Preclinical Autoimmune Disease: a Comparison of Rheumatoid Arthritis, Systemic Lupus Erythematosus, Multiple Sclerosis and Type 1 Diabetes

Abstract

The preclinical phase of autoimmune disorders is characterized by an initial asymptomatic phase of varying length followed by nonspecific signs and symptoms. A variety of autoimmune and inflammatory manifestations can be present and tend to increase in the last months to years before a clinical diagnosis can be made. The phenotype of an autoimmune disease depends on the involved organs, the underlying genetic susceptibility and pathophysiological processes. There are different as well as shared genetic or environmental risk factors and pathophysiological mechanisms between separate diseases. To shed more light on this, in this narrative review we compare the preclinical disease course of four important autoimmune diseases with distinct phenotypes: rheumatoid arthritis (RA), Systemic Lupus Erythematosus (SLE), multiple sclerosis (MS) and type 1 diabetes (T1D). In general, we observed some notable similarities such as a North-South gradient of decreasing prevalence, a female preponderance (except for T1D), major genetic risk factors at the HLA level, partly overlapping cytokine profiles and lifestyle risk factors such as obesity, smoking and stress. The latter risk factors are known to produce a state of chronic systemic low grade inflammation. A central characteristic of all four diseases is an on average lengthy prodromal phase with no or minor symptoms which can last many years, suggesting a gradually evolving interaction between the genetic profile and the environment. Part of the abnormalities may be present in unaffected family members, and autoimmune diseases can also cluster in families. In conclusion, a promising strategy for prevention of autoimmune diseases might be to address adverse life style factors by public health measures at the population level.

Keywords: environmental risk factors; genetic risk factors; multiple sclerosis (MS); pathophysiological process; prodromal phase; rheumatoid arthritis (RA); systemic lupus erythematosus (SLE); type 1 diabetes (T1D).

Figure 1

Primary site of onset. This illustration shows the primary site of initiation of the autoimmune process in RA, SLE, MS, and T1D. RA is represented in purple, SLE in orange, MS in blue and T1D in green.

Figure 2

This illustration shows an overview of the transition from at-risk to disease diagnosis. In purple is represented RA, in orange SLE, in blue MS, and in green T1D. *Also known as “incomplete Lupus”. ACPA, Anti-citrullinated protein antibody; RF, Rheumatoid factor; anti-CarP, anti-carbamylated; ANA, antinuclear antibody; anti-dsDNA, anti-double strand DNA; anti-RNP, anti-nuclear ribonucleoprotein; IAA, autoantibodies against insulin; IA-2, autoantibodies against insulinoma-associated antigen-2; GAD or GADA, autoantibodies against glutamic acid decarboxylase; anti-ZnT8, autoantibodies against zinc-transporter 8; ICA, islet cell antibodies.