Mixed Connective Tissue Disease: Difference between revisions

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== Systemic Involvement  ==
== Systemic Involvement  ==


MCTD has a systemic component that has potentially drastic effects on many systems of the body including:[[Image:Malar_rash.png|thumb|right|<a title="By Doktorinternet (Own work) [CC BY-SA 4.0 (http://creativecommons.org/licenses/by-sa/4.0)], via Wikimedia Commons" href="https://commons.wikimedia.org/wiki/File%3ALupusfoto.jpg"><img width="256" alt="Lupusfoto" src="https://upload.wikimedia.org/wikipedia/commons/5/52/Lupusfoto.jpg"/></a>]]<br>  
MCTD has a systemic component that has potentially drastic effects on many systems of the body including:&nbsp;[[Image:Malar_rash.png|thumb|right|Malar rash]]<br>  
 
 


[[Image:SystemicInvolvement.png]]  
[[Image:SystemicInvolvement.png]]  
 
<div>
<br>
<br>
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== Medical Management (current best evidence)  ==
== Medical Management (current best evidence)  ==

Revision as of 22:49, 10 April 2016

 

Welcome to PT 635 Pathophysiology of Complex Patient Problems This is a wiki created by and for the students in the School of Physical Therapy at Bellarmine University in Louisville KY. Please do not edit unless you are involved in this project, but please come back in the near future to check out new information!!

Definition/Description[edit | edit source]

Mixed connective tissue disease (MCTD) is a systemic disease which consists of clinical symptoms observed in the three following disorders: systemic lupus erythematosus, polymyositis, and systemic sclerosis.[1] [2] MCTD is considered an overlapping disease due to the features of these three disorders which can be categorized broadly as arthritic changes, cardiopulmonary dysfunctions, skin changes, muscle weakness, kidney disease, and dysfunctions of the esophagus.[3]

The symptoms associated with the three underlying disorders do not usually present all at once.[4] In fact, it usually takes several years before the symptoms of each individual disorder present which ultimately complicates the diagnosis of MCTD.[4] Typically, the hands are affected and present as the first symptom of MCTD. Swelling to the fingers or the presentation of “sausage fingers” is common.[5] As the disease progresses, it can often affect the organs such as lungs, heart or the kidneys.[3] There is no definite cure for MCTD, however side effects can be managed through the use of medications.[5]



Prevalence[edit | edit source]

It has been reported that 80% of individuals diagnosed with MCTD are women with the highest prevalence under the age of thirty years of age.[4] Other sources have reported statistics collected from patients from 5 years of age through 80, with the peak prevalence around 20 years of age. [6] It is estimated that this disease occurs in about 3.8 out of every 100,000 individuals. [2] 
 

Characteristics/Clinical Presentation [5][edit | edit source]

The initial sign of MCTD may be shown as a presentation of puffy and swollen hands, Raynaud’s phenomenon, and polyarthritis.[1][2][3][7][8]

Some of the “classical conditions or signs” of MCTD include:

 
Raynaud phenomenon
  • Inflammation of muscles and joints
  • Pulmonary hypertension
  • Raynaud phenomenon
  • Swollen fingers, often “sausage like” and can be a temporary stage of the disease but also can progress into limited movement of the fingers due to thinning of fingers and thickening of the skin[2]

The chart below lists some of the symptoms common versus uncommon symptoms in early stages of MCTD.[5]

Common.png

Associated Co-morbidities[edit | edit source]

Associated Co-morbidities

Medications
[edit | edit source]

  • Corticosteroids[4][6]
  • Anti-malarial drugs[4]
  • Calcium channel blockers[4]
  • Nonsteroidal anti-inflammatory drugs[2][6]
  • Immunosuppressive drugs[6]
  • Calcium channel blockers[2][4]
  • Phosphodiesterase inhibitors[2]
  • Endothelin receptor antagonists[2]
  • Prostoglandins[2]
  • Proton pump inhibitors[2]

Diagnostic Tests/Lab Tests/Lab Values[edit | edit source]

Laboratory Testing Often Includes:[2]

  • Anti-U1-RNP (rubonucleoprotein) antigens
  • Urinalysis
  • Muscle enzymes (myositis involvement)
  • Complete blood count (CBC)
  • Antinuclear antibodies
  • Lipase and amylase (pancreatitis involvement)
  • Routine blood chemistry

To check for systemic involvement, the following imaging testing can be performed[2]

  • Chest radiography- assesses for infiltrates, effusions, and cardiomegaly
  • MRI- asses for neuropsychiatric signs or symptoms
  • CT scan/ultrasound- evaluates abdominal pain in cases of suspected serositis, pancreatitis, and/or visceral perforation related to vasculitis
  • Echocardiography- assesses for effusion, chest pain, pulmonary hypertension, or valvular disease

Systemic involvement tests may also include cardiopulmonary testing, such as:[10]

  • Electrocardiography
  • Pulmonary function tests
  • Six minute walk test [3]


Currently, there are three different criteria sets given by three authors: Modified Sharp et al (1987), Alarcon Segovia et al (1987), Kauskawa et al (1987).[9] However, there is no standard or universal criteria set. There are currently three different criteria classification systems that are associated to predicting the probability that an individual may have MCTD. Listed below are the criteria sets that are presently used in the diagnosing MCTD.

Etiology/Causes[edit | edit source]

The exact cause of MCTD is unknown, but it has been classified as an autoimmune disorder. Individuals with this disease have high levels of antinuclear antibodies (ANAs) and antibodies to U1 snRNP.[3] Due to the high number of autoimmune antigens in the body, the body will try to protect itself but instead attack healthy tissues.

MCTD has been linked to occur in individuals who report in having a family member who also has a connective tissue disease.[5] Also, certain exposures to chemicals or viruses such as silica or polyvinyl chloride have been found as potential causes of MCTD.[5]

Systemic Involvement[edit | edit source]

MCTD has a systemic component that has potentially drastic effects on many systems of the body including: 

Malar rash



SystemicInvolvement.png



Medical Management (current best evidence)[edit | edit source]

Since no cure has yet to be discovered for this disease, medical management is focused on treating the patient’s symptoms through the use of medication and minimizing systemic involvement. The symptoms of arthritis and/or arthralgia are often managed through the use of nonsteroidal anti-inflammatory drugs and hydroxychloroquine. Proton pump inhibitors are used to help control symptoms of esophageal reflux and calcium channel blockers are used in the treatment of Raynaud phenomenon. Low-dose corticosteroids and methotrexate are used in the treatment of synovitis and phosphodiesterase inhibitors, prostaglandins, and/or endothelin receptor antagonists are used to control pulmonary hypertension.[2]

The individual with MCTD should follow up with their physician in regard to screening for systemic involvement and depending on the impairments found, the patient should be referred to the appropriate specialist.

Physical Therapy Management (current best evidence)[edit | edit source]

Since there has been limited research regarding physical therapy treatment in patients with MCTD, interventions should be tailored to address the impairments of each individual. Although each person presents differently, there are some common areas that need to be addressed in all cases. Individuals with MCTD often present with decreased aerobic capacity and weakness of the proximal musculature.[10] Physical therapists should treat according to the common deficits seen in the disease as well as personal impairments that arise with each case.

Common areas of focus may include:

  • Educate patient regarding joint protection
  • Aerobic and endurance training
  • Range of motion exercises to maintain available range
  • Passive stretching, including splinting for joint protection
  • Strengthening total body exercises (including proximal musculature)
  • Skin education and management
  • Energy conservation techniques

Differential Diagnosis [2][edit | edit source]

  • Systemic Lupus Erythematosus- chronic inflammatory disease characterized by protean manifestations with a relapsing and remitting course
  • Scleroderma- progressive skin hardening and induration
  • Dermatomyositis- idiopathic inflammatory myopathy with characteristic signs commonly present in the skin, muscles, and joints
  • Polymyositis- idiopathic inflammatory myopathy which results in symmetrical proximal muscle weakness
  • Primary pulmonary hypertension- elevated pulmonary artery pressure with no known cause, if left untreated will lead to right-sided heart failure
  • Raynaud phenomenon- recurrent vasospasms of the fingers or toes which usually occurs as a result of stress or exposure to the cold
  • Bacterial sepsis- the presence of infection along with the systemic inflammatory response syndrome
  • Pleuritis- inflammation in the lining of the lungs
  • Rheumatoid arthritis- chronic systemic inflammatory disease with an unknown cause

Case Reports/ Case Studies[edit | edit source]

Karmacharya P, Mainali N, Aryal M, Lloyd B. Recurrent case of ibuprofen-induced aseptic meningitis in mixed connective tissue disease. Case Reports [Internet]. 2013 [2016 Apr 8];2013(apr30 1):bcr2013009571-bcr2013009571. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3645838/

Souto Filho J, de Barros P, da Silva A, Barbosa F, Ribas G. Thrombotic Thrombocytopenic Purpura Associated with Mixed Connective Tissue Disease: A Case Report. Case Reports in Medicine [Internet]. 2011 [Cited 2016 Apr 8];2011:1-5.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3170900/

Fantò M, Salemi S, Socciarelli F, Bartolazzi A, Natale G, Casorelli I et al. A Case of Subacute Cutaneous Lupus Erythematosus in a Patient with Mixed Connective Tissue Disease: Successful Treatment with Plasmapheresis and Rituximab. Case Reports in Rheumatology [Internet]. 2013 [Cited 2016 Apr 8];2013:1-4. 

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3745888/

Resources
[edit | edit source]

About Mixed Connective Tissue Disease

www.mayoclinic.org/diseases-conditions/mixed-connective-tissue-disease/basics/definition/con-20026515

Help finding a rheumatologist
http://www.rheumatology.org/

Lupus Foundation of America, Inc.
[1]

Recent Related Research (from Pubmed)
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Extension:RSS -- Error:

Not a valid URL: <!--?xml version="1.0" encoding="utf-8"?--> <rss version="2.0"><channel><title>pubmed: mixed connective tis...</title> <link></link>http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=Search&amp;db=PubMed&amp;term=mixed%20connective%20tissue%20disorder <description>NCBI: db=pubmed; Term=mixed connective tissue disorder</description> <language>en-us</language> <docs>http://blogs.law.harvard.edu/tech/rss</docs> <ttl>1440</ttl> [[Image:]] <title>NCBI pubmed</title> <url>http://www.ncbi.nlm.nih.gov/entrez/query/static/gifs/iconsml.gif</url> <link></link>http://www.ncbi.nlm.nih.gov/sites/entrez <description>PubMed comprises more than 24 million citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.</description> <item><title>Estimating the incidence of connective tissue diseases and vasculitides in a defined population in Northern Savo area in 2010.</title> <link></link>http://www.ncbi.nlm.nih.gov/pubmed/27053177?dopt=Abstract <description><!--[CDATA[<table border="0" width="100%"-->[[Image:]]

'''Estimating the incidence of connective tissue diseases and vasculitides in a defined population in Northern Savo area in 2010.'''

Rheumatol Int. 2016 Apr 6;

Authors: Elfving P, Marjoniemi O, Niinisalo H, Kononoff A, Arstila L, Savolainen E, Rutanen J, Kaipiainen-Seppänen O

Abstract<br> Objective of the study was to evaluate the annual incidence and distribution of autoimmune connective tissue diseases and vasculitides during 2010. All units practicing rheumatology in the Northern Savo area, Finland, participated in the study by collecting data on newly diagnosed adult patients with autoimmune connective tissue disease or vasculitis over 1-year period. Seventy-two cases with autoimmune connective tissue disease were identified. The annual incidence rates were as follows: systemic lupus erythematosus 3.4/100,000 (95 % CI 1.4-7.0), idiopathic inflammatory myopathies 1.9 (0.5-5.0), systemic sclerosis 4.4 (2.0-8.3), mixed connective tissue disease 1.0 (0.1-3.5), Sjögren's syndrome 10.7 (6.7-16.1) and undifferentiated connective tissue disease 13.6 (9.0-19.6). The annual incidence rates among vasculitis category were as follows: antineutrophil cytoplasmic antibody-associated vasculitis 1.5/100,000 (95 % CI 0.3-4.3), central nervous system vasculitis 0.5 (0-2.7) and Henoch-Schönlein purpura 1.5 (0.3-4.3). The annual incidence of giant cell arteritis in the age group of 50 years or older was 7.5/100,000 (95 % CI 3.2-14.8). The longest delay from symptom onset to diagnosis occurred in systemic sclerosis. The incidences of autoimmune connective tissue diseases and vasculitides were comparable with those in published literature. The present study showed female predominance in all connective tissue diseases, excluding idiopathic inflammatory muscle diseases and mean age at onset of disease around 50 years of age. Despite improved diagnostic tools, diagnostic delay is long especially among patients with systemic sclerosis.<br>

PMID: 27053177 [PubMed - as supplied by publisher]

]]&gt;</description> <author>Elfving P, Marjoniemi O, Niinisalo H, Kononoff A, Arstila L, Savolainen E, Rutanen J, Kaipiainen-Seppänen O</author> <category>Rheumatol Int</category> <guid ispermalink="false">PubMed:27053177</guid> </item> <item><title>Pulmonary involvement in systemic sclerosis: A clinical profile.</title> <link></link>http://www.ncbi.nlm.nih.gov/pubmed/27051100?dopt=Abstract <description><!--[CDATA[<table border="0" width="100%"-->[[Image:]] '''Pulmonary involvement in systemic sclerosis: A clinical profile.'''

Lung India. 2016 Mar-Apr;33(2):144-7

Authors: Deepa AS, Rachel RP, Ramchandran P, Devaraj U, Arnold SA, Shobha V, D'souza G

Abstract<br> BACKGROUND: Systemic sclerosis is a generalized disorder of connective tissue affecting skin and internal organs. Lung involvement accounts for significant morbidity and is a leading cause of mortality in patients.<br> OBJECTIVES: This study intends to study the frequency of occurrence of pulmonary involvement in progressive systemic sclerosis (PSS) and to describe the clinical and radiological picture of pulmonary involvement in PSS.<br> MATERIALS AND METHODS: This was a descriptive cross-sectional study. A detailed history, modified Rodnan score, clinical examination, routine investigation, antinuclear antibody, immuno biot, chest X-ray (CXR), pulmonary function test (PFT), and 6 min walk test (6MWT) were performed on all patients. High resolution computed tomography was done on those who consented.<br> RESULTS: Hundred subjects with PSS were included in the study; 90 were females and 10 were males. Common presenting complaints were skin thickening in 98% and Raynaud's phenomenon in 98%. Skin thickening of digits beyond metacarpo phalangeal was seen in 98%, face and neck in 92%, and hands in 92%. Chest wall thickening was seen in 40 subjects (40%). 90 (90%) of the studied subjects had pulmonary involvement, longer duration of disease was significantly associated with pulmonary involvement (P &lt; 0.05). Dyspnea, cough, bilateral crepitations, CXR, Borg score, and Rodnan score was found to be significantly associated with severe pulmonary involvement (P &lt; 0.05).<br> CONCLUSION: The prevalence of pulmonary involvement in this cohort study was 90%. Almost 1/3(rd) of patients, that is 29 (29%) were detected to have pulmonary involvement despite being asymptomatic for respiratory complaints, hence early screening and evaluation is recommended. PFT and 6MWT are noninvasive, cost-effective, and easily available screening tests which can be used in resource-limited settings.<br>

PMID: 27051100 [PubMed]

]]&gt;</description> <author>Deepa AS, Rachel RP, Ramchandran P, Devaraj U, Arnold SA, Shobha V, D'souza G</author> <category>Lung India</category> <guid ispermalink="false">PubMed:27051100</guid> </item> <item><title>Quantitative ELISA-Like Immunohistochemistry of Fibroblast Growth Factor 23 in Diagnosis of Tumor-Induced Osteomalacia and Clinical Characteristics of the Disease.</title> <link></link>http://www.ncbi.nlm.nih.gov/pubmed/27034530?dopt=Abstract <description><!--[CDATA[<table border="0" width="100%"-->[[Image:]] [[Image:]] Related Articles '''Quantitative ELISA-Like Immunohistochemistry of Fibroblast Growth Factor 23 in Diagnosis of Tumor-Induced Osteomalacia and Clinical Characteristics of the Disease.'''

Dis Markers. 2016;2016:3176978

Authors: Hu F, Jiang C, Zhang Q, Shi H, Wei L, Wang Y

Abstract<br> Tumor-induced osteomalacia (TIO) is a rare acquired paraneoplastic disorder and fibroblast growth factor 23 (FGF23) plays a key role in its pathogenesis. This study was conducted to describe a novel FGF23 detecting procedure and describe clinical features of the disease. Fourteen TIO cases were retrieved and FGF23 expression was measured by quantitative ELISA-like immunohistochemistry using formalin-fixed and paraffin-embedded tissues. As summarized from 14 TIO cases, clinical features of TIO were long-standing history of osteomalacia, hypophosphatemia, and urinary phosphate wasting. The associated tumors were mostly benign phosphaturic mesenchymal tumors mixed connective tissue variant (PMTMCT) which could be located anywhere on the body, and most of them could be localized by conventional examinations and octreotide scanning. By quantitative ELISA-like immunohistochemistry, all the 14 TIO cases had high FGF23 expression (median 0.69, 25%-75% interquartile 0.57-1.10, compared with 26 non-TIO tumors of median 0.07, 25%-75% interquartile 0.05-0.11, p &lt; 0.001). The quantitative ELISA-like immunohistochemistry was a feasible and reproducible procedure to detect the high FGF23 expression in formalin-fixed and paraffin-embedded biopsies or specimens. Since TIO was often delay-diagnosed or misdiagnosed, clinicians and pathologists should be aware of TIO and PMTMCT, respectively. <br>

PMID: 27034530 [PubMed - in process]

]]&gt;</description> <author>Hu F, Jiang C, Zhang Q, Shi H, Wei L, Wang Y</author> <category>Dis Markers</category> <guid ispermalink="false">PubMed:27034530</guid> </item> <item><title>Laparoscopic Antireflux Surgery in Patients with Connective Tissue Diseases.</title> <link></link>http://www.ncbi.nlm.nih.gov/pubmed/27027697?dopt=Abstract <description><!--[CDATA[<table border="0" width="100%"-->Related Articles '''Laparoscopic Antireflux Surgery in Patients with Connective Tissue Diseases.'''

J Laparoendosc Adv Surg Tech A. 2016 Mar 30;

Authors: Menezes MA, Herbella FA, Patti MG

Abstract<br> Different connective tissue diseases (CTDs), such as dermatomyositis, mixed CTD, rheumatoid arthritis, polymyositis, lupus, and Behçet's, may affect the esophagus, impairing its motor function. The muscular atrophy and fibrosis caused by the autoimmune vasculitis and neuronal dysfunction affect the esophageal body and the lower esophageal sphincter, leading to a clinical presentation of dysphagia and gastroesophageal reflux disease (GERD). The belief that the impaired esophageal motility may negatively affect surgical outcome has led to the common recommendation of avoiding laparoscopic antireflux surgery (LARS) for fear of creating or worsening dysphagia. This review focuses on the evaluation of the outcome of LARS in patients with CTD. Specifically, this review shows that the literature on LARS and CTDs is scarce and most studies have a small number of patients and a short follow-up. Furthermore, a subanalysis of the outcome based on the type of CTD or the manometric profile is still elusive. In the setting of these limitations, it appears that results are good and comparable to those of patients with GERD and without a CTD. Morbidity and mortality are insignificant even considering the systemic manifestations of the CTD. LARS should not be denied to patients with CTD and GERD.<br>

PMID: 27027697 [PubMed - as supplied by publisher]

]]&gt;</description> <author>Menezes MA, Herbella FA, Patti MG</author> <category>J Laparoendosc Adv Surg Tech A</category> <guid ispermalink="false">PubMed:27027697</guid> </item> <item><title>Acute arterial ischemia in a patient with polyarthritis.</title> <link></link>http://www.ncbi.nlm.nih.gov/pubmed/27017540?dopt=Abstract <description><!--[CDATA[<table border="0" width="100%"-->[[Image:]] Related Articles '''Acute arterial ischemia in a patient with polyarthritis.'''

Reumatol Clin. 2016 Mar 23;

Authors: Soro Marín S, Júdez Navarro E, Alamillo Sanz AS, Sánchez Nievas G

Abstract<br> Cryoglobulins are immunoglobulins that precipitate at cold temperatures. Their presence can be related to a type of vasculitis referred to as cryoglobulinemia. This condition, especially mixed cryoglobulinemia, has been associated with viral infections like hepatitis C virus in 60%-90% of cases, but it has also been reported in relation to connective tissue diseases, usually resulting in a more severe course. We describe the case of a patient with seronegative polyarthritis who developed acute arterial ischemia in association with cryoglobulinemia, with a good response to rituximab therapy.<br>

PMID: 27017540 [PubMed - as supplied by publisher]

]]&gt;</description> <author>Soro Marín S, Júdez Navarro E, Alamillo Sanz AS, Sánchez Nievas G</author> <category>Reumatol Clin</category> <guid ispermalink="false">PubMed:27017540</guid> </item> </channel>

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Recent Related Research (from Pubmed)
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References
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  1. 1.0 1.1 Fagundes MN, Caleiro MT, Navarro-rodriguez T, et al. Esophageal involvement and interstitial lung disease in mixed connective tissue disease. Respir Med [Internet]. 2009 [cited 2016 Mar 12];103(6):854-60. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19201182
  2. 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 2.12 2.13 2.14 2.15 Mixed Connective-Tissue Disease: Background, Pathophysiology, Etiology [Internet]. Emedicine.medscape.com. 2016 [cited 8 April 2016]. Available from: http://emedicine.medscape.com/article/335815-overview
  3. 3.0 3.1 3.2 3.3 3.4 Mixed Connective Tissue Disease (MCTD) - NORD (National Organization for Rare Disorders) [Internet]. NORD (National Organization for Rare Disorders). 2016 [cited 8 April 2016]. Available from: http://rarediseases.org/rare-diseases/mixed-connective-tissue-disease-mctd/
  4. 4.00 4.01 4.02 4.03 4.04 4.05 4.06 4.07 4.08 4.09 4.10 4.11 4.12 4.13 4.14 Mixed connective tissue disease - Mayo Clinic [Internet]. Mayoclinic.org. 2016 [cited 2016 Apr 8]. Available from: http://www.mayoclinic.org/diseases-conditions/mixed-connective-tissue-disease/basics/definition/con-20026515
  5. 5.0 5.1 5.2 5.3 5.4 5.5 5.6 5.7 Mixed Connective Tissue Disease [Internet]. My.clevelandclinic.org. 2016 [cited 2016 Apr 8]. Available from: https://my.clevelandclinic.org/health/diseases_conditions/hic_Mixed_Connective_Tissue_Disease
  6. 6.0 6.1 6.2 6.3 Mixed Connective Tissue Disease (MCTD) [Internet]. Merck Manuals Consumer Version. 2016 [cited 2016 Apr 8]. Available from: https://www.merckmanuals.com/home/bone,-joint,-and-muscle-disorders/autoimmune-disorders-of-connective-tissue/mixed-connective-tissue-disease-(mctd)
  7. 7.0 7.1 Tani C, Carli L, Vagnani S, et al. The diagnosis and classification of mixed connective tissue disease. J Autoimmun [Internet]. 2014 [Cited 2016 Mar 12];48-49:46-9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24461387
  8. 8.0 8.1 8.2 Cappelli S, Bellando randone S, Martinović D, et al. "To be or not to be," ten years after: evidence for mixed connective tissue disease as a distinct entity. Semin Arthritis Rheum [Internet]. 2012 [cited 2016 Mar 12];41(4):589-98. Available from http://www.ncbi.nlm.nih.gov/pubmed/21959290
  9. 9.0 9.1 9.2 Ungprasert P, Wannarong T, Panichsillapakit T, et al. Cardiac involvement in mixed connective tissue disease: a systematic review. Int J Cardiol [Internet]. 2014 [Cited 2016 Mar 12];171(3):326-30. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24433611
  10. 10.0 10.1 Van der net J, Wissink B, Van royen A, Helders PJ, Takken T. Aerobic capacity and muscle strength in juvenile-onset mixed connective tissue disease (MCTD). Scand J Rheumatol [Internet]. 2010 [Cited 2016 Mar 12];39(5):387-92. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20604672