Chapter 35. Rheumatoid Arthritis
Rheumatoid arthritis (RA) is an immune inflammatory (autoimmune) rheumatic disorder characterized by severe progressive joint and internal organs damage, developing in accordance with a complex interaction of environmental factors and genetic predisposition leading to global disorders in humoral and cellular immune system.
RA is one of the most common chronic inflammatory diseases, with prevalence in the population of 1%, and economic burden for the society comparable with that of coronary heart disease (CAD). The disease is 2.5 times more common in females than in males; however, in rheumatoid factor (RF) seropositive patients (see below) and in the elderly these gender differences are less pronounced. In the absence of effective therapy, the life expectancy of RA patients is 3 years less in women, and 7 years less in men — primarily due to high risk of cardiovascular diseases (CVD), osteoporosis (OP), severe infections, and cancer. In many RA patients, life prognosis is as unfavorable as in those with lymphogranulomatosis, type 2 diabetes mellitus (DM), three-vessel coronary artery disease and stroke. RA causes persistent disability in half of patients during the first 3–5 years from the onset of the disease, and 1/3 of patients become fully disabled persons after 20 years.
Etiology and Pathogenesis
Although etiology of RA is unknown, the risk of disease development is linked to a wide range of genetic, hormonal and environmental (smoking, air pollution, infectious agents) and metabolic factors (vitamin D deficiency, obesity, low polyunsaturated fatty acid intake), as well as to disorders of intestinal, oral cavity and pulmonary microbiome.
The pathogenesis of RA is determined by the complex interaction of environmental factors with a genetic predisposition that leads to the innate and acquired immune system disorders revealed long before the development of clinical symptoms. This causes a variety of clinical, pathological, immunological manifestations and makes RA more similar to clinical immunological syndrome than to a single nosological entity.
The essence of RA pathological process lies in systemic autoimmune inflammation that primarily affects synovial membrane of the joints. RA evolution includes several consecutive (or discrete) stages. Pre-clinical stages transform into “symptomatic” disease developing into clinical laboratory symptom complex characteristic of early, and further — advanced RA. It is assumed that subclinical synovitis development is observed as early as in preclinical RA and is associated with local microtrauma, damage to joint microvasculature, complement system activation and/or effect of pathogenic autoantibodies (immune complexes) causing activation of periarticular osteoclasts expressing citrullinated proteins, that lead to bone destruction, and with the synthesis of “pro-inflammatory” mediators inducing pain and inflammation development. In RA, a massive immune cell infiltration (T-lymphocytes, B-lymphocytes, plasma cells, macrophages, mast cells, activated stromal cells and synovial fibroblasts) in synovial tissue is identified. The nature of interaction of these cells and a profile of pro-inflammatory mediator synthesis vary significantly depending on the stage of the disease.
RA is a classic B-cell autoimmune disorder characterized by the synthesis of a wide range of autoantibodies with different specificity, detected in more than 90% of patients. Moreover, B-cells participate in T-cells co-stimulation, cause activation of osteoclasts and synthesize a wide range of pro-inflammatory cytokines (TNF-α, lymphotoxin, IL-6, etc.). The most typical autoantibodies for RA include RF IgG, IgM, and IgA-isotypes reacting with Fc-fragment of IgG molecule, and autoantibodies reacting with antigenic epitopes that are universally characterized by post-translational modification (citrulination, carbamylation, acetylation, peroxidation, etc.). A special significance is attached to citrullination, that represents a biochemical process mediated by petidyl arginine deaminase-2 and -4 enzyme and consisting of conversion of coded positively charged amino acid arginine into neutrally charged amino acid citrulline. Overproduction of anti-citrullinated protein antibodies (ACPA) (especially combined with IgM and IgA RF) is associated with the disease activity, joint destruction progression, extraarticular (systemic) manifestations, general risk of death due to comorbid conditions (primarily, cardiovascular complications), and pharmacotherapy “resistance”, or conversely, “sensitivity”.
The two main clinical immunological RA subtypes are distinguished: ACPA-positive and ACPA-negative. They differ in the molecular pathogenesis mechanisms, genetic and environmental predisposition factors, severity, and response to treatment conducted. IgM RF and ACPA are revealed in serum of RA patients, as well as in patients with arthralgia or nonspecific musculoskeletal symptoms developing for many years before the onset of RA that is considered as important evidence of preclinical systemic “autoimmune” phase of this disease. ACPA (and RF) are not only sensitive and specific biomarkers of RA, but also can have a pathogenetic role acting as additional mediators of bone tissue inflammation and destruction. This, in turn, depends on exposure to additional exogenous or endogenous factors (the so-called “second hit”), enhancing autoantibodies pro-inflammatory potential. The development of chronic joint inflammation may be associated with the formation of the so-called “pro-inflammatory phenotype” of antibodies, the feature of that is a disruption of glycosylation (the process of attaching monosaccharides to protein) Fc- and Fab-fragments of Ig molecule.