Corneal Disease in Rheumatoid Arthritis

Introduction

Rheumatoid arthritis (RA) is a chronic, systemic, autoimmune inflammatory disease of unknown etiology. The incidence of RA is approximately 1%, although this increases with advancing age. Women are affected approximately three times more often than men, with the peak age of onset occurring between the fourth and sixth decades of life. RA most commonly presents as a symmetric polyarthritis of both small and large synovial joints. Extra articular disease in tissues such as the eye, pleura, pericardium, and nerves has also been found in RA patients.

Previously, the diagnosis of RA was based on a set of criteria put forth by the American Rheumatism Association. However, the American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) recently revised these criteria to focus on identifying patients at an earlier disease stage. Current classification is based on the following: (1) presence of synovitis in at least one joint; (2) absence of an alternative diagnosis for synovitis; and (3) total score of at least six from sum of individual scores in four domains (number and site of involved joints, serologic abnormality, elevated acute phase response, symptom duration at least 6 weeks). ^,

Early diagnosis and aggressive treatment of RA is imperative, since delays lead to well-recognized increases in morbidity and mortality. Studies have demonstrated that inadequately treated patients with RA have a mortality rate of approximately 40%–50% at 5 years. Patients presenting with ophthalmic disease are often those with severe, long-standing RA with high titers of rheumatoid factor (RF). Fortunately, extra articular disease is now less common than before as a result of current approaches that address RA aggressively early in the course of the disease.

Pathogenesis

The etiopathogenesis of RA is unknown. The current model, or so-called shared epitope, holds that the disease develops in the genetically predisposed host upon exposure to an as yet unknown stimulus or antigen in the environment. The hypothesis is that an interaction between host and foreign antigen (such as an unidentified infectious agent) sets off an immunologic reaction to self which is inappropriately perpetuated. Inflammatory cytokines tumor necrosis factor alpha (TNF-α) and interleukin-1 (IL-1) appear to be largely responsible for driving the inflammatory cascade, which leads to inflammation of synovial joints and the damage to the articular structures. ^,

RFs are antibodies, most commonly immunoglobulin M (IgM), with affinity for the Fc region of human IgG. Serum RFs can be detected in 70%–80% of RA patients; however, the diagnostic utility of RF is limited by its poor specificity because it is found in 5%–10% of healthy individuals. Nonetheless, the presence of RF and increasing titers of the antibody are predictive for the development of RA in patients without active disease. In patients with an established diagnosis of RA, high titers of RF (at least three times the upper limit of normal) are associated with a higher incidence of extra articular manifestations, more severe joint destruction, and worse prognosis.

Another process thought to be important in initiating the autoimmune response that leads to the development of RA is citrullination, a posttranslational modification of proteins in which peptidyl-arginine is converted to peptidyl-citrulline. Antibodies to citrullinated peptides/proteins (anti-CCP) can be measured by enzyme-linked immunosorbent assays (ELISAs) and have been found to have a comparable sensitivity to RF but with a higher specificity (95%–98%), thus allowing for earlier detection of disease. The combination of a positive anti-CCP with a positive RF further increases the specificity for RA. A Swedish study of blood bank samples showed that each of these tests had approximately a 70% sensitivity for detecting the individuals who ultimately developed RA, and the combination of these two tests resulted in 99% specificity.

Clinical Manifestations