NORD gratefully acknowledges Eric L. Greidinger, MD, Staff Physician, Miami VAMC, Associate Professor of Medicine and Microbiology & Immunology, University of Miami Miller School of Medicine, for assistance in the preparation of this report.
Mixed connective tissue disease (MTCD) is an uncommon systemic inflammatory rheumatic condition. MCTD is a specific subset of the broader category of rheumatic “overlap syndromes”, a term used to describe when a patient has features of more than one classic inflammatory rheumatic disease. These classic rheumatic diseases include systemic lupus erythematosus, polymyositis, scleroderma and rheumatoid arthritis. Individuals with an overlap syndrome may, but need not meet, complete diagnostic criteria for one (or more than one) classic rheumatic disease. MCTD is distinguished from other overlap syndromes by a laboratory result: MCTD patients have rheumatic overlap syndrome plus anti-RNP antibodies. Additionally, it has been proposed that the term “MCTD” be reserved for patients with clinical features that include at least one of the following “common manifestations”: Raynaud’s phenomenon, puffy fingers or swollen hands.
Individuals with MCTD have symptoms that overlap with those of two or more inflammatory rheumatic diseases. These diseases, in which autoimmunity, excess immune activation and inflammation are hallmarks, include systemic lupus erythematosus, polymyositis, scleroderma and rheumatoid arthritis. (For more information on these disorders, see the Related Disorders section of this report.) While inflammatory rheumatic diseases have at times been referred to as “connective tissue diseases”, this can cause confusion with other conditions which are characterized by biochemically abnormal connective tissues (such as Ehlers-Danlos syndrome or Marfan syndrome) in which autoimmunity, excess immune reactions and inflammation need not occur, and which are not part of MCTD.
A condition known as Raynaud’s phenomenon may precede the development of additional symptoms of MCTD. Raynaud’s phenomenon, which is seen also in over 95% of patients with 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 also 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 thickening changes on the fingers and face like those seen in scleroderma. Muscle weakness due to inflammation (myositis) of the muscles can also occur, typically primarily affecting large centrally-located muscle groups. 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 with a delay of months to years 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 lung 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 neurologic findings of aseptic meningitis (an inflammation of the lining surfaces that surround the brain and spinal cord, without an associated infection) or trigeminal neuralgia (an impairment in the function of one of the major cranial nerves that supplies sensory and motor functions to parts of the face) have been observed to occur with increased frequency in MCTD.
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 patients. Enlargement of the lymph nodes (lymphadenopathy), enlargement of the spleen (splenomegaly), enlargement of the liver (hepatomegaly) and intestinal involvement may also occur in some patients.
Although medications may be required to help control MCTD, the condition has been reported to eventually enter spontaneous sustained remission in as many as 40% of patients.
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 MCTD can occur anytime from early childhood to elderly adulthood, but the average age of onset is 37 years. Approximately 75 percent of patients are female. The point prevalence of MCTD has been found to be 3.8 per 100,000 adults in Norway, and is thought to be similar in many other parts of the world, though much higher prevalence of MCTD has been noted in some countries, notably in Japan.
Debate exists in the medical literature as to whether MCTD is a distinct syndrome or should be considered either as a subset of lupus or as instances of undifferentiated autoimmune rheumatic disease.
MCTD 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). Several sets of diagnostic criteria for MCTD have been published that have similar performance characteristics. After diagnosis, ongoing surveillance for the potential for late-emerging lung disease is typically performed; serial pulmonary function testing is often an aspect of this assessment.
The treatment of MCTD is based upon the specific symptoms that present in each person. Although no controlled treatment studies have been performed in MCTD itself, some patients with MCTD have been included in previous trials of lupus, scleroderma, myositis and rheumatoid arthritis. 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, the use of additional disease-modifying anti-rheumatic drugs (DMARDs) for rheumatoid arthritis-like polyarthritis, the use of anti-fibrotics approved for use in other forms of pulmonary fibrosis for the treatment of MCTD-associated pulmonary fibrosis, and the use of treatments approved for other forms of pulmonary hypertension for MCTD-associated pulmonary hypertension.
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, can occur in MCTD.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are sometimes used to help control mild inflammatory symptoms, though their use must be balanced with their risk for gastrointestinal, renal and other complications. Rarely, NSAIDs can cause aseptic
meningitis in some individuals; this seems to occur more often in patients with MCTD compared to other groups.
Research into MCTD is ongoing. Reports have identified novel strategies to treat mouse models of MCTD that await follow-up with translational human studies. Also, a large number of anti-rheumatic medications with novel mechanisms of action 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:
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Some current clinical trials also are posted on the following page on the NORD website: https://rarediseases.org/for-patients-and-families/information-resources/news-patient-recruitment/
For information about clinical trials sponsored by private sources, contact: www.centerwatch.com
For information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
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INTERNET Greidinger EL. Mixed Connective Tissue Disease. Medscape Reference. Updated January 21, 2021. Available at: http://emedicine.medscape.com/article/335815-overview Accessed Nov 23, 2021.
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