Etiology of Rheumatoid Arthritis
Osler, writing on the etiology of rheumatoid arthritis (RA) in The Principles and Practices of Medicine in 1892, remarked that the etiology was unknown: "The true nature of the disease is still obscure," that there was a predilection of cases among females: "Females are more liable to the disease than males. In Garrod’s table of 500 cases there were 411 females (82%) and 89 males;" that the disease predominantly affected individuals in the most productive years of life: "It most commonly sets in between the ages of 20 and 30, but it may begin as late as age 50;" and that there seemed to be a genetic component: "Heredity influences are not uncommon." In Garrod’s cases there were 216 incidences (43%) of a family history of joint disease.10589
Even 115 years after Osler’s seminal work, the etiology of RA has still not been scientifically established. It is believed that RA may develop in individuals with a genetic predisposition to the disease. Genetic Factors in Rheumatoid Arthritis Etiology. There is evidence that smoking may enhance the interaction of these factors. Smoking Hypothesis in Rheumatoid Arthritis
Genetic Factors in Rheumatoid Arthritis Etiology
Genetic factors clearly play a role in the development of rheumatoid arthritis (RA), as well as in the pathophysiology of RA. Family studies reveal that RA has a genetic component, and a positive family history is a factor for increased risk of developing the disease. Genetic Factors in Pathophysiology.6604, 6605, 10508 Human leukocyte antigens are an important genetic factor.10508, 10646 Silman, et al., reported similar increased concordance in monozygotic (15%) versus dizygotic twins (4%).6604 In addition, Seldin, et al., noted that siblings of patients with RA had a 2- to 4-fold risk of developing RA, compared with siblings of unaffected individuals.6605 Osler, writing on the etiology of RA in The Principles and Practices of Medicine in 1892, proposed a genetic component for the disease, stating that heredity influences are not uncommon. In Garrod’s cases there were 216 incidences (43%) of a family history of joint disease.10589
Immunoregulatory Abnormalities and Autoimmunity in Rheumatoid Arthritis
The mistaken identity theory of autoimmune disease suggests that a pathological organism may cause an appropriate immune response that results in the production of antibodies that are specific to that organism. The mistaken identity theory assumes that the antibodies that are produced lack sufficient specificity to that pathogen. These less specific antibodies theoretically mount an immune response against an inappropriate target, the synovium, because it is molecularly similar to an identifying molecule on the offending organism that generated the initial immune reaction.
Autoimmune diseases are diseases of immune dysregulation and inherently require that the affected individual have a defect in the ability to distinguish "self" from "nonself" (i.e., foreign molecules). There are markers on many cells of the body, called major histocompatibility complex, that facilitate this self-identifying feature of the immune system. Certain kinds of these markers permit the inappropriate immune response associated with rheumatoid arthritis (RA) to occur. A majority of patients diagnosed with RA have a cluster of markers known as the human leukocytic antigen (HLA)-DR4/DR1 (See Genetic Factors in Pathophysiology) whereas only a minority of unaffected controls do. About 61% of RA patients express HLA-DRB1*0401, and if HLA-DRB1*0401 is present, 90% of RA patients are anti-cyclic citrullinated peptide positive (See Anti-Cyclic Citrullinated Peptide Test).10264 The development of RA therefore is likely to require a genetic susceptibility to the disease in individuals who have inherited these specific markers. This inappropriate autoimmune response begins a cascade that ultimately results in the inflammation and thickening of, and damage to, the tissues that comprise the synovium. This cascade results in the release of molecular mediators of inflammation and structural damage that include tumor necrosis factor-α (TNF-α); the proinflammatory interleukins (IL)-1, IL-6, IL-8 (neutrophil chemotactic factor), IL-15; E-selectin; soluble intercellular adhesion molecule-1; transforming growth factor beta; fibroblast growth factor; and platelet-derived growth factor. Matrix metalloproteinase is likewise increased within the RA joint leading to the degradation of articular cartilage. This inflammatory cascade of cytokines (See Cytokine Dysregulation) at the site of inflammation is accompanied by the recruitment of inflammatory cells from blood to the rheumatoid joint ultimately resulting in erosion of bone and loss of articular cartilage.
Smoking Hypothesis in Rheumatoid Arthritis
Rheumatoid arthritis (RA) is a complex immune-mediated inflammatory disease that involves both genetic and environmental factors (See Genetic Factors in Rheumatoid Arthritis Etiology that may promote disease susceptibility. Research substantiates that individuals who are genetically susceptible to RA are more likely to develop the condition if they smoke, and that smoking may increase the severity of RA.6607, 6606 Uhlig, et al., found that current smoking was a risk factor (odds ratio [OR] 1.46; 95% confidence interval [CI], 1.10-1.94) of developing RA, not significantly so in , females, but significantly in males (OR 2.38; 95% CI, 1.45-3.92), and dramatically in males with seropositive RA (OR 4.77; 95% CI, 2.09-10.90).10153 However, Costenbader, et al., conducted a prospective analysis of smoking and the risk of RA among a huge cohort of 103,818 females in the Nurses’ Health Study and did find a significant association. These researchers found a total of 680 RA cases, diagnosed from 1976 and 2002, and concluded that past and current cigarette smoking were related to the development of RA, in particular seropositive RA. Both smoking intensity and duration were directly related to risk, with prolonged increased risk after cessation.6606
Tobacco was first introduced to Europeans on October 15, 1492, when Columbus landed in the Americas and noted in his diary that he observed a Native American sailing in a canoe with water, food, and "some dried leaves which are in high value among them (tobacco leaves)."10162 Columbus introduced tobacco to Europe on his return from his first voyage at his home port of Palos on March 15, 1493.
During the 1500s, tobacco use spread rapidly throughout all of Europe. Tobacco was introduced to Europe about the time of the explosive spread of RA throughout the Old World, and this association of events may not be coincidental based on research published in January 2006 by Klareskog, et al.. Over the past 2 decades, investigation into the epidemiology of RA Epidemiology of Rheumatoid Arthritis has led to progress in identifying and defining these factors that increase susceptibility to developing RA, with the strongest associations demonstrated for 2 factors: human leukocytic antigen (HLA)-DRB1 “shared epitope” ( Genetic Factors in Pathophysiology) and exposure to tobacco smoke. Previously, it was not known whether these 2 factors interacted with each other, and a mechanism linking their interaction to the subsequent development of RA had not been proposed until recently. The development of RA is associated with the presence of antibodies to deiminated proteins such as anti-cyclic citrullinated peptide (anti-CCP) antibodies (See Anti-Cyclic Citrullinated Peptide Test). Autoantibodies directed against citrulline-containing proteins have a specificity of nearly 100% in patients with RA. Lundberg, et al., postulated that citrullination, an enzymatic modification of the amino acid arginine, results in citrullinated residues that may break immunologic tolerance and lead to RA.10425 Klareskog, et al., presented results from their Epidemiological Investigation of Rheumatoid Arthritis (EIRA) study that indicate a clear relationship between smoking, anti-CCP antibodies, and HLA-DRB1. Their results suggest that previous smoking induces a dose-dependent peptide deimination (CCP) that, in the presence of the HLA-DRB1 shared epitope, leads to increased risk of developing RA.4533
Figure – Relationship of Smoking, the HLA–DRB1 Shared Epitope, and the Development of RA
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References:| 4533. | Klareskog L, Stolt P, Lundberg K, et al. A new model for an etiology of rheumatoid arthritis: smoking may trigger HLA-DR (shared epitope)-restricted immune reactions to autoantigens modified by citrullination. Arthritis Rheum. 2006;54(1):38-46. |
| 6604. | Silman AJ, MacGregor AJ, Thomson W, et al. Twin concordance rates for rheumatoid arthritis: results from a nationwide study. Br J Rheumatol. 1993;32(10):903-907. |
| 6605. | Seldin MF, Amos CI, Ward R, Gregersen PK. The genetics revolution and the assault on rheumatoid arthritis. Arthritis Rheum. 1999;42(6):1071-1079. |
| 6606. | Costenbader KH, Feskanich D, Mandl LA, Karlson EW. Smoking intensity, duration, and cessation, and the risk of rheumatoid arthritis in women. Am J Med. 2006;119(6):503-511. |
| 6607. | Gorman JD. Smoking and rheumatoid arthritis: another reason to just say no. Arthritis Rheum. 2006;54(1):10-13. |
| 10153. | Uhlig T, Hagen KB, Kvien TK. Current tobacco smoking, formal education, and the risk of rheumatoid arthritis. J Rheumatol. 1999;26(1):47-54 . |
| 10162. | Medieval Sourcebook: Christopher Columbus: Extracts from Journal. Internet Medieval Sourcebook website. http://www.fordham.edu/halsall/source/columbus1.html. Published March 1996. Accessed March 2, 2007. |
| 10264. | Senkpiehl I, Marget M, Wedler M, et al. HLA-DRB1 and anti-cyclic citrullinated peptide antibody production in rheumatoid arthritis. Int Arch Allergy Immunol. 2005;137(4):315-318. |
| 10425. | Lundberg K, Nijenhuis S, Vossenaar ER, et al. Citrullinated proteins have increased immunogenicity and arthritogenicity and their presence in arthritic joints correlates with disease severity. Arthritis Res Ther. 2005;7(3):R458-R467. |
| 10508. | Aho K, Koskenvuo M, Tuominen J, Kaprio J. Occurrence of rheumatoid arthritis in a nationwide series of twins. J Rheumatol . 1986 Oct;13(5):899-902. |
| 10589. | Osler W. The Principles and Practice of Medicine. New York, NY: D. Appleton and Company; 1892. |
| 10646. | Deighton CM, Walker DJ, Griffiths ID, Roberts DF. The contribution of HLA to rheumatoid arthritis. Clin Genet. 1989;36(3):178-182. |
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