Multiple observational studies [2
] and experimental studies in laboratory animals have established an association between RA and periodontitis [29
]. RA and periodontitis share many similarities in pathophysiology and clinical progression [2
]. Early studies suggested that non-steroidal inflammatory agents might hold promise in controlling the progression of these disorders; however, this class of drugs has shown minimal or no effect on RA [31
] and periodontitis [32
]. The development of new anti-rheumatic agents, including DMARDs and biologics, that target specific molecular factors in the inflammatory cascade, offers the potential to slow or arrest the progression of these disorders [33
In this systematic review, we examined the relative effect of anti-rheumatic agents on the levels of inflammatory biomarkers and periodontal inflammation in RA patients with periodontitis. Of particular interest were studies comparing the periodontal and inflammatory profile of RA patients on different anti-rheumatic agents to otherwise healthy adults with and without periodontitis. Studies were case-controlled in design [16
], using study populations of convenience, with only one study matching for age and gender [25
]. The smoking status of subjects was generally adjusted for in the statistical analysis, although 3 studies did not specify the smoking status of subjects [21
]. RA was diagnosed according to the criteria of the American College of Rheumatology [34
] in all but 3 studies, which did not specify the criteria for diagnosis [21
]. The duration of RA was highly variable, ranging from 1 year to over 25 years; however, the duration from the time of diagnosis or treatment was not provided in 2 studies [22
Currently, non-steroidal anti-inflammatory drugs and steroids are used early in treatment to reduce inflammation and pain and to slow joint damage in RA patients. Disease modifying antirheumatic drugs, including methotrexate, leflunomide, hydroxychloroquine, sulphasalazine, and minocycline, and immunosuppressants are frequently necessary to slow the progression of erosive articular damage over time. The latter drugs, however, are associated with significant risk of liver damage, bone marrow suppression, and severe lung infections [35
]. Biologic therapies targeting cytokines also have been successfully used in controlling RA [35
]. The latter agents block or antagonize the actions of TNF-alpha, which is considered the "master regulator" of the inflammatory response in both RA [36
] and periodontitis [37
Most studies compared RA patients with periodontitis to healthy adults without evidence of destructive periodontal disease [19
]. RA patients were found to have higher plaque scores and BOP scores compared to healthy patients without periodontitis. Of the available studies examining the biomarkers of inflammation, the majority compared GCF or salivary levels rather than serum levels [16
]. Limited comparative data are available on the inflammatory biomarkers in RA patients compared to systemically healthy patients without periodontitis. Levels of IL-1β and TNF-α were found to be higher in the GCF and saliva [17
], but not the serum [23
], in RA patients with periodontitis compared to healthy subjects without periodontitis. Higher levels of TNF-α were found in the saliva [25
] but not the serum [23
] of RA subjects. These latter studies provide limited evidence suggesting that elevations in local but not systemic levels of these inflammatory cytokines are present in RA patients, despite anti-rheumatic treatment, compared to healthy persons without periodontitis. Consistent with elevations in local TNF-α expression, RA patients were also found to have higher BOP scores compared to healthy controls.
RA patients on anti-rheumatic agents were found to exhibit lower local IL-1β and TNF-α levels than otherwise healthy patients with periodontitis. Local IL-4 levels were also found to be lower in RA patients than in periodontitis patients. Limited data suggest that RA patients receiving anti-TNF-α medication may exhibit lower local IL-1β and TNF-α levels as well as less gingival inflammation, based on GI and BOP scores, than patients with periodontitis. However, interpretation of this evidence is necessarily limited due, in part, to both the observational design and small number of studies.
Smoking is a significant modifiable risk factor for periodontitis [38
]. Recent research suggests that long-term smoking markedly increases the risk of RA in men and women [39
]. One possible mechanism for the higher prevalence of periodontitis in RA patients may reflect the increased risk for oral colonization by P. gingivalis
, a causative agent of periodontitis [40
]. These observations are consistent with the hypothesis that P. gingivalis
, which expresses PAD, plays a crucial role in the initiation and/or propagation of periodontitis-associated RA [5
]. In studies included in this meta-analysis, the percentage of RA subjects that smoked ranged from about 7 to 41%; however, 2 studies excluded smokers and 2 studies did not specify the smoking status.
Ortiz et al. [26
] reported that anti-TNF-α therapy without periodontal treatment had no significant effect on the periodontal condition. RA patients receiving periodontal treatment had a significant decrease in the mean RA disease activity score, the erythrocyte sedimentation rate, and serum TNF-α level. However, there was no clinical improvement in these parameters in patients that did not receive periodontal treatment. Anti-TNF-α therapy resulted in a significant improvement in gingival inflammation, BOP scores, and the clinical attachment level [26
]. Pers et al. [27
] evaluated the impact of an anti-TNF-α agent administered over a period of nearly 2 years on the periodontal status of 40 subjects with RA. Clinical attachment loss was significantly reduced after anti-TNF-α treatment, suggesting that TNF-α blockade in RA patients can limit periodontal breakdown. These results are consistent with the hypothesis that anti-TNF-α treatment is effective in improving periodontal status and reducing the biomarkers of inflammation.
RA and periodontitis share many similarities in pathophysiology and clinical progression, suggesting that treatment of RA with anti-rheumatic agents, particularly anti-TNF-α agents, may reduce the progression of destructive periodontal disease. Currently, insufficient evidence is available to determine whether traditional anti-rheumatic agents are beneficial in controlling periodontitis. There are limited data, however, suggesting that anti-TNF-α agents can reduce local production of inflammatory cytokines and periodontal inflammation in RA patients with periodontitis. Future studies are warranted to examine the benefits of TNF-α therapy in controlling periodontal inflammation and breakdown.