Mixed Connective Tissue Disease

Disease Overview

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. The anti-ribonucleoprotein (RNP) immune response is an autoimmune response where the body’s defense system produces antibodies that mistakenly attack ribonucleoproteins which are structures found in all cells.

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.

MCTD is an autoimmune condition. Treatment is similar to the treatment of other autoimmune conditions.

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Synonyms

• MCTD
• Sharp syndrome

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Signs & Symptoms

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.

The symptoms of MCTD can vary from person to person. The most common symptoms include:

• Raynaud’s phenomenon: (seen in over 90% of people with MCTD and is often the first sign before other symptoms appear)

• • Painfully cold fingers and toes
  • Fingers/toes turn white or blue in response to cold or stress

• Joint pain and swelling: (these symptoms are common and may mimic those of rheumatoid arthritis)

• • Polyarthralgia: Pain in multiple joints
  • Arthritis: Inflammation of the joints causing stiffness, pain and swelling
• Skin changes:
  • Lupus-like skin rashes especially in sun-exposed areas
  • Thickening of the skin on fingers and the face (similar to scleroderma)
  • Hair loss (alopecia)
• Muscle weakness:
  • Weakness due to muscle inflammation (myositis) especially in large muscles close to the trunk (hips, shoulders)
• Swollen hands and fatigue:
  • Puffiness in the hands, along with severe tiredness are common early symptoms
• Esophageal dysfunction:
  • Trouble swallowing solid foods
  • Heartburn (gastroesophageal reflux) due to issues with the esophagus, the tube that connects your throat to your stomach

• Lung problems: (About half of people with MCTD may develop lung issues, but these often appear months to years after other symptoms begin.)

• • Pulmonary hypertension: High blood pressure in the lungs leading to shortness of breath
  • Interstitial lung disease (ILD): Lung inflammation and scarring, making it difficult to breathe
  • ILD can occur earlier or later in the disease course. Pulmonary hypertension, on the other hand, is a more serious and often later complication that can dramatically affect prognosis.
  • Heart involvement: (less common than lung issues but can be serious when it occurs)
  • Inflammation of the heart lining (pericarditis)
• Kidney (renal) disease:
  • Occurs in about 10% of the affected people and tends to be milder than in lupus
• Neurological issues:
  • Neurologic abnormalities are noted in approximately 10% percent of people affected with MCTD
  • Aseptic meningitis: Inflammation of the brain’s protective lining without an infection
  • Trigeminal neuralgia: Intense pain resulting from impairment in the function of one of the major cranial nerves that supplies sensory and motor functions to parts of the face
• Blood disorders:
  • Anemia: Low red blood cell count, leading to fatigue
  • Leukopenia: Low white blood cell count which may make the person more prone to infections
  • Enlargement of the lymph nodes, spleen, or liver may also occur in some people

MCTD can affect organs differently in each person. Some people may have more severe symptoms in certain organs, which can define patterns or subtypes of the disease:

• Vascular symptoms:
  • People with more vascular problems such as Raynaud’s or pulmonary hypertension may be at higher risk for lung-related complications.
• Muscle symptoms (myositis):
  • People with more muscle involvement may be more likely to develop interstitial lung disease (ILD).
• Rheumatoid arthritis-like symptoms:
  • Some people with more classic arthritis symptoms may have a lower risk of major organ damage compared to other subtypes.

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Causes

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 anti-ribonucleoprotein (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, i.e., anti-RNP antibodies mistakenly attack the body’s own ribonucleoproteins after exposure from dead or damaged cells, which can trigger an autoimmune response.

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.

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Affected populations

The onset of MCTD can occur anytime from early childhood to elderly adulthood, but the average age of onset is 37 years. Approximately 75% 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. In a population-based study from Olmsted County, Minnesota, the incidence of MCTD was 1.9 per 100,000 adults per year.

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.

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Disorders with Similar Symptoms

The symptoms of the following disorders can be similar to those of MCTD. Comparisons may be useful for a differential diagnosis:

Systemic lupus erythematosus (lupus) is a chronic, autoimmune disorder in which multiple targets are attacked, typically including dead cell debris and connective tissue structures. In autoimmune disorders, the body’s own immune system attacks cells and tissues causing inflammation and malfunction of various organ systems. In lupus, organ systems often involved include the skin, kidneys, blood and joints. Many different symptoms can be associated with lupus, but most affected individuals do not experience all of the symptoms. In many patients, lupus may be a mild disorder affecting only a few organ systems. In other patients, it may result in serious complications.

Systemic scleroderma is an uncommon autoimmune disease characterized by abnormally increased production and accumulation of collagen, the body’s major structural protein, in skin and other organs of the body, in combination with abnormal blood vessel function leading to Raynaud’s phenomenon. Major targets of the autoimmune response in scleroderma include self-proteins that can become more likely to provoke an immune reaction under conditions of erratic blood flow (leading to “ischemia-reperfusion injury”). Associated symptoms, which may vary widely from person to person, may include Raynaud’s phenomenon, abnormal tightness, thickening, “waxiness” and loss of elasticity of the skin, shortness of breath, difficulty swallowing, muscle weakness, joint pain, heart abnormalities including irregular heartbeats (palpitations), kidney (renal) abnormalities and/or other symptoms and findings.

Polymyositis is a rare autoimmune disease characterized by inflammatory damage in muscle fibers. The major symptom of this disorder is muscle weakness, usually in the neck, trunk, shoulders and thighs. Eventually, it may become difficult for patients to rise from a sitting position, climb stairs, lift objects and/or reach overhead. Other tissues can also develop inflammation in cases of myositis, including the skin (in which case the term dermatomyositis rather than polymyositis is used), the joints, lungs (interstitial pneumonitis) and heart.

Rheumatoid arthritis (RA) is a chronic progressive form of inflammatory arthritis that can lead to joint destruction. Rheumatoid arthritis is characterized by inflammation of the joints (arthritis) on both sides of the body (symmetrical) leading to swelling, pain and decreased mobility. The course of the disease is highly variable.

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Diagnosis

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). The Anti-RNP antibodies are almost always present in MCTD, but they can also be seen in other diseases. Diagnosis requires clinical features in addition to lab results.

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 lung function testing is often an aspect of this assessment.

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Standard Therapies

Treatment

Mixed connective tissue disease (MCTD) is a rare condition that presents a unique set of challenges for both the affected people and their doctors. Due to its rarity, there are no randomized controlled trials specifically guiding treatment and therapies are generally based on the symptoms and which organs are affected. 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 the affected people.

The focus of treatment is to manage symptoms, control inflammation and prevent long-term complications.

People with MCTD are at risk for several serious complications that require early detection and ongoing monitoring, such as pulmonary hypertension (high blood pressure in the lungs, which can lead to heart failure), kidney problems, heart and vascular issues, including atherosclerosis (hardening of the arteries), esophageal reflux and malabsorption.

Without proper treatment, these complications can significantly impact the quality of life and may become life-threatening.

According to the specific symptoms treatment may include:

• Arthritis (joint inflammation) and arthralgia (joint pain) can be improved with:
  • Nonsteroidal anti-inflammatory drugs (NSAIDs)
  • Antimalarial drugs such as hydroxychloroquine
  • Oral or intra-articular corticosteroid courses, typically at low dose, if needed
    • For more severe cases such as refractory synovitis, the swelling is in the synovial membrane that lines joints and does not get better with corticosteroids. Methotrexate and other disease-modifying anti-rheumatic drugs (DMARDs), a class of drugs that treat inflammatory conditions such as arthritis and other disorders are used.
• Gastrointestinal issues
  • Proton pump inhibitors (PPIs), a class of drugs that reduce the amount of acid produced in the stomach or histamine blockers, medication that reduces the amount of stomach acid, are prescribed to manage esophageal reflux.
  • Lifestyle changes such as elevating the head of the bed and avoiding dietary triggers can also help.
  • In cases of severe esophageal motility disorder treatment may include prokinetics (such as metoclopramide (Reglan), which improve the motility of the esophagus and stomach and help reduce reflux of gastric contents) and fundoplication, a surgical procedure that treats stomach acid reflux by reinforcing the lower esophageal sphincter.
• Raynaud’s phenomenon can be treated with vasodilators such as calcium channel blocking agents and phosphodiesterase-5 inhibitors as they widen and relax blood vessels.
  • Avoiding cold temperatures, caffeine and smoking is important
  • In more severe cases topical nitroglycerin or prostaglandins may be used
• Pulmonary hypertension can be treated with vasodilator medications such as:
  • Phosphodiesterase inhibitors (medication that causes blood vessels to relax and widen, improving circulation and lowering blood pressure)
  • Endothelin receptor antagonists (e.g., ambrisentan), a medication that reduces a substance called endothelin in the blood that narrows blood vessels and increases the blood pressure in the pulmonary arteries)
  • Prostaglandins, medications that widen blood vessels both on pulmonary and systemic arteries endothelin receptor antagonists
  • Phosphodiesterase-5 (PD5) inhibitors (e.g., sildenafil) which by inhibiting the PD5, help the blood vessels to relax and increase blood flow to the lungs lowering blood pressure
• MCTD-related interstitial lung disease, a group of disorders that cause inflammation, irritation, or scarring in the lungs and air sacs resulting in breath difficulties
  • Common treatments include corticosteroids in combination with corticoid-sparing medications such as mycophenolate mofetil, cyclophosphamide and rituximab
  • Rituximab and cyclophosphamide have comparable outcomes but rituximab generally has fewer side effects
  • In advanced ILD cases, nintedanib, an anti-fibrotic drug, may be beneficial
• Blood Disorders

• Autoimmune hemolytic anemia and thrombocytopenia are initially treated with steroids
• If the condition is resistant to treatment, rituximab may be considered.

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 people, despite the potential for significant long-term side effects. Some people with MCTD can develop a complication known as scleroderma renal crisis which is more likely to occur with the use of high-dose corticosteroids and presents a serious risk.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are sometimes usedto control mild inflammatory symptoms, although these medications may have side effects such as gastrointestinal, renal and other complications. Rarely, NSAIDs can cause aseptic meningitis, which appears to occur more frequently in people with MCTD compared to the general population

MCTD affects multiple organs and managing it requires a team of specialists working together. The specialists may include rheumatologists (specialists that manage autoimmune and inflammatory aspects, pulmonologists (for lung problems), cardiologists (for heart problems), nephrologists (for kidney problems), gastroenterologists (for gastrointestinal problems), as well as physical and occupational therapists to assist with maintaining mobility and managing daily activities and mental health professionals who may provide support for emotional and psychological well-being.

Maintaining a healthy lifestyle is critical for people with MCTD. A heart-healthy diet including supplements such as omega-3 fatty acids and having regular exercise can help reduce the risk of complications like cardiovascular disease. Physical activity should be tailored to the person’s needs, especially when having arthritis or joint pain. It’s also important to regularly monitor symptoms, as early detection of complications like pulmonary hypertension and ILD can significantly improve outcomes.

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Clinical Trials and Studies

Research is ongoing to better understand the mechanisms behind MCTD and develop more effective treatments. Current studies focus on immunosuppressive therapies and medications that target fibrosis. These advances hold promise for improved care and potentially even a cure in the future.

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
TTY: (866) 411-1010
Email: [email protected]

Some current clinical trials also are posted on the following page on the NORD website: https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

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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References

TEXTBOOKS

Greidinger EL. Overlap Syndromes, In: Systemic Lupus Erythematosus: Basic, Applied, and Clinical Aspects, 2e, Tsokos G Ed., New York: Elsevier, 2019.

Greidinger EL, Mixed Connective Tissue Disease, In: Encyclopedia of Medical Immunology: Autoimmune Diseases, MacKay I and Rose NR Eds., New York: Springer, 2014. ISBN 13: 9780387848280.

Bennett RM. Overlap Syndromes, In: Kelley & Firestein’s Textbook of Rheumatology, 10e, Firestein GS, Budd RC, Gabriel SE, McInnes IB, O’Dell JR Eds., Philadelphia, 2017.

JOURNAL ARTICLES

Tanaka Y, Kuwana M, Fujii T, et al. 2019 Diagnostic criteria for mixed connective tissue disease (MCTD): From the Japan research committee of the ministry of health, labor, and welfare for systemic autoimmune diseases. Modern Rheumatol 2021; 31(1):29-33. https://doi.org/10.1080/14397595.2019.1709944

Carpintero MF, Martinez L, Fernandez I, Romero AC, Mejia C, Zang YJ, Hoffman RW, Greidinger EL. Diagnosis and risk stratification in patients with anti-RNP autoimmunity. Lupus 2015 Sep;24(10):1057-66. https://www.ncbi.nlm.nih.gov/pubmed/25736140

Zang Y, Martinez L, Fernandez I, Pignac-Kobinger J, Greidinger EL. Conservation of Pathogenic TCR Homology across Class II Restrictions in Anti-Ribonucleoprotein Autoimmunity: Extended Efficacy of T Cell Vaccine Therapy. J Immunol. 2014;192(9):4093-102.

Szodoray P, Hajas A, Kardos L, et al. Distinct phenotypes in mixed connective tissue disease: subgroups and survival. Lupus 2012;21:1412-22. https://www.ncbi.nlm.nih.gov/pubmed/22864236

Gunnarsson R, Molberg O, Gilboe IM, Gran JT; PAHNOR1 Study Group. The prevalence and incidence of mixed connective tissue disease: a national multicentre survey of Norwegian patients. Ann Rheum Dis. 2011 Jun;70(6):1047-51. https://www.ncbi.nlm.nih.gov/pubmed/21398332

Maldonado M, Perez M, Pignac-Kobinger J, Triana E, Tozman E, Greidinger EL, Hoffman RW. Clinical and Immunologic Manifestations of Mixed Connective Tissue Disease (MCTD) in Miami Population Compared to Midwestern Caucasian MCTD Population. J Rheumatol. 2008;35:429-37. https://www.ncbi.nlm.nih.gov/pubmed/18260175

Yang YH, et al. Childhood mixed connective tissue disease. J Formos Med Assoc. 2000;99:158-61.

Burdt MA, et al. Long-term outcome in mixed connective tissue disease: longitudinal clinical and serological findings. Arthritis Rheum. 1999;42:899-909.

INTERNET

Sapkota B, Al Khalili Y. Mixed Connective Tissue Disease. [Updated 2024 Jul 27]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK542198/ Accessed Oct 10, 2024.

Greidinger EL. Mixed Connective-Tissue Disease (MCTD). Medscape Reference. December 22, 2022.  https://emedicine.medscape.com/article/335815-overview Accessed Oct 10, 2024.

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