The diagnosis and clinical significance of polyautoimmunity

Abstract

Autoimmune diseases (ADs) are chronic and heterogeneous conditions that affect specific target organs or multiple organ systems. The chronic nature of these diseases places a significant burden on the utilization of medical care, direct and indirect economic costs, and quality of life. ADs are observed in genetically susceptible individuals in whom their clinical expression is modified by permissive and protective environments occurring over time. These are complex traits, meaning that their inheritance does not follow a single-gene dominant or single-gene recessive Mendelian law, and thus that they are polygenic. ADs are often diagnosed according to classification criteria, however they share similar subphenotypes including signs and symptoms, non-specific autoantibodies and other immune changes, which are prone to taxonomic problems. Polyautoimmunity is defined as the presence of more than one AD in a single patient. When three or more ADs coexist, this condition is called multiple autoimmune syndrome (MAS), which represents the best example of polyautoimmunity as well as the effect of a single genotype on diverse autoimmune phenotypes. Its study will provide important clues to elucidate the common mechanisms of ADs (i.e., the autoimmune tautology).

Introduction

The mosaic of autoimmunity describes the multi-factorial origin and diversity of autoimmune disease (AD) expression [1] (Fig. 1). This term implies that different combinations of many factors involved in autoimmunity produce several distinct clinical presentations that represent the wide spectrum of AD. The term “kaleidoscope of autoimmunity” portrays the possible change from one disease to another or the fact that more than one disease may coexist in the same individual or family [2]. The fact that ADs share several clinical signs and symptoms (i.e. subphenotypes), physiopathological mechanisms, and genetic factors has been called the autoimmune tautology and indicates that they have several common mechanisms [3], [4], [5], [6], [7]. Autoimmune tautology (from Greek tauto, “the same” and logos, “word/idea”) means that one AD is similar to a second one, to a third one, and so on. ADs cannot be equal because the target cell and organ are different in each case, and the trigger factors and age at onset vary among ADs.

Several subphenotypes are shared by ADs including signs and symptoms such as arthralgia, arthritis, alopecia, fatigue, photosensitivity, Raynaud's phenomenon as are non-specific autoantibodies (e.g., antinuclear antibodies, rheumatoid factor, anti-Ro antibodies) and high levels of cytokines which raises taxonomic concerns and explain why classification criteria may lack of accuracy. ADs have a heterogeneous spectrum; the disease course differs from patient to patient and through different phases within the same patient. Depending on the duration and activity of the disease, these subphenotypes might change. Mathematical approaches for precisely defining subphenotypes based on accurate clinical and immunological databases combined with strengthening molecular genetic analyses and immunological pathways (e.g., type I interferon activation, reduced B and T cell regulatory function) have significant promise for a better understanding of ADs.