Rheumatoid arthritis: An editorial perspective based on cytokine imbalance

Abstract

Rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and Sjögren's syndrome (SS) are distinct systemic rheumatic and autoimmune diseases with overlapping clinical features and laboratory findings. Although the majority of patients fit the textbook descriptions of these disorders, there are occasional patients whose illness defies precise diagnostic classification. Examples are mixed connective tissue disease, rheumatoid arthritis and systemic vasculitis, and the overlap SS/SLE syndrome with anti-Ro autoantibodies [1]. Cytokine abnormalities are prominent in all rheumatic diseases. This editorial focuses on cytokine abnormalities in RA and particularly in the rheumatoid synovium, but because of these disease interrelationships has implications for SS and SLE as well. The pathology in RA can be dominated by the systemic features, particularly when rheumatoid lung, severe vasculitis or Felty's syndrome are present. Rheumatoid factor was the first autoantibody to be extensively studied from functional, pathological and immunogenetic aspects. For most patients, however, joint inflammation with its predilection to progress to joint destruction comes to dominate the clinical picture. For the clinical immunologist, the ability to study synovial fluid and cells offers an investigative opportunity not generally found in other rheumatic diseases, i.e. to take measurements where the action is, directly at the site of autoimmune attack. Careful histopathologic studies performed decades ago are the basis for our understanding of immunopathogenic events in the rheumatoid synovium. These studies highlight the intense chronic inflammatory activity with activated macrophages, lymphocytic and plasma cell infiltration, germinal center formation, and tissue destruction. Local production of rheumatoid factor and immune complexes, as well as complement consumption, were demonstrated 20 years ago in an investigative era dominated by humoral immunity. At the same time there is intense synovial cell proliferative activity leading to an invasive mass of fibrous tissue called the pannus. The accompanying local osteoporosis, destruction of cartilage and erosion of bone are attributed to production of inflammatory mediators, enzymes (collagenases, proteases and hydrolases), reactive oxygen species and numerous metabolites and byproducts produced by unknown causes and progressing through the interlocking mechanisms of the immune/inflammatory cascade. In this current era, research is dominated by cellular immunity and rapidly expanding knowledge of cytokines, factors released by cells which function normally to mediate the controlled processes of the immune response but also function pathologically in immune mediated inflammation. Fifty years ago an American cartoonist named Rube Goldberg drew intricate designs, part human and part machine, in which an action initiated at one end (e.g. the pull of a lever) would lead through a series of interlocking and highly complex steps to an action at the opposite end (e.g. the delivery of a newspaper). If any one of these steps occurred asynchronously, disaster might follow (e.g. the striking of a hammer on someone's head instead of on a peg). So may we characterize the processes of chronic immune-mediated inflammation as exemplified in the rheumatoid synovium. They appear as a series of interlocking events, neither one by itself inherently abnormal, which nervertheless constitutes an ensemble which by its disorder and mismanaged regulation leads to pain and crippling. How this process may arise and what may be done to set it straight are the subjects of this editorial. For want of a better term, we will refer to this Rube Goldberg machine in RA as cytokine imbalance.