I was fascinated when, some years ago, I first encountered the notion that rheumatoid arthritis (RA) was a new disease. The resultant focus by some rheumatologists to look for examples of RA in antiquity helped rekindle my own interest in the arts.1,2
The Historical View
The first series of patients with classic RA appeared in 1800, described by a French medical student, Augustin-Jacob Landre-Beauvais, in his doctoral thesis, as recounted by Short in 1974. The term “rheumatoid arthritis” was introduced by Garrod in 1859.3,4 Watson, Buchanan, and Murdoch speculated further that RA, this new disease in history, was still evolving and would disappear perhaps by end of this century.5 Indeed, these intriguing essays provoked efforts to identify earlier examples of RA in art, literature, history, archeology, and paleopathology. Despite rather extensive investigations, it can be argued that RA was at least uncommon before the 19th century.6
What, then, might this suggest about the etiology or pathogenesis of RA? Buchanan and Murdoch wondered about a “slow virus” infection. Others thought about other microbes or lifestyle changes or consequences of the industrial revolution. Gerry Weissmann, a brilliant and imaginative thinker, and colleagues—including my friend and former colleague Elliot Rosenstein—hypothesized that importation of sugar from the West Indies to Europe and a resultant epidemic of periodontal disease was linked to the appearance of RA. The connection, Porphyromonas gingivalis, occuring in peridontitis, produces peptidyl arginine deiminase, which citrullinates proteins leading to inflammation and consequent RA.7-12
What’s the evidence? There is a link between sugar, periodontal disease, and RA. Weissmann has summarized the information about sugar trade between the Americas and Europe.8,9 West Indian sugar trade peaked in c. 1755–1765. Thereafter, the British government taxed molasses and sugar, “the white gold of the upper class.”
Of course, we know of the colonial reaction in 1773, protesting taxation without representation and dumping tea and sugar into Boston Harbor. By 1771, this tax netted England 326,000 pounds (revenue); by 1800, sugar consumption was 160 million pounds per year, providing 3 million pounds’ revenue by 1815. Tea flavored with sugar had reached the middle class.
Prime Minister Gladstone finally abolished the tax in 1874, in order to make sugar accessible to ordinary British people. It was during that time that tooth decay and periodontal disease increased and RA appeared.8,9
What the Research Shows
What is the connection between periodontal disease and RA? They share pathogenetic mechanisms and immunologic and pathologic findings. Elliot and his wife Laura Kushner (a periodontologist), together with Robert Greenwald and Gerry Weissmann, have summarized these. Both share HLA-DRR4. Oral pathogens promote elaboration of rheumatoid factors. Immunologic events include generation of immune complexes and complement with phagocyte activation. And P. gingivalis uniquely possesses the enzyme peptidyl arginine deiminase (PAD), which can deiminate arginine in fibrin.7 Others have reported the association of the two disorders and certain of their clinical manifestations.13-17
What is RA’s connection with citrullination and anticitrullinated protein (ACPA) antibodies? The fundamental role of ACPAs and RA is now accepted, with considerable attention now to investigating their role in pathogenesis of disease (which is mostly beyond the scope of this discussion). ACPAs precede RA, are predictive of RA, and have been found in serum and synovial immune deposits in patients with early and established disease.18-26 Antibodies to human citrullinated alpha enolase and P. gingivalis enolase cross react, suggesting important linkage and/or molecular mimicry in disease pathogenesis.27 Studies of the repertoires of ACPAs in RA patients with and without periodontal disease showed distinct ACPA reactivities compatible with the possibility that uncitrullinated peptide breaks tolerance in periodontal disease with epitope spreading to citrullinated epitopes. This, in some patients, might eventuate in or contribute to RA.28
Further, patients with RA had antibodies to P. gingivalis more frequently than controls, although less frequently than patients with periodontal disease, and with correlations to RA-related autoantibody and CRP levels.29 And, in patients with RA, both patients and their relatives had antibodies to P. gingivalis, which were associated with ACPA.30 These observations are consistent with a role for P. gingivalis in RA, but do not themselves represent proof, as other explanations for these data are possible.
Finally, are there experimental studies examining these putative associations? These were interesting. In one study, mice (DR4-IE transgenic, C57BL/6, and control) were immunized with recombinant human alpha enolase and P. gingivalis enolase, citrullinated or uncitrullinated; DR4-IE subjects developed arthritis and antibodies to citrullinated and unmodified human alpha enolase and arginine-bearing control peptide. These data support a possible role for P. gingivalis enolase in RA.31 In other experiments, using a model of chronic antigen-induced arthritis, it was found that the model mimicked several features of RA and periodontal disease, with associated manifestations of both disorders.32
Whether or not importation of sugar from the Americas led to emergence of RA in Europe may never be known. But, certainly, RA and periodontal disease share common clinical, immunopathologic, serologic, and epidemiologic features. Several lines of evidence intersect at P. gingivalis and its peptidyl arginine deiminase, suggesting a role in the immunopathogenesis of RA.
Dr. Panush is professor of medicine, division of rheumatology, department of medicine, Keck School of Medicine, University of Southern California in Los Angeles.
- Panush RB, Caldwell JR, Panush RS. Corot’s ‘gout’ and a ‘gypsy girl’. JAMA. 1990;204:1136-1138.
- Panush RS. Rheum With A View. Why I sometimes read poetry instead of medicine—and why you should, too. The Rheumatologist, November 2011, pp 47-49.
- Short C. The antiquity of rheumatoid arthritis. Arthritis Rheum. 1974;17:193-205.
- Garrod AB. The Nature and Treatment of Gout and Rheumatic Gout. London, Walton and Maberly, 1859.
- Buchanan WW, Murdoch RM. That rheumatoid arthritis will disappear. J Rheum. 1979;6:324-329.
- Appelboom T, ed. Art, History and Antiquity of Rheumatic Diseases. Elsevier, Brussels, Erasmus Foundation, 1987.
- Rosenstein ED, Greenwald RA. Kushner LJ, Weissmann G. Hypothesis: The humoral immune response to oral bacteria provides a stimulus for the development of rheumatoid arthritis. Inflammation. 2004;28:311-318.
- Weissmann G. Is sugar the missing link in RA? Internal Medicine News. 2006;39(16):11.
- Weissmann G. The pathogenesis of rheumatoid arthritis. Bull NYU Hospital for Joint Diseases. 2006;64:12-15.
- Rosenstein ED, Weissmann G, Greenwald RA. Porphyromonas gingivalis, periodontitis and rheumatoid arthritis. Med Hypotheses. 2009;73:457-458.
- Kubetin SK. Single enzyme implicated in periodontitis link to RA. Rheumatology News. May 1, 2010, p 24.
- Rosenstein ED, Scher JU, Bretz WA, Weissmann G. Rheumatoid arthritis and periodontitis: A possible link via “citation.” Anaerobe. 2012;18:162.
- Gleissner C, Willershausen B, Kaesser U, Bolten WW. The role of risk factors for periodontal disease in patients with rheumatoid arthritis. Eur J Med Res. 1998;3:387-392.
- Mercado FB, Marshall RI, Klestov AC, Bartold PM. Relationship between rheumatoid arthritis and periodontitis. J Periodontol. 2001;72:779-787.
- Loyola-Rodrigues JP, Martinez-Martinez RWE, Abud-Mendoza C, Patino-Marin BN, Seymour GJ. Rheumatoid arthritis and the role of oral bacteria. J Oral Microbiol. 2010; 2:5784.
- Routsias JG, Goules JD, Charalampakis G, Pikazis D. Autopathogenic correclation of peridontitis and rheumatoid arthritis. Rheumatology. 2011;50:1189-1193.
- De Smit M, Westra A, Vissink A, Doornbos-van der Meer B, van Winkelhoff AJ, Brouwer E. Patients with rheumatoid arthritis and periodontitis have higher disease activity and a more pronounced antibody response against Porphyromonas gingivalis. Ann Rheum Dis. 2012;71:A26-A27.
- van Venrooij WJ, Pruijn GJ. Citrullination: A small change for a protein with great consequences for rheumatoid arthritis. Arthritis Res. 2000;2:249-251.
- Van Venrooij WJ, Pruijin GJ. An important step towards completing the rheumatoid arthritis cycle. Arthritis Res Ther. 2008;10:117.
- Willemze A, Ioan-Facsinay A, El-Gabalawy H. Anti-citrullinated protein antibody response associated with synovial immune deposits in a patient with suspected early rheumatoid arthritis. J Rheum. 2008;35:2282-2284.
- Lundberg, Kinloch A, Fisher BA, et al. Antibodies to citrullinated alpha-enolase peptide 1 are specific for rheumatoid arthritis and cross-react with bacterial enolase. Arthritis Rheum. 2008;58:3009-3019.
- Demoruelle MK, Deane K. Antibodies to citrullinated protein antigens (ACPAs): Clinical and pathophysiologic significance. Curr Rheum Rep. 2011;13:421-430.
- Willemze A, Trouw LA, Toes RE, Huizinga TWJ. The influence of ACPA status and characteristics on the course of RA. Nature Rev Rheum. 2012;8:144-152.
- Darrah E, Rosen A, Giles JT, Andrade F. Peptidylarginine deiminase 2, 3 and 4 have distinct specificities against cellular substrates: Novel insights into autoantigen selection in rheumatoid arthritis. Ann Rheum Dis. 2012;71:92-98.
- Brink M, Ronnelid J, Hannson M, et al. Antibodies against native collagen and citrullinated proteins precede the development of rheumatoid arthritis with a consecutive pattern. Ann Rheum Dis. 2012; 71:A22.
- Ponchel F, Hensor EMA, Parmar R, et al. Predicting the evolution of inflammatory arthritis in ACPA-positive individuals: Can T cell subset help? Ann Rheum Dis. 2012;71:A21-A22.
- Lundberg K, Wegner N, Yucel-Lindberg T, Venables PJ. Periodontitis in RA-the citrullinated enolase connection. Nat Rev Rheumatol. 2010; 6:727-730.
- De Pablo P, Dietrich T, Chapple I, et al. Is periodontal disease a risk factor for rheumatoid arthritis? The anticitrullinated antibody repertoire in periodontal disease. Ann Rheum Dis. 2012;71:28-29.
- Mikuls TR, Payne JB, Reinhardt RA, et al. Antibody responses to Porphyromonas gingivalis (P. gingivalis) in subjects with rheumatoid arthritis and periodontitis. Int Immunopharmacol. 2009;9:38-42.
- Hitchon CA, Chandad F, Ferucci ED, et al. Antibodies to Porphyromonas gingivalis are associated with anticitrullinated protein antibodies in patients with rheumatoid arthritis and their relatives. J Rheumatol. 2010;37:1105-1112.
- Kinloch AJ, Alzabin S, Brintnell W, et al. Immunization with Porphyromonas gingivalis enolase induces autoimmunity to mammalian alpha-enolase and arthritis in DR4-IE-transgenic mice. Arthritis Rheum. 2011;12:3818-3823.
- Queiroz-Junior CM, Madeura FM, Coelho FM, et al. Experimental arthritis triggers periodontal disease in mice: Involvement of TNF-alpha and the oral microbiota. J Immunol. 2011;187:3821-3830.