, Sjogren syndrome, Polymyositis, Rheumatoid arthritis (RA) and Mixed connective disease.
The laboratory screening test for connective tissue disease is ANA (anti nuclear antibody) test. The test is expressed as I:80 to 1: 640 dilutions. However about 15% of the population have a positive test without ever having any disease, these ANA tests are positive only in lower dilution (1:80).
The mixed connective disease (MCTD), as the name indicates, has some of the characteristics of other CT diseases and was previously named Overlap Syndrome.
MCTD (mixed connective tissue disease)
MCTD is a rare autoimmune disease; it is triggered by an unidentified agent. The antibodies generated are directed against collagen fibers wherever they are present. Those cells turn out excess collagen which causes the thickening of skin and fibrosis of internal organs. To describe a full spectrum of MCTD, a synopsis of common manifestations of the other CTDs is presented here.
1. Lupus Erythematosus (SLE).
SLE is a systemic disease that affects many organs and is a steadily progressive illness. Deaths are due to renal or respiratory failure if treatment is not available. However, not every patient follows the progressive course, many just have skin or liver disease only, while others may have skin and lung involvement. The lesions produced by SLE on the individual organs are summarized below. -
Skin. The term erythematosus of SLE is taken from a butterfly red colored skin rashes develop over the bridge of the nose and on checks. Other skin lesions are coin sized dry skin patches on sun exposed skin, resembling psoriasis. And subcutaneous lesions with rolled up raised margins localize lesions are seen on the neck, front of the chest and exposed areas of arms.
Joints. The finger joints of both hands and feet are commonly involved. The stiffness, swelling and joint pain are usual symptoms.
Kidneys. Glomerulonephritis is common. Nephritis is due to immune-complex induced damage to the capillaries of glomeruli. This leads to hypertension, renal insufficiency and renal failure.
Pulmonary. Pleurisy is the most likely to develop when the lungs are involved. Pulmonary fibrosis, pulmonary hypertension and respiratory insufficiency lead to respiratory failure. At times small vessel vasculitis produces pulmonary infiltrates and patchy areas of consolidation.
Liver: Lupus hepatitis is a known feature, often just the liver enzymes are elevated and in others, more liver damage and jaundice develop.
Heart. Sterile pericarditis, myocarditis, coronary artery disease and conduction abnormalities are usual findings. In addition, cardiac valve damage and sterile vegetative emboli to the brain may happen.
Brain. Encephalitis, small vessel strokes, transient ischemic attacks. delirium, psychosis, anxiety and seizures may develop.
Eye. Blurred vision, exudative macular detachment, cystoid macular edema, and ptosis may develop.
Hematology. Anemia, thrombocytopenia, leukopenia, lymphadenopathy and splenomegaly are seen.
Coagulation. Prolongation of coagulation due to lupus-anticoagulant can cause serious problem in certain situations.
Confirmatory serology for SLE. In SLE the ANA test is invariably positive. Several antibody tests are also positive. But the confirmatory test is anti-Native double stranded DNA ( sdDNA). This test is the gold standard diagnostic test of SLE.
2. Systemic Sclerosis (SS), and Scleroderma.
It is a rare disease, one in a million per year is seen in cold climate countries, still less prevalent in tropical countries.
SS is characterized by diffuse fibrosis of the skin and fibrosis of the internal organs. But not every patient has the same degree of involvement. All patients have positive ANA in high titers, and 70 % of them have positive Anti SCL 70 antibody tests, this test now known is known as the Anti topoisomerase I test. This test is positive in about 50 % of cases of diffuse SS. When the lesions are confined to limited areas of the skin, the term Scleroderma is used and in 20% of cases, this test is positive.
The following variants of SS are important.
a. CREST syndrome. CREST stands for calcinosis, Raynaud's phenomenon, esophageal dysfunction, sclerodactyly and telangiectasia. The skin lesions in CREST Syndrome are limited to the distal extremities, face and neck.
b. Diffuse disease. The thickening of the skin with areas of increased pigmentation and patchy areas of depigmentation is present all over the body including the trunk. A test that measures antibodies against Topoisomerase I titer becomes positive in over 50 % of patients.
In contrast, in diseases limited to the skin and few other places, a different antibody test - The Antocentromere antibody test becomes positive in over 50 cases. About 20% of patients with limited SS have anti-topoisomerase I positivity. In 14 % of cases of limited. the SS U1-RNP antibody test is positive; it indicates the presence of Pulmonary fibrosis.
c. Raynaud's phenomenon. Intense blanching of fingers and toes during exposure to cold is associated with pain. Anti U 11 and U12- RNP antibody tests in Raynaud's is associated with GI, Pulmonary involvement and higher mortality.
When SS produces fibrosis in the lungs, kidneys and GI tract the disease produces pulmonary insufficiency, renal insufficiency, hypertension, reflux esophagitis and hypomotility of GI tract including the esophagus respectively. In renal crisis due to uncontrollable hypertension and renal failure in systemic sclerosis, Anti RNA polymerase III antibody test becomes positive.
3. Sjogren syndrome. Dryness of mouth and eyes and their consequences are the presenting symptoms. The lachrymal glands and salivary glands typically show lymphoid foci with the destruction of glandular elements and fibrosis. ANA is positive in over 95%of cases and anti SS-A and SS-B positive in 65% of cases. SS is often associated with symptoms of RA, biliary ductal inflammation, Hashimoto thyroiditis, polyarteritis and pulmonary fibrosis.
4. Polymyositis and myopathy. Patients typically present with muscle weakness and muscle pain. Muscle enzymes- CPK and Aldolase levels are high indicating muscle necrosis and inflammation. Dermatomyositis is a variant of myositis. Dermatomyositis presents as bilateral "heliotropic rashes”. Another subvariant is Antisynthetase syndrome which is characterized by muscle disease associated with non-erosive arthritis, Raynaud's phenomenon, hyperkeratosis along the palmar and radial aspects of the fingers, pulmonary fibrosis and the presence of anti-Jo-1 antibodies.
5. Rheumatoid arthritis (RA). It is a common disease (about 1% of the population), in contrast with the previous illness mentioned under CTD. It is also different from the rest in having a negative ANA test in 80 % of cases. The blood tests for RA are Rheumatoid Factor (present in all cases), and anti-CCP antibodies (cyclic citrullinated peptides) present in 80 % of cases. Clinical features of RA are dominated by symmetrical polyarthritis of small joints of fingers and toes, The 1st (proximal interphalangeal) joint arthritis at the beginning of the illness is very characteristic. Swelling, pain and morning stiffness of hands and red discoloration of the overlying skin point to an early diagnosis. As the disease advances other small joints like wrist joints, upper cervical spine, temporomandibular, and sternoclavicular joints are affected. Low grade fever, loss of weight and other clinical and laboratory tests follow the general features of CTD. X-rays of the hands show Erosion of bones at the joint faces and osteoporosis. These findings are also distinct features of RA. Extra articular features are subcutaneous nodules over the bony prominence, pleural effusion (small amount), pulmonary fibrosis, pericarditis, vasculitis and enlarged spleen.
Mixed Connective Tissue Disease.
Most patients with MCTD are young females between 25 -30 yrs. of age. In Native Americans of Minnesota, the incidence is 6 per100, 000 and 2/100,000 in white females. The onset of the disease is insidious and begins with arthralgia of the fingers of both hands which become white, numb and painful on exposure to cold. Later finger joints swell and become painful. Raynaud's phenomenon and myalgia are common symptoms. All MCTD patients carry HLA-DRB1 positive markers in their white blood cells (lymphocytes & monocytes). The blood levels of U-1 RNP (Ribonuclear Protein) antibodies in high titers (over 1:125) or over 25 U are seen in over 95% of patients with MCTD. MCTD is a slowly progressive disease but in some patients, the progression may be arrested for years, in others the disease shows features of one or other connective tissue disease mentioned above. However, the initial phase of MCTD resembles RA but soon the disease takes a course resembling scleroderma and Raynaud's features dominate. Though dryness of the eyes is present, other typical features of Sjogren syndrome are absent. Later, as GI, Pulmonary, and Renal symptoms develop the diseases acquire SLE like illness, but the CNS is very rarely affected. Pulmonary fibrosis is the most devastating aspect of MCTD and death is generally from respiratory failure or pulmonary infection.
Treatment.
The management of MCTD is based on individual patients because no two patients are having the same system involvement.
The general approach is to use well known immune suppression drugs and symptomatic therapy for individual organ system dysfunction and degree of disability. Disease modifying agents are added and watched for side effects and therapy is modified based on progress over adverse effects.
Prognosis. Over all prognosis of MCTD is favorable over SLE and SS. A 10 year survival rate of MCTD is 80%. Those who develop Pulmonary fibrosis have the worst prognosis.
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