Cytokine Milieu in Undifferentiated Connective Tissue Disease: a Comprehensive Review

Abstract

Undifferentiated connective tissue disease (UCTD) is a unique clinical entity, a potential forerunner of well-established systemic autoimmune/rheumatic diseases. UCTD is characterized by the presence of various clinical symptoms, as well as a diverse repertoire of autoantibodies, resembling systemic autoimmune diseases. Since approximately one-third of these patients consequently transform into a full-blown systemic autoimmune/rheumatic disease, it is of major importance to assess pathogenic factors leading to this progression. In view of the fact that the serological and clinical picture of UCTD and systemic autoimmune diseases are very similar, it is assumed that analogous pathogenic factors perpetuate both disease entities. In systemic autoimmune conditions a quantitative and qualitative impairment of regulatory T cells have been shown previously and in parallel a relative dominance of proinflammatory Th17 cells has been introduced. Moreover the imbalance between regulatory and Th17 cells plays a pivotal role in the initiation and propagation of UCTD. Additionally, we depict a cytokine imbalance, which give raise to a biased T-cell homeostasis from the UCTD phase throughout the fully developed systemic autoimmune disease stage. The levels of IL-6, IL-12, IL-17, IL-23 and IFN- were pathologically increased with a parallel reduction of IL-10. We believe that the assessment of Th17/Treg cell ratio, as well as the simultaneous quantitation of cytokines may give a useful diagnostic tool at the early UCTD stage to identify patients with a higher chance of consecutive disease progression towards serious systemic autoimmune diseases. Moreover, the early-targeted immunomodulating therapy in these patients may decelerate, or even stop this progression, before the development of serious autoimmune conditions with organ damage.

Clinical and Serologic Features in Patients With Incomplete Lupus Classification Versus Systemic Lupus Erythematosus Patients and Controls

“…Insights into the immunopathology of ILE would support the establishment of evidence‐based treatment regimens for ILE patients. Patterns of immune dysregulation in ILE are suspected to coincide with those observed in SLE . For example, lupus‐associated autoantibodies and soluble mediator dysregulation accumulate prior to clinical SLE onset; these autoantibodies are also observed in ILE (), and there is some evidence of soluble mediator dysregulation .…”

Undifferentiated connective tissue diseases and adverse pregnancy outcomes. An undervalued association?

“…In almost a third of cases, these disorders precede a diagnosis of full‐blown rheumatic disease by months or years but can also remain stable for years with minimal disease activity . Biologically, UCTDs are accompanied by impaired regulatory T cells leading to an imbalance between pro‐ and anti‐inflammatory cytokines, characterized by increased peripheral levels of IL‐6, IL‐1, IL‐12, and IL‐17, and simultaneous reduction in IL‐10 …”

Early, Incomplete, or Preclinical Autoimmune Systemic Rheumatic Diseases and Pregnancy Outcome

“…Growing evidence suggests that these preclinical phases can be associated with an upregulation of inflammatory cytokines and endothelial dysfunction leading to systemic adverse effects, such as accelerated atherosclerosis and cardiovascular and lung diseases (6)(7). Although retrospective epidemiologic data suggest that adverse pregnancy outcomes often antedate the subsequent development of SLE, RA ,SS, or anti-phospholipid syndrome (APS), the effect of preclinical autoimmune systemic diseases on pregnancy outcome has not been well studied.…”

“…Most affected subjects, at least in the first stages of these diseases, have a limited number of laboratory abnormalities and clinical symptoms and usually do not meet classification criteria . There is a growing body of evidence that these preclinical phases can be associated with up‐regulation of inflammatory cytokines and endothelial dysfunction leading to systemic adverse effects, such as accelerated atherosclerosis and cardiovascular and lung diseases .…”