Mixed Connective-Tissue Disease (MCTD): Practice Essentials, Pathophysiology, Etiology (original) (raw)

Practice Essentials

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]

MCTD has since been more completely characterized and is now recognized to consist of the following core clinical and laboratory features [3, 4] :

Different classification and diagnostic criteria for MCTD have been developed. [6] These include the Alarcón-Segovia diagnostic criteria [7, 8] and, more recently, a set of criteria from a Japanese multispecialty consensus panel. [9] See DDx/Diagnostic Considerations.

Nevertheless, whether MCTD is a distinct disease entity has been in question since shortly after its original description. A minority of authors continues to suggest that MCTD would be better characterized as subgroups or early stages of disorders such as SLE or systemic sclerosis. [10] Other authors propose that MCTD cases should not be distinguished from undifferentiated autoimmune rheumatic disease. [11, 12]

The overall goals of therapy for MCTD are to control symptoms, to maintain function, and to reduce the risk of future disease consequences. Medical therapy targets control of disease activity in general and management of specific organ involvement, while monitoring for and mitigating the risks of complications either of the condition itself (eg, pulmonary hypertension, interstitial lung disease) or of its treatment (eg, infection).

eMedicine Logo

Pathophysiology

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. [18]

Oka and colleagues performed genotyping of HLA-DRB1 and -DQB1 in 116 Japanese MCTD patients and 413 controls and analyzed the genotype frequencies. The analysis showed that HLA-DRB1*04:01 and DRB1*09:01 were risk alleles for Japanese MCTD. DRB1*13:02 was also confirmed to be protective against MCTD in Japanese patients. [19]

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 with epitope spreading had a 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). [20]

eMedicine Logo

Etiology

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 and other danger signal sensors induced by end-organ injury, are proposed current theories of pathogenesis.

It is notable that the RNA component unique to the U1-small nuclear ribonucleoprotein, U1-RNA, is among the most prevalent RNAs present in cellular apoptotic debris, and that U1-RNA is an agonist for autoimmunity-associated endosomal Toll-lIke receptors, including TLR7 and TLR3. [21, 22] These observations promote the hypothesis that immune recognition of apoptotic debris may play a key role in the etiology of anti-RNP autoimmunity, as in MCTD.

eMedicine Logo

Epidemiology

United States

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. [23] 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). [24]

International

In an epidemiologic survey in Japan, MCTD has a reported prevalence of 2.7 cases per 100,000 population. [25] 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. [26]

Mortality/Morbidity

Long-term outcome studies have established pulmonary hypertension as the most common disease-related cause of death. [27] 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. [28]

Race-, Sex-, and Age-related Variances

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. [29]

MCTD is far more common in females than in males. Estimates of the female-to-male ratio vary from approximately 3:1 to 16:1. [26, 25]

The onset of MCTD is typically at 15-25 years of age, but can occur at any age.

eMedicine Logo

Prognosis

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. [30] The following were the strongest predictors of ILD progression:

eMedicine Logo

Patient Education

Education about MCTD and its treatment is essential. Active participation in the decision-making process empowers patients in their own care. Education about disease decreases the risk of patients developing learned helplessness and improves functional outcomes. For patient education information, see What Is Mixed Connective Tissue Disease (MCTD)?.

eMedicine Logo

  1. 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. [QxMD MEDLINE Link].
  2. Zandman-Goddard G, Solomon M, Rosman Z, Peeva E, Shoenfeld Y. Environment and lupus related diseases. Lupus. 2011 Nov 7. [QxMD MEDLINE Link].
  3. Yoshida S. Pulmonary arterial hypertension in connective tissue diseases. Allergol Int. 2011 Nov. 60(4):405-9. [QxMD MEDLINE Link].
  4. 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. [QxMD MEDLINE Link].
  5. 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. [QxMD MEDLINE Link].
  6. 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. Journal of Rheumatology. 1996 Dec. 23 (12):2055-62. [QxMD MEDLINE Link].
  7. 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. [QxMD MEDLINE Link].
  8. 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.
  9. Tanaka Y, Kuwana M, Fujii T, Kameda H, Muro Y, Fujio K, 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 Rheumatology. 2021 Jan. 31:29-33. [QxMD MEDLINE Link]. [Full Text].
  10. Martínez-Barrio J, Valor L, López-Longo FJ. Facts and controversies in mixed connective tissue disease. Med Clin (Barc). 2017 Aug 29. [QxMD MEDLINE Link].
  11. Ciang NC, Pereira N, Isenberg DA. Mixed connective tissue disease-enigma variations?. Rheumatology (Oxford). 2017 Mar 1. 56 (3):326-333. [QxMD MEDLINE Link].
  12. Alves MR, Isenberg DA. "Mixed connective tissue disease": a condition in search of an identity. Clinical and Experimental Medicine. 2020 May. 20:159-166. [QxMD MEDLINE Link]. [Full Text].
  13. 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. [QxMD MEDLINE Link].
  14. Ascherman DP, Zang Y, Fernandez I, Clark ES, Khan WN, Martinez L, et al. An Autoimmune Basis for Raynaud's Phenomenon: Murine Model and Human Disease. Arthritis & Rheumatology. 2018 Sep. 70:1489-1499. [QxMD MEDLINE Link]. [Full Text].
  15. Carpintero MF, L Martinez L, Fernandez I, Garza Romero AC, Mejia C, Zang YJ, et al. Diagnosis and risk stratification in patients with anti-RNP autoimmunity. Lupus. 2015 Sep. 24:1057-66. [QxMD MEDLINE Link]. [Full Text].
  16. Paradowska-Gorycka A, Wajda A, Stypinska B, Walczuk E, Rzeszotarska E, Walczyk M, et al. Variety of endosomal TLRs and Interferons (IFN-α, IFN-β, IFN-γ) expression profiles in patients with SLE, SSc and MCTD. Clinical & Experimental Immunology. 2020 Dec 17. [QxMD MEDLINE Link]. [Full Text].
  17. Carnero-Montoro E, Barturen G, Povedano E, Kerick M, Martinez-Bueno M, PRECISESADS Clinical Consortium; Esteban Ballestar E, et al. Epigenome-Wide Comparative Study Reveals Key Differences Between Mixed Connective Tissue Disease and Related Systemic Autoimmune Diseases. Frontiers in Immunology. 2019 Aug 7. 10:1880. [QxMD MEDLINE Link]. [Full Text].
  18. Flåm ST, Gunnarsson R, Garen T, Norwegian MCTD Study Group, Lie BA, Molberg Ø. The HLA profiles of mixed connective tissue disease differ distinctly from the profiles of clinically related connective tissue diseases. Rheumatology (Oxford). 2015 Mar. 54 (3):528-35. [QxMD MEDLINE Link].
  19. Oka S, Higuchi T, Furukawa H, Shimada K, Hashimoto A, Komiya A, et al. Predisposition of HLA-DRB1*04:01/*15 heterozygous genotypes to Japanese mixed connective tissue disease. Sci Rep. 2022 Jun 15. 12 (1):9916. [QxMD MEDLINE Link]. [Full Text].
  20. 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. [QxMD MEDLINE Link].
  21. Greidinger EL, Zang Y, Martinez L, Jaimes K, Nassiri M, Bejarano P, et al. Differential tissue targeting of autoimmunity manifestations by autoantigen-associated Y RNAs. Arthritis Rheum. 2007 May. 56 (5):1589-97. [QxMD MEDLINE Link].
  22. Hardy MP, Audemard É, Migneault F, Feghaly A, Brochu S, Gendron P, et al. Apoptotic endothelial cells release small extracellular vesicles loaded with immunostimulatory viral-like RNAs. Sci Rep. 2019 May 10. 9 (1):7203. [QxMD MEDLINE Link].
  23. 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. [QxMD MEDLINE Link].
  24. 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. [QxMD MEDLINE Link].
  25. 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.
  26. 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. [QxMD MEDLINE Link].
  27. 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. [QxMD MEDLINE Link].
  28. 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. [QxMD MEDLINE Link].
  29. 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. [QxMD MEDLINE Link].
  30. 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. [QxMD MEDLINE Link].
  31. 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. [QxMD MEDLINE Link].
  32. 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. [QxMD MEDLINE Link].
  33. 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. [QxMD MEDLINE Link]. [Full Text].
  34. 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. [QxMD MEDLINE Link].
  35. 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. [QxMD MEDLINE Link]. [Full Text].
  36. 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. [QxMD MEDLINE Link].
  37. 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. [QxMD MEDLINE Link].
  38. Yasuoka H, Shirai Y, Tamura Y, Takeuchi T, Kuwana M. Predictors of Favorable Responses to Immunosuppressive Treatment in Pulmonary Arterial Hypertension Associated With Connective Tissue Disease. Circulation Journal. 2018 Jan 25. 82:546-554. [QxMD MEDLINE Link]. [Full Text].
  39. Vacchi C, Sebastiani M, Cassone G, Cerri S, Della Casa G, Salvarani C, et al. Therapeutic Options for the Treatment of Interstitial Lung Disease Related to Connective Tissue Diseases. A Narrative Review. J Clin Med. 2020 Feb 3. 9 (2):[QxMD MEDLINE Link]. [Full Text].
  40. Flaherty KR, Wells AU, Cottin V, Devaraj A, Walsh SLF, Inoue Y, et al. Nintedanib in Progressive Fibrosing Interstitial Lung Diseases. N Engl J Med. 2019 Oct 31. 381 (18):1718-1727. [QxMD MEDLINE Link].

Author

Eric L Greidinger, MD Associate Professor, Department of Medicine, Division of Rheumatology and Immunology, University of Miami, Leonard M Miller School of Medicine, Miami Veterans Affairs Medical Center

Eric L Greidinger, MD is a member of the following medical societies: American College of Physicians, American College of Rheumatology

Disclosure: Received research grant from: Corbus Pharmaceuticals; Eli Lilly & Company; Horizon Pharmaceuticals; INFLARX GBMH, Mitsubishi Pharmaceuticals, Reatta Pharmaceuticals, Swedish Orphan Biovitrum AB.

Specialty Editor Board

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.

Chief Editor

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

Herbert S Diamond, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American College of Rheumatology, American Medical Association, Phi Beta Kappa

Disclosure: Nothing to disclose.

Additional Contributors

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.

Acknowledgements

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.