Mixed Connective Tissue Disease (MCTD) and Lupus

Mixed Connective Tissue Disease is one of the most complicated conditions to diagnose and treat, especially as it often mimics the symptoms of lupus. This article sheds some light on this misunderstood condition.

Introduction

“Connective tissue” is a general term used to describe a diverse number of tissue structures within the body.  The various kinds of connective tissues are far more numerous than, for example, muscle tissues.  However, they can all be defined as tissues that support, protect or connect one organ or tissue structure to another.  As such, they are found everywhere in the body.  Examples include ligaments and tendons, bone and cartilage, fat (adipose) tissue, and the tissues that surround organs and hold the skin together.  Some authorities even add blood and lymph to the list.

Each has its own structures and functions, but most are made up of fibers, usually proteins like collagen and elastin that give the tissues strength and flexibility. Connective tissue disease can affect any part of the body.   Often the collagen and elastin become inflamed which not only affects the connective tissue itself, but the parts of the body that the tissue connects together as well.

Connective tissue diseases include:

There are also two different types of connective tissue disease:

  • Definitive connective tissue diseases (DCTD) are the diseases above that can be clearly diagnosed because they neatly fall into classification criteria.
  • Undifferentiated connective tissue disease (UCTD), which does not easily fall into classification criteria and cannot be readily identified as one disease or another. Often, an individual may initially be diagnosed with UCTD, but once more symptoms manifest and testing is done, will eventually be diagnosed as having a DCTD.

Researchers of a 2009 study acknowledge that there are some conflicting opinions among the healthcare community as to whether or not UCTD is a distinct disease – some believe it is, while others believe it is the precursor to lupus or another DCTD. In about 70% of the cases, UCTD remains indefinite for years. Regardless, the researchers agree that an individual with UCTD needs very strict monitoring.

Some individuals, however, find themselves facing multiple connective tissue disease diagnoses and are, therefore, diagnosed as having mixed connective tissue disease (MCTD). This often happens to individuals with lupus.  Keep reading in order to find out more about this complex and often misunderstood condition.

Mixed Connective Tissue Disease (MCTD)

During his residency at Stanford University in 1972, rheumatologist Dr. Gordon C. Sharp and his cohort of residents began to notice something interesting with many of the individuals they saw over a period of years in their rheumatology clinic. Several not only had one connective tissue disease, but the symptoms of several autoimmune connective tissue diseases as well. This syndrome typically included symptoms of systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), polymyositis and scleroderma … all present at the same time. These individuals also had a unique antibody profile which included a “high titer of antinuclear antibody by complement fixation” that remained even when the individual was experiencing low-disease activity or remission. The young colleagues eventually coined the term, “mixed connective tissue disease (MCTD),” for this syndrome … sometimes referring to it as “Sharp syndrome.”

Not all connective tissue diseases are autoimmune diseases. Granulomatosis and polyangiitis, Churg Strauss syndrome, microscopic polyangiitis and Sjögren’s are connective tissue diseases, but are not considered autoimmune diseases.  MCTD is characterized by the presence of at least two of the autoimmune connective tissue diseases described below:

  • Systemic lupus erythematosus (SLE): Affecting up to approximately 5 million people world-wide, SLE is an autoimmune disease that causes the immune system to start attacking itself and develop antibodies against its own cells. SLE can manifest in the skin, kidneys, heart, joints, blood vessels (vasculitis) and lungs, causing wide-spread inflammation and damage. There are four types of lupus which includes cutaneous lupus, drug-induced lupus, neonatal lupus and childhood lupus.
  • Rheumatoid Arthritis (RA): Primarily affecting the joints of the hands, knees and ankles, RA is an autoimmune disease that causes inflammation and pain. Women have a three-times greater risk than men of developing RA. An individual’s immune system attacks the lining of the joints called the synovium causing tenderness, discomfort and swelling. If left untreated, RA can eventually affect other organs and structures such as the eyes, lungs and heart.
  • Systemic sclerosis: Systemic sclerosis is an autoimmune condition that affects the tissue of the skin and organs. Similar to scleroderma, excess collagen production – a protein that helps give structure and strength to connective tissue in the body – causes fibrosis which is a buildup of scar tissue. When an individual has scleroderma, the skin is affected. When systemic sclerosis is present, however, the skin and the organs may become involved. There are three types of systemic sclerosis which includes limited cutaneous systemic scleroderma, diffuse cutaneous systemic scleroderma and systemic sclerosis sine scleroderma.
  • Polymyositis/Dermatomyositis: Myositis is muscle inflammation that may be caused by autoimmune disease or even injury. Polymyositis is the inflammation of the muscles that are closest to the trunk of your body and can affect both sides of the body equally. Dermatomyositis not only affects the same muscles as polymyositis, but can cause skin rashes as well. Symptoms of these two conditions may also include difficulty breathing, weakness when walking and standing or being prone to tripping and falling. Complications may include aspiration pneumonia, difficulty swallowing (dysphagia) and even respiratory failure.

Is MCTD an overlap disease of lupus?

Some believe that MCTD is an overlap disease of lupus because having SLE leaves an individual wide open to acquiring other autoimmune connective tissue diseases. Others do not because it can be hard to determine which condition manifested first, the lupus or another condition. Dr. Sharp and others believe that MCTD may indeed be its own unique syndrome because of its distinct characteristics and biological profile. In order to be inclusive of all opinions and individual experience, Kaleidoscope Fighting Lupus has chosen to include MCTD in its list of overlap diseases. However, we understand there are those in the medical and lupus communities who may feel otherwise and we respect all opinions.

What causes MCTD?

It is not known what specifically causes MCTD, though an individual with lupus or any autoimmune disease may certainly be more prone to it. A family history of autoimmune disease may contribute to the development of MCTD, though it is still unclear as to what role genetics may play. The Mayo Clinic acknowledges that researchers are actively working to learn more about MCTD and its causes.

Antibody Profile of MCTD

While the causes of MCTD are unknown, researchers have found that there are specific antibodies present in all individuals diagnosed with MCTD and in some individuals who also have lupus. Dr. Sharp originally identified a specific antibody to an extractable nuclear antigen (ENA) in the blood serum of individuals eventually diagnosed with MCTD that was different than the antibody to ENA found in individuals with lupus only. This unique serum profile is one of the main reasons why Dr. Sharp, his colleagues and others believe that MCTD is its own rheumatic syndrome, independent of other connective tissue diseases such as lupus.

Since 1972, continued research has uncovered more serological information regarding MCTD. A 2015 article describes how specific antibodies against U1 small nuclear ribonucleoprotein complex (U1-snRPN) and anti-U1-70 kd autoantibodies have been detected in all individuals with MCTD and in some who also have lupus. Dr. Pepmueller also discusses that the first clue that an individual has MCTD is not only the presence of U1-snRPN antibodies, but also the presence of a high number of antinuclear antibodies (ANA), which is common in those with lupus.

Symptoms of MCTD

Chiara Tani and other researchers list the following as the most common symptoms of MCTD based on their studies:

While a healthcare practitioner may suspect that an individual with lupus may also have MCTD, it can be very hard to diagnose this with certainty. MCTD exhibits symptoms similar to lupus.  Robert W. Hoffman, Nikolaus Berzuczko and Kyle Perkins suggest the reasons for the difficulty with diagnosis:

  • There are no biomarkers that can definitively identify either disease.
  • While there are criteria for diagnosing lupus, there is none that has been universally agreed to for MCTD – as you will read later.
  • No one knows exactly what causes either condition or why either they affects only certain individuals.
  • The symptoms and manifestations of lupus and MCTD can change over time, and they often mimic each other.

Hoffman and his colleagues found that while individuals may be suspected of having MCTD, they also meet the criteria for a SLE diagnosis. However, by analyzing key clinical features of each disorder, they found some distinct differences supporting the argument that MCTD may be its own entity. In their studies, the main features of lupus include: malar rash, proteinuria (protein in the urine), fever, anti-DNA antibodies, and cellular casts found in the urine. The main features of MCTD include: Raynaud’s phenomenon, swollen hands, gastroesophageal symptoms (gastrointestinal and esophageal), sclerodactyly (thickening and tightness of the skin), telangiectasia (spider veins), arthralgia and membranous inflammation of the kidney.

Diagnosing MCTD

All of this is quite complicated and so it can be very difficult to diagnose MCTD. There is not one standardized set of criteria like there is for conditions such as RA.  Clinicians have instead developed four sets of criteria over the years that may be used by healthcare practitioners to help determine whether or not an individual has MCTD. In general, the criteria are as follows:

Sharp’s Criteria

The focus is on the presence of symptoms from major criteria including: myositis, pulmonary involvement, Raynaud’s phenomenon or esophageal hypomotility, swollen hands and the presence of antibodies for ENA Ab N, anti-U1-RNP Ab positive and anti-Sm negative. Typically, an individual needs to have at least four of the major criteria and the presence of high amounts of anti-U1-RNP Ab.

Kasukawa’s Criteria

Here, the focus is on evaluating the presence of common symptoms, which include Raynaud’s phenomenon, swollen fingers or hands and the presence of anti-RNP Ab positive. An individual must have at least one of these common criteria and anti-RNP Ab positive plus one or more of the following: SLE-like symptoms, systemic sclerosis-like symptoms and polymyositis-like symptoms.

Alarcón-Segovia Criteria

The focus is on the serological criteria, which include the presence of Anti-RNP Ab and at least three of the following clinical criteria: edema in the hands, Raynaud’s phenomenon, myositis, acrosclerosis (progressive systemic sclerosis found in Raynaud’s) and synovitis (inflammation of the joints between bones).

Kahn Criteria

The focus is on serological criteria including the presence of anti-RNP Ab and at least two of the following symptoms: synovitis, myositis and swollen fingers.

In a 2020 International Journal of Rheumatology study, researchers Kevin John and colleagues suggest that out of all the criteria listed above, the Kasukawa criteria is best used to rule out MCTD because the researchers found it to be the most sensitive of the criteria, and that Alarcón-Segovia or Kahn criteria are the best to diagnose MCTD because they offer the most specific criteria.

Complications of MCTD

If MCTD is not properly diagnosed and treated, several complications may occur including: 

  • Pulmonary disorders: Pulmonary hypertension – high blood pressure in the lungs – may occur and is the main cause of death with MCTD. Tani and other researchers found that lung fibrosis is present in up to 52% of individuals with MCTD and 19% of those individuals have severe lung fibrosis which can impair pulmonary function. Interstitial lung disease may also develop which can cause scarring in the lungs making breathing difficult.
  • Cardiovascular disorders: Tani and others found that early atherosclerosis is an “emerging issue” in MCTD and needs more study. Inflammation of the tissues around the heart (pericarditis) may occur and is the cause of death in approximately 20% of individuals with MCTD, according to the Mayo Clinic.
  • Renal involvement: Researchers Oscar-Danilo Ortega-Hernandez and Yehuda Shoenfeld observed that approximately 25% of individuals with MCTD develop renal complications including nephritis. In children with MCTD, nephritis is diagnosed more frequently than in adults. Renal conditions can sometimes lead to kidney failure.
  • Neurological disease: Ortega-Hernandez and Shoenfeld note that individuals with undiagnosed MCTD may develop peripheral neuropathy and other neuropathies. However, the researchers acknowledge that there is a lack of solid research and study in this area.
  • Hematological manifestations: Individuals with MCTD may develop anemia (red blood cell or hemoglobin deficiency), leucopenia (white blood cell deficiency), and hypergammaglobulinemia (increase levels of immunoglobulin in blood serum).
  • Gastrointestinal/digestive tract involvement: An individual may develop problems swallowing and digesting food and may experience abdominal pain. Ortega-Hernandez and Shoenfeld observed that many individuals also experience esophageal dysfunction and acid reflux symptoms.
  • Tissue involvement: Undiagnosed and untreated Raynaud’s can lead to tissue death from gangrene.

Treating & Managing MCTD

The following medications are often prescribed to treat the symptoms of MCTD:

  • Corticosteroids such as prednisone to control inflammation;
  • Antimalaria drugs that can often treat flares;
  • Calcium channel blockers to treat Raynaud’s phenomenon;
  • Immunosuppressants such as azathioprine, mycophenolate and cyclosporine; and
  • Pulmonary hypertension medications.

The Mayo Clinic recommends the following lifestyle practices that can help individuals with MCTD, as well as lupus, manage their symptoms:

  • Taking over-the-counter non-steroidal anti-inflammatory drugs such as naproxen sodium or ibuprofen to treat mild pain and inflammation;
  • Keeping hands warm in order to help reduce Raynaud’s phenomenon symptoms;
  • Reducing stress to help alleviate Raynaud’s phenomenon symptoms as well as other symptoms that are often exacerbated by stress;
  • Quitting smoking to help reduce the chances of experiencing a Raynaud’s phenomenon flare.

Ortega-Hernandez and Shoenfeld acknowledge that “no controlled clinical trials have been performed, so treatment must rely largely upon the conventional therapies that are used to treat similar clinical manifestation in other rheumatic diseases.”

Prognosis

While there is no cure for MCTD, most of an individual’s symptoms can be managed.  A 2017 study conducted by researchers at the University of Oslo found that while long-term remission of MCTD was rare, individuals did experience an improvement of some disease manifestations over time such as arthritis, rash and alopecia. The researchers also noted that MCTD may “run a milder course” than lupus.  Dr. Peri Hickman Pepmueller suggests that myositis symptoms respond well to treatment and may also decrease over time. Dr. Pepmueller also observed that while some individuals do experience renal involvement, severe renal disease is not common.

The University of Oslo researchers did find, however, that while disease activity may decrease over time, organ damage may increase. More research needs to be done to better understand the course MCTD may take.

In Conclusion

As you may have determined after reading this article, MCTD is very, very complicated for both the individual who has it as well as the healthcare community. Paying close attention to new symptoms and to one’s overall health as well as communicating openly with healthcare practitioners are very important for early detection of MCTD.  Advocating for an individual’s own healthcare and raising awareness for conditions such as MCTD will help in gathering the support needed for clinicians to develop better diagnostic tools and drug therapies through research and study.

 

References
Conti, V., Esposito, C., Fantauzzi, A., Pastori, D., Mezzaroma, I., & Aiuti, F. (2010). Undifferentiated connective tissue disease – an unsolved problem: Revision of literature and case studies. International Journal of Immunopathology and Pharmacology, 23(1), 271-278. Retrieved March 15, 2020 from https://journals.sagepub.com/doi/pdf/10.1177/039463201002300125
Hoffman, R., Bezruczko, N., & Perkins, K. (2012). An external validation study of a classification of mixed connective tissue disease and systemic lupus erythematosus patients. The Journal of Applied Measurement, 13(2), 205-214. Retrieved March 15, 2020 from https://www.researchgate.net/profile/Kyle_Perkins/publication/229159519_An_external_validation_study_of_a_classification_of_mixed_connective_tissue_disease_and_systemic_lupus_erythematosus_patients/links/0fcfd501fed148d567000000.pdf
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Author: Liz Heintz

Liz Heintz is a technical and creative writer who received her BA in Communications, Advocacy, and Relational Communications from Marylhurst University in Lake Oswego, Oregon. She most recently worked for several years in the healthcare industry. A native of San Francisco, California, Liz now calls the beautiful Pacific Northwest home.

All images unless otherwise noted are property of and were created by Kaleidoscope Fighting Lupus. To use one of these images, please contact us at [email protected] for written permission; image credit and link-back must be given to Kaleidoscope Fighting Lupus.

All resources provided by us are for informational purposes only and should be used as a guide or for supplemental information, not to replace the advice of a medical professional. The personal views expressed here do not necessarily encompass the views of the organization, but the information has been vetted as a relevant resource. We encourage you to be your strongest advocate and always contact your healthcare practitioner with any specific questions or concerns.