Mixed Connective-Tissue Disease
Mixed connective-tissue disease (MCTD) was first recognized by Sharp and colleagues (1972) in a group of patients with overlapping clinical features of systemic lupus erythematosus (SLE), scleroderma, and myositis, with the presence of a distinctive antibody against what now is known to be U1-ribonucleoprotein (RNP). [1, 2]
Nevertheless, whether MCTD is a distinct disease entity has been in question since shortly after its original description. A minority of authors continue to suggest that MCTD represents subgroups or early stages of disorders such as systemic lupus erythematosus (SLE) or systemic sclerosis, or an overlap syndrome.  Ciang and colleagues propose that MCTD would more accurately be termed undifferentiated autoimmune rheumatic disease. 
Pathophysiologic abnormalities that are believed to play a role in MCTD include the following:
In a study of a nationwide MCTD cohort in Norway, Flåm and colleagues found that HLA-B*08 and DRB1*04:01 were risk alleles for MCTD, while DRB1*04:04, DRB1*13:01 and DRB1*13:02 were protective. Risk alleles for SLE, systemic sclerosis, and polymyositis/dermatomyositis were distinct from those for MCTD. 
Over time, some patients with MCTD also develop anti-Sm autoantibodies—an expansion of the autoimmune response known as epitope spreading. Escolà-Vergé reported that epitope spreading occurred in 13 (43%) of 40 patients with MCTD, mainly during the first 2 years after diagnosis.Compared with patients who did not have epitope spreading, patients Patients with epitope spreading had significantly lower prevalence of skin sclerosis (0% vs. 44%, P = 0.004) and a higher prevalence of interstitial lung disease (46% vs. 15%, P = 0.05). 
The fundamental cause of MCTD remains unknown. Autoimmunity to components of the U1-70 kd snRNP is a hallmark of disease. Anti-RNP antibodies can precede overt clinical manifestations of MCTD, but overt disease generally develops within 1 year of anti-RNP antibody induction.
The loss of T-lymphocyte and B-lymphocyte tolerance, due to cryptic self-antigens, abnormalities of apoptosis, or molecular mimicry by infectious agents, and driven by U1-RNA-induced innate immune responses, are proposed current theories of pathogenesis.
A population-based study from Olmsted County, Minnesota found that MCTD occurred in about 2 persons per 100,000 per year. Diagnosis was frequently delayed, with a median of 3.6 years elapsing from first symptom to fulfillment of diagnostic criteria.  A study in American Indian and Alaska Native adults found a prevalence of 6.4 per 100,000 (95% confidence interval 2.8-12.8). 
In an epidemiological survey in Japan, MCTD has a reported prevalence of 2.7 cases per 100,000 population.  A population-based study in Norway found the point prevalence rate to be 3.8 cases per 100,000 adult population, with a female-to-male ratio of 3.3, and an annual incidence rate of 2.1 per million. 
Long-term outcome studies have established pulmonary hypertension as the most common disease-related cause of death.  Immunoglobulin G (IgG) anticardiolipin antibodies are a marker for development of pulmonary hypertension. Infections are also a major cause of death.
Cardiac disease, most often pericarditis, is also common in MCTD patients, with prevalence estimates ranging from 13% to 65%. Other cardiac abnormalities include conduction abnormalities, pericardial effusion, mitral valve prolapse, diastolic dysfunction, and accelerated atherosclerosis. In three prospective studies with 13-15 years of follow-up, MCTD patients had an overall mortality rate of 10.4%, and 20% of these deaths were directly attributable to cardiac causes. 
MCTD has been reported in all races. The clinical manifestations of MCTD are similar among various ethnic groups; however, one study observed ethnic differences in the frequency of end-organ involvement. 
The onset of MCTD is typically at 15-25 years of age, but can occur at any age.
Most patients with MCTD have a favorable outcome. Cases of MCTD with typical clinical or serologic features occasionally evolve into scleroderma, SLE, or another rheumatic disease.
Pulmonary hypertension is the most common disease-associated cause of death. Careful monitoring and aggressive treatment may improve the outcome of pulmonary hypertension.
A long-term observational nationwide cohort study from Norway found that interstitial lung disease (ILD) was present in 41% of MCTD patients and progressed in 19% of patients across the observation period of a mean of 6.4 years.  The following were the strongest predictors of ILD progression:
Sharp GC, Irvin WS, Tan EM, et al. Mixed connective tissue disease–an apparently distinct rheumatic disease syndrome associated with a specific antibody to an extractable nuclear antigen (ENA). Am J Med. 1972 Feb. 52(2):148-59. [Medline].
Zandman-Goddard G, Solomon M, Rosman Z, Peeva E, Shoenfeld Y. Environment and lupus related diseases. Lupus. 2011 Nov 7. [Medline].
Yoshida S. Pulmonary arterial hypertension in connective tissue diseases. Allergol Int. 2011 Nov. 60(4):405-9. [Medline].
Cappelli S, Bellando Randone S, Martinovic D, Tamas MM, Pasalic K, Allanore Y, et al. “To Be or Not To Be,” Ten Years After: Evidence for Mixed Connective Tissue Disease as a Distinct Entity. Semin Arthritis Rheum. 2011 Sep 27. [Medline].
Gunnarsson R, El-Hage F, Aaløkken TM, Reiseter S, Lund MB, Garen T, et al. Associations between anti-Ro52 antibodies and lung fibrosis in mixed connective tissue disease. Rheumatology (Oxford). 2016 Jan. 55 (1):103-8. [Medline].
Martínez-Barrio J, Valor L, López-Longo FJ. Facts and controversies in mixed connective tissue disease. Med Clin (Barc). 2017 Aug 29. [Medline].
Ciang NC, Pereira N, Isenberg DA. Mixed connective tissue disease-enigma variations?. Rheumatology (Oxford). 2017 Mar 1. 56 (3):326-333. [Medline].
Hoffman RW, Rettenmaier LJ, Takeda Y, et al. Human autoantibodies against the 70-kd polypeptide of U1 small nuclear RNP are associated with HLA-DR4 among connective tissue disease patients. Arthritis Rheum. 1990 May. 33(5):666-73. [Medline].
Flåm ST, Gunnarsson R, Garen T, Lie BA, Molberg O. The HLA profiles of mixed connective tissue disease differ distinctly from the profiles of clinically related connective tissue diseases. Rheumatology (Oxford). 2014 Sep 3. [Medline].
Escolà-Vergé L, Pinal-Fernandez I, Fernandez-Codina A, Callejas-Moraga EL, Espinosa J, Marin A, et al. Mixed Connective Tissue Disease and Epitope Spreading: An Historical Cohort Study. J Clin Rheumatol. 2017 Apr. 23 (3):155-159. [Medline].
Ungprasert P, Crowson CS, Chowdhary VR, Ernste FC, Moder KG, Matteson EL. Epidemiology of Mixed Connective Tissue Disease 1985-2014: A Population Based Study. Arthritis Care Res (Hoboken). 2016 Mar 4. [Medline].
Ferucci ED, Johnston JM, Gordon C, Helmick CG, Lim SS. Prevalence of Mixed Connective Tissue Disease in a Population-Based Registry of American Indian/Alaska Native People in 2007. Arthritis Care Res (Hoboken). 2017 Aug. 69 (8):1271-1275. [Medline].
Nakae K, Furusawa F, Kasukawa R, et al. . A nationwide epidemiological survey on diffuse collagen diseases: Estimation of prevalence rate in Japan. Kasukawa R, Sharp G, eds. Mixed Connective Tissue Disease and Anti-nuclear Antibodies. Amsterdam: Excerpta Medica; 1987. 9.
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. [Medline].
Burdt MA, Hoffman RW, Deutscher SL, et al. Long-term outcome in mixed connective tissue disease: longitudinal clinical and serologic findings. Arthritis Rheum. 1999 May. 42(5):899-909. [Medline].
Ungprasert P, Wannarong T, Panichsillapakit T, Cheungpasitporn W, Thongprayoon C, Ahmed S, et al. Cardiac involvement in mixed connective tissue disease: a systematic review. Int J Cardiol. 2014 Feb 15. 171(3):326-30. [Medline].
Maldonado ME, Perez M, Pignac-Kobinger J, et al. Clinical and immunologic manifestations of mixed connective tissue disease in a Miami population compared to a Midwestern US Caucasian population. J Rheumatol. 2008 Mar. 35(3):429-37. [Medline].
Reiseter S, Gunnarsson R, Mogens Aaløkken T, Lund MB, Mynarek G, Corander J, et al. Progression and mortality of interstitial lung disease in mixed connective tissue disease: a long-term observational nationwide cohort study. Rheumatology (Oxford). 2018 Feb 1. 57 (2):255-262. [Medline].
Szodoray P, Hajas A, Kardos L, et al. Distinct phenotypes in mixed connective tissue disease: subgroups and survival. Lupus. 2012 Nov. 21(13):1412-22. [Medline].
Jais X, Launay D, Yaici A, et al. Immunosuppressive therapy in lupus- and mixed connective tissue disease-associated pulmonary arterial hypertension: a retrospective analysis of twenty-three cases. Arthritis Rheum. 2008 Feb. 58(2):521-31. [Medline].
Kobayashi Y, Shimojima Y, Kondo Y, Takamatsu R, Miyazaki D, Kishida D, et al. Protein-losing Gastroenteropathy Related to Mixed Connective Tissue Disease: A Case Report of a Successful Outcome and Literature Review. Intern Med. 2017. 56 (15):2057-2062. [Medline]. [Full Text].
Amigues JM, Cantagrel A, Abbal M, Mazieres B. Comparative study of 4 diagnosis criteria sets for mixed connective tissue disease in patients with anti-RNP antibodies. Autoimmunity Group of the Hospitals of Toulouse. J Rheumatol. 1996 Dec. 23 (12):2055-62. [Medline].
Alarcón-Segovia D, Cardiel MH. Comparison between 3 diagnostic criteria for mixed connective tissue disease. Study of 593 patients. J Rheumatol. 1989 Mar. 16 (3):328-34. [Medline].
Alarcon-Segovia D, Villareal M. Classification and diagnostic criteria for mixed connective tissue disease. Kasukawa R, Sharp GC, eds. Mixed Connective Tissue Disease and Anti-Nuclear Antibodies. Amsterdam: Excerpta Medica; 1987. 33-40.
Niklas K, Niklas A, Mularek-Kubzdela T, Puszczewicz M. Prevalence of pulmonary hypertension in patients with systemic sclerosis and mixed connective tissue disease. Medicine (Baltimore). 2018 Jul. 97 (28):e11437. [Medline]. [Full Text].
Khanna D, Gladue H, Channick R, Chung L, Distler O, Furst DE, et al. Recommendations for screening and detection of connective tissue disease-associated pulmonary arterial hypertension. Arthritis Rheum. 2013 Dec. 65 (12):3194-201. [Medline].
Kusunose K, Yamada H, Hotchi J, Bando M, Nishio S, Hirata Y, et al. Prediction of Future Overt Pulmonary Hypertension by 6-Min Walk Stress Echocardiography in Patients With Connective Tissue Disease. J Am Coll Cardiol. 2015 Jul 28. 66 (4):376-84. [Medline].
Eric L Greidinger, MD Associate Professor, Department of Medicine, Division of Rheumatology and Immunology, University of Miami Miller School of Medicine, Miami Veterans Affairs Medical Center
Disclosure: Received research grant from: Reatta Pharmacueticals.
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Elliot Goldberg, MD Dean of the Western Pennsylvania Clinical Campus, Professor, Department of Medicine, Lewis Katz School of Medicine at Temple University
Disclosure: Nothing to disclose.
Herbert S Diamond, MD Visiting Professor of Medicine, Division of Rheumatology, State University of New York Downstate Medical Center; Chairman Emeritus, Department of Internal Medicine, Western Pennsylvania Hospital
Disclosure: Nothing to disclose.
Bryan L Martin, DO Associate Dean for Graduate Medical Education, Designated Institutional Official, Associate Medical Director, Director, Allergy Immunology Program, Professor of Medicine and Pediatrics, Ohio State University College of Medicine
Bryan L Martin, DO is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American College of Allergy, Asthma and Immunology, American College of Osteopathic Internists, American College of Physicians, American Medical Association, American Osteopathic Association
Disclosure: Nothing to disclose.
Robert W Hoffman, DO, FACP, FACR Chief, Division of Rheumatology and Immunology, Professor, Departments of Medicine and Microbiology & Immunology, University of Miami, Leonard M Miller School of Medicine
Robert W Hoffman, DO, FACP, FACR is a member of the following medical societies: American Association for the Advancement of Science, American Association of Immunologists, American College of Physicians, American College of Rheumatology, and Clinical Immunology Society
Disclosure: Nothing to disclose.
Mixed Connective-Tissue Disease
Research & References of Mixed Connective-Tissue Disease|A&C Accounting And Tax Services