Preventing Rheumatoid Arthritis? The Links to Mucosa

Physicians usually view rheumatoid arthritis (RA) as an autoimmune inflammatory disease arising in a joint. However, research published within the past year has increased and refined support for the concept that this autoimmunity may arise initially in mucosal surfaces, predominantly the lung, the oral cavity, and the digestive system, prompted by the presence of microbes.

Much of this evidence focuses on the presence of antibodies to citrullinated peptides at mucosal surfaces of patients with early RA or individuals at risk of RA. If substantiated, this scenario should have a considerable impact on the way rheumatologists manage RA, much as the link to H. pylori transformed our understanding of the origin of gastric ulcers.

The picture of RA etiology that is emerging leads us to inquire whether it and similar autoimmune conditions may eventually become preventable diseases, with prevention approaches focusing perhaps on mucosal inflammation and infection, rather than on joint disease.

Lung Disease

Several studies published in 2012 have strengthened the association between lung disease and preclinical RA.

•   Individuals not diagnosed with RA but at high risk, possessing antibodies to citrullinated peptides (CCP+) or at least two isotypes of rheumatoid factor antibodies, showed a high prevalence of disease in regions of the airway associated with inflammatory reactions (bronchial wall thickening, bronchiectasis, bronchiolitis). In this study, 5 of 42 subjects went on to develop RA within a median of 14 months.¹
•   A cohort of 74 CCP+ individuals with respiratory disease but no evidence of RA showed lung phenotypes similar to those of RA patients, and a few have gone on to develop RA.²
•   Among CCP+ patients with very early RA, inflammatory lung changes appear in images from high-resolution computed tomography. Lung biopsies of these same patients reveal citrullinated peptides in a majority of samples.³
•   Pilot results from a study initiated by one of us (KD), among subjects with established RA and others at risk due to a family history of RA, showed the presence of at least one RA-related antibody in the sputum of more than one-third (8/21) of seronegative subjects with a family history of RA. Sputum originates in the airways, the location of inflammatory response within the lung, supporting the idea that these autoimmune phenomena may arise within the lung and then disseminate to the joints via the circulation.⁴Periodontal Disease

In addition to the above lung findings, other evidence emerging in the past year adds to the increasingly convincing evidence regarding periodontal disease, and the microbe Porphyromonas gingivalis that most often causes it, as important factors in RA pathogenesis.

•   Two intriguing case control studies, both involving DMARD-naive patients with early-onset RA, show a striking increase of periodontitis in these populations.^5,6
•    Porphyromonas gingivalis may play a role in establishing tolerance by introducing new epitopes that incite an autoantibody response. For instance, this microbe has been found to have a unique ability to citrullinate peptides by producing the enzyme peptidylarginine deaminase (PPAD), through the post-translational modification of arginine- containing peptides.⁷
•    Expression of RA-related autoantibodies including  anti-CCP antibodies and rheumatoid factor in individuals at increased risk for developing RA is associated with expression of antibodies to P. gingivalis.⁸

An ongoing study supported by the American College of Rheumatology has enrolled 618 patients with RA and controls with osteoarthritis to examine  whether infection with P. gingivalis is associated with RA by observing the periodontal status of these individuals. (This is a larger challenge than anticipated, because so many patients with existing RA have lost so many teeth already). It is also examining banked sera from RA patients to look for novel proteins expressed by the microorganism that may drive autoimmunity in RA, and to determine whether immune responses to these factors predict future RA.

The circumstantial evidence for the scenario that begins with autoimmunity in the mucosa and ends with RA is compelling. There are marked similarities in histology, anatomy, and inflammatory pathways between the inflammatory disorders that involve mucosal tissue and those that involve the joints, and they also share some risk factors, including factors both genetic (HLA types) and environmental (smoking and infection). However, numerous questions remain to be resolved:

1. Is the association driven by shared risk factors? Because the association with smoking is not universal, exactly what role does it play in this sequence of events?
2. How does the autoimmunity move from the mucosal tissue to the joints (if it does)? Through shared antigens, epitope spread, immune complexes, or all of the above?
3. Could one mucosal site influence another? For instance, could periodontal disease contribute to lung inflammation? Does gastrointestinal inflammation influence genitourinary tract disorders?

The current attention paid to P. gingivalis is well justified, in that it is a predominant cause of periodontitis. However, the microbiome at the mucosal surface is composed of numerous bacteria that have shown a complex relationship promoting their mutual survival. Whether elements of this collaboration also promote auto-immunity is a matter that deserves further study from the viewpoint of systems biology. 

Natural history studies of rheumatoid arthritis are also crucial to answering these questions. They are expensive and difficult, but worthwhile if we believe that understanding the origins of this disease is important to its prevention and effective treatment.

This review is adapted from presentations by the authors at the 2012 annual meeting of the American College of Rheumatology.

References:

REFERENCES

1. Demoruelle MK, Weisman MH, Simonian PL. Brief report: airways abnormalities and rheumatoid arthritis-related autoantibodies in subjects without arthritis: early injury or initiating site of autoimmunity?Arthritis Rheum. (2012) Jun;64(6):1756-61
2. Fischer A, Solomon JJ, du Bois RM, et alLung disease with anti-CCP antibodies but not rheumatoid arthritis or connective tissue diseaseRespir Med. (2012) Jul;106(7):1040-7.
3. Reynisdottir G, Karimi G, Ytterberg J et al. Early Signs of Subclinical Inflammation and Local Antibody Production in Early Rheumatoid Lungs. American College of Rheumatology 2012 Annual Meeting. Abstract #1491
4. Willis VC, Demoruelle MK, Derber LA et al. <a href=" Abstract #423 http://www.rheumatology.org/apps/MyAnnualMeeting/ExploreMeeting/AbstractDetail?abstractId=29747>Autoantibodies in Patients with Established Rheumatoid Arthritis and Subjects At-Risk for Future Clinically Apparent Disease. 5. Scher JU, Ubeda C, Equinda M et al.Periodontal disease and the oral microbiota in new-onset rheumatoid arthritis.Arthritis Rheum. (2012) Oct;64(10):3083-94.
6. Potikuri D, Dannana KC, Kanchinadam S et alPeriodontal disease is significantly higher in non-smoking treatment-naive rheumatoid arthritis patients: results from a case-control study.Ann Rheum Dis. (2012) Sep;71(9):1541-4
7. Mikuls TR, Thiele GM, and JB Payne. Periodontitis and Porphyromonas gingivalis: Possible Roles in Rheumatoid Arthritis Risk and Progression.Int J Clin Rev (2012) 04:01
8. Mikuls TR, Thiele GM, Deane KD et al. Porphyromonas gingivalis and disease-related autoantibodies in individuals at increased risk of rheumatoid arthritis.Arthritis Rheum. (2012) 64(11):3522-30