What is the pathophysiology of mixed connective-tissue disorder (MCTD)?

Updated: Oct 01, 2018
  • Author: Eric L Greidinger, MD; Chief Editor: Herbert S Diamond, MD  more...
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Answer

Pathophysiologic abnormalities that are believed to play a role in MCTD include the following:

  • B-lymphocyte hyperactivity, resulting in high levels of anti–U1-RNP and anti–U1-70 kd autoantibodies
  • T-lymphocyte activation, with anti–U1-70 kd–reactive T lymphocytes circulating in the peripheral blood
  • Apoptotic modification of the U1-70 kd antigen
  • Immune response against apoptotically modified self-antigens
  • Genetic association with major histocompatibility genes human leukocyte antigen (HLA)–DRB1*04/*15 [8]
  • Vascular endothelial proliferation with widespread lymphocytic and plasmacytic infiltration of tissues
  • Activation of Toll-like receptors in a pattern that may differ from that of SLE

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. [9]

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). [10]


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