NORD gratefully acknowledges Eric L. Greidinger, MD, Staff Physician, Miami VAMC, Associate Professor of Medicine, Chief, Division of Rheumatology, University of Miami Miller School of Medicine, for assistance in the preparation of this report.
Individuals with mixed connective tissue disease have symptoms that overlap with those of two or more connective tissue diseases. These diseases include systemic lupus erythematosus, polymyositis, scleroderma, and rheumatoid arthritis. (For more information on these disorders, see the Related Disorders section of this report.)
A condition known as Raynaud’s phenomenon may precede the development of additional symptoms of MCTD. Raynaud’s phenomenon, which is seen also in scleroderma, is characterized by painfully cold fingers and toes with blue and/or white color changes caused by spasm of blood vessels in the hands and feet in response to cold or stress. It occurs in approximately 90 percent of individuals with MCTD.
Pain in multiple joints (polyarthralgia) or inflammation of joints (arthritis) also occurs in the majority of affected individuals. Lupus-like skin inflammation in sun-exposed areas and hair loss are common, as are skin scarring changes on the fingers and face like those seen in scleroderma. Muscle weakness due to inflammation (myositis) of proximal muscle groups can also occur. Additional frequent symptoms include hand swelling and fatigue.
Dysfunction of the esophagus occurs in at least half of individuals with MCTD. The esophagus is the tube that carries food from the mouth to the stomach. Esophageal trouble most often manifests as heartburn (gastroesophageal reflux) and difficulty swallowing solid foods. Nearly half of individuals with MCTD may develop clinically significant lung involvement, typically sometime after the condition first emerges. MCTD lung disease may lead to breathing (respiratory) difficulties caused either by high blood pressure in the lungs (pulmonary hypertension) or by causing lung inflammation and scarring in and around the air sacs (interstitial lung disease).
Heart (cardiac) involvement is less common in MCTD than lung problems, but can be serious when it occurs.
Kidney (renal) disease occurs much less often in MCTD than in lupus (10 percent of individuals with MCTD) and is often mild in MCTD.
Neurologic abnormalities are noted in approximately 10 percent of individuals with MCTD.
The low levels of circulating red blood cells (anemia) and a reduction in the white blood cell count (leukopenia) occur in 30 to 40 percent of cases. Disease of the lymph nodes (lymphadenopathy), enlargement of the spleen (splenomegaly), enlargement of the liver (hepatomegaly), and intestinal involvement may also occur in some cases.
Although medications may be required to help control MCTD, the condition has been reported to eventually enter sustained remission in as many as 40% of cases.
Among patients with MCTD, patterns of organ targeting have been reported that suggest disease subtypes. Some patients have more vascular manifestations, and have higher risk for pulmonary hypertension. Some patients have more myositis manifestations and have higher risk for interstitial lung disease. Some patients with more classic rheumatoid arthritis manifestations may have a lower risk of major internal organ damage.
MCTD is caused by immune reactions against self (autoimmunity). The anti-RNP immune response that helps define the disease also appears to mediate some of the damage it induces. The RNP molecules are usually in the nucleus of all human cells, where they help to manufacture messenger RNA, and where the immune system cannot find them. However, in dead or dying cells, RNP molecules can become exposed to the immune system. Since RNP molecules are nearly identical in humans to their counterparts in single celled organisms without immune systems, the human immune system can be fooled into responding to RNP as if it were from a dangerous invader.
Several genes that control the immune system’s responsiveness to invaders and the ability to hide or destroy dead cell debris influence the risk of developing MCTD. Prior immune exposures to other things that look like RNP (such as with prior viral infections) may also increase the risk. Additional effects of heredity and the environment on the risk for developing MCTD and on its manifestations and severity are likely.
The onset of mixed connective tissue disease can occur anytime from early childhood to elderly adulthood, but the average age of onset is 37 years. Approximately 75 percent of individuals are female. The point prevalence of MCTD has been found to be 3.8 per 100,000 adults in Norway, and is felt to be similar in many other parts of the world, though much higher prevalence of MCTD has been noted in some ethnic/geographic groups, notably in Japan.
Debate exists in the medical literature as to whether mixed connective tissue disease is a distinct syndrome or should be considered a subset of lupus.
Mixed connective tissue disease may be diagnosed based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic findings, and specialized tests such as blood tests that reveal abnormally high levels of antibodies to the U1 small nuclear ribonucleoprotein (anti-RNP).
The treatment of mixed connective tissue disease is based upon the specific symptoms that present in each case. Although, no controlled studies have been performed in MCTD, some patients with MCTD have been included in previous trials of lupus, scleroderma, myositis, and rheumatoid arthritis patients. In general, it appears that these MCTD subgroups respond similarly to treatments as have been reported in larger classical rheumatic disease-specific patient cohorts. These observations and accumulated clinical experience by MCTD experts supports the use of antimalarials for potential lupus-like disease modifying effects, the use of vasodilators to treat Raynaud’s phenomenon, the use of proton pump inhibitors for GERD, and the use of additional disease-modifying anti-rheumatic drugs (DMARDs) for rheumatoid arthritis-like polyarthritis.
Cohort studies of MCTD patients with pulmonary hypertension or other lung disease have suggested that these patients may be more likely to respond well to a course of aggressive immunosuppression than is typical for patients with similar lung disease stemming from other causes.
Low-to-moderate doses of corticosteroids are often effective for rapid control of disease flares, and may be used as part of long-term therapy in some patients, despite their substantial long-term drug toxicities. Scleroderma renal crisis, a serious complication of scleroderma that is more likely after the use of high dose corticosteroids, has been infrequently reported in MCTD.
Nonsteroidal anti-inflammatory drugs (NSAIDs) may also be used to help control mild inflammatory symptoms, though their use must be balanced with their risk for gastrointestinal complications. NSAIDs rarely can cause aseptic meningitis in some individuals; this seems to occur slightly more often in patients with MCTD compared to other groups.
Research into mixed connective tissue diseases is ongoing. Recent reports have identified promising novel strategies to treat mouse models of MCTD that need to be followed up with translational human studies. Also, a large number of new anti-rheumatic medications have recently been developed or are being developed for the treatment of one or more of the classical rheumatic diseases. The potential for these drugs for the treatment of MCTD patients is another topic of keen interest.
A major goal at this time continues to be to better understand the mechanisms involved in the MCTD disease process. Discoveries of this sort could be a major step forward in discovering better treatment or a cure.
Information on current clinical trials is posted on the Internet at www.clincaltrials.gov . All studies receiving U.S. government funding, and some supported by private industry, are posted on this government website.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
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Some current clinical trials also are posted on the following page on the NORD website:
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For information about clinical trials conducted in Europe, contact:
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