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Rheumatoid Arthritis

Andrew P. Cope

Rheumatoid arthritis (RA) is one of the most common chronic European League Against Rheumatism (ACR/EULAR) classifica-
inflammatory diseases and in modern times has become a tion criteria are applied. These rates plateau between the ages
prototype disease entity for defining the molecular and pathologi- of 45 and 75 years in some series but can increase steadily with
cal basis of chronic inflammatory syndromes. The term rheumatoid age until the seventh decade, declining thereafter. The largest
arthritis was coined by Garrod in 1859. However, this was probably difference in incidence between the sexes occurs in those under
an inappropriate use of the term because it encompassed poly- 50 years of age. Past evidence indicates that the incidence may
articular osteoarthritis as well as inflammatory polyarthritis. In be in decline, at least for seropositive disease. Large cross-sectional
spite of references to inflammatory afflictions of joints by the population samples indicate that disease prevalence, which ideally
likes of Galen, Sydenham, and Heberden, the first convincing should include all past and inactive cases, ranges from 0.5–2%
case reports of the disease, described in terms that would be for Caucasian European and North American populations over
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recognizable today, were published in 1800 by Landré-Beauvais, the age of 15, with a female to male excess of 2–4 times. Despite
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who labeled the disease “la goutte asthénique primitive.” This similar prevalence estimates for these geographically diverse
description was distinct because all patients were female, an populations, greater diversity has been documented for rural
observation that was significant when the most important dif- African populations, where the prevalence has been reported to
ferential diagnosis at that time was polyarticular gout, a disease be as low as 0.1%, and for Native Americans (including the
predominantly of males. Pima, Yakima, and Chippewa tribes), where the prevalence may
Today we recognize RA as a chronic inflammatory disorder be as high as 5%. Such variance across geographical borders
of joints of unknown etiology in which the major target tissue likely reflects distinct environmental factors and sociodemographic
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is the synovial lining of joints, bursae, and tendon sheaths. determinants as well as a spectrum of genetic admixture. Lifetime
Although traditionally considered an autoimmune disease, RA risk has been estimated at 4% for women and 3% for men.
differs from organ-specific autoimmune disease entities in several Complex polygenic autoimmune syndromes like RA are
respects. From the outset of clinically apparent disease, the diseases of low penetrance, where thresholds of disease expression
systemic immuno-inflammatory process, driven by cytokines may be higher in males. This is based in part on the observation
and other inflammatory mediators, promotes the activation and that the increased risk of disease in siblings of probands (denoted
proliferation of stromal joint tissues, in particular the fibroblastic λs) is rather small; the λs for RA (risk to sibling divided by
synovial lining layer. This appears to contrast with organ-specific population risk) are estimated to be 3, whereas the λs for systemic
autoimmune diseases, such as type 1 diabetes or autoimmune lupus erythematosus (SLE) may be as high as 30; for celiac disease
thyroiditis, characterized by an antigen-driven immune- the λs are closer to 50. Recent insights into familial clustering
inflammatory response in situ leading to targeted cellular indicate that family history remains a strong independent risk
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destruction of autoantigen-expressing pancreatic β-islet or thyroid factor for RA but that this risk does not differ by gender. This
tissue cells. In RA, once the inflammatory process is established, implies that nongenetic factors influence gender bias. Twin studies
the inflammatory synovium, or pannus, may invade and erode also provide compelling evidence for genetic effects, given the
underlying cartilage and bone. Unlike autoimmune diseases that excess concordance rates for monozygotic (12–15%) compared
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target single organs or tissues, RA is a systemic inflammatory with dizygotic twins (<5%, and probably nearer to 3.5%). These
disease that likely encompasses a heterogeneous syndrome with concordance rates appear somewhat low, but compared with a
marked variation in clinical expression that most clinicians today background prevalence of 1% in outbred populations, genetic
would acknowledge is more than one disease entity. Indeed, it epidemiology studies report heritability estimates of 68% for
is now apparent that the disease is heterogeneous not only those patients who carry antibodies to citrullinated protein
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clinically but also pathologically, serologically, and genetically. antigens (ACPAs ) and 66% for those who do not (ACPAs ),
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indicating substantial genetic influence. Human leukocyte antigen
EPIDEMIOLOGY (HLA) is thought to contribute 35–40% of this value. This
“missing heritability” leaves a substantial contribution to disease
The incidence of RA (the rate of new cases arising in a given susceptibility from environmental factors, influenced by occupa-
period) is 0.1–0.2 per 1000 of the population for males and tion, socioeconomic status, exposure to infectious pathogens,
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0.2–0.4 per 1000 for females. Rates as high as 0.4 per 1000 have and lifestyle factors—a conglomeration of factors termed the
been reported when the 2010 American College of Rheumatology/ “exposome.”
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