Determining the Right Time for the Right Treatment—Application to Preclinical Rheumatoid Arthritis | Geriatrics | JAMA Network Open | JAMA Network
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Invited Commentary
June 7, 2019

Determining the Right Time for the Right Treatment—Application to Preclinical Rheumatoid Arthritis

Author Affiliations
  • 1Santé Ingéniérie Biologie Saint-Etienne, Institute National de la Santé et de la Rechereche Médicale, U1059, Université de Lyon, Saint-Etienne, France
  • 2Department of Rheumatology, Hôpital Nord, University Hospital Saint-Etienne, Saint-Etienne, France
JAMA Netw Open. 2019;2(6):e195358. doi:10.1001/jamanetworkopen.2019.5358

Preclinical rheumatoid arthritis (RA) is an emerging concept but lacks clear definition. The concept is based on immunological abnormalities that appear up to 10 years before the onset of clinical RA. The recognition of preclinical RA opens opportunities for improving outcomes of patients who subsequently develop RA. This could be the next huge challenge after the window of opportunity and the treat to target strategy, which revolutionized the management and the outcome of RA in the past 20 years.1,2 The next steps should be exploring ways to prevent RA onset in a subgroup of people with high risk of RA. Improving the understanding of RA pathogenesis is necessary to determine the various risk factors and select the right subset of people with high risk of developing RA.

The study by Mankia et al3 reported new data that periodontal disease (PD) associated with Porphyromonas gingivalis is more likely to be present in people at risk of having RA and in people with early RA than in healthy control individuals. Periodontal disease is characterized by the loss of tooth-supporting tissues, with prevalence of severe forms of approximately 10%.4 The association of PD with RA is not new, and PD and RA share similar genetic and environmental factors.5 However, a specific characteristic of RA is the development of anti–cyclic citrullinated peptide (CPP) some years before onset of RA. In addition, the risk of RA is greater with more severe PD,6 but the missing link between these 2 diseases is suspected to be variations in the oral microbiome. Among all bacteria from the oral microbiome, 2 bacteria have been previously described to induce citrullinated proteins: P gingivalis, which has a specific deiminase enzyme, and Aggregatibacter actinomycetemcomitans, which induces citrullination in neutrophils by neutrophil extracellular trap activation and release through leukotoxin A.7 The emerging hypothesis for the association of PD with RA is that severe PD induces the production of an excess of citrullinated protein. This excess causes a break of tolerance with anti-CPP induction.

A 2015 study by Seror et al8 reported increased P gingivalis in patients with early stages of RA, and a 2019 study9 using a rat model confirmed the specific involvement of P gingivalis in arthritis. After an induction of PD via P gingivalis, a preclinical phase with immunologic abnormalities was observed, including anti-CCP, high interleukin 17A, and the chemokine CXCL 1 in the blood similar to preclinical RA. After 8 months, Courbon et al9 observed arthritis with bone damage similar to the damage in the rat adjuvant-induced arthritis model at the time of the arthritis onset.

Since the diseases are associated,5 therapy for 1 disease may be effective in preventing or improving outcomes in the other. In addition to reducing RA activity, RA therapy (rituximab or tocilizumab) also decreases the gingival inflammation and gingival bone destruction associated with PD.5 In contrast, infliximab worsens gingival inflammation but prevents gingival bone loss.5 Despite many studies, including a 2-center randomized clinical trial from 2019,4 no clear evidence of intensive PD treatment (ie, full-mouth nonsurgical scaling and root planning with or without antibiotics) on RA disease activity has been reported in established RA.

Considering that PD may precede RA, it is not surprising that targeting PD in patients with established RA is too late to influence the RA activity. The study by Mankia et al3 provides more information on this topic, as the authors confirmed increased prevalence of PD in patients with RA associated with anti-CCP. They provide new evidence for the association of PD with preclinical RA with anti-CCP as well as a clear involvement of P gingivalis compared with A actinomycetemcomitans in this population. This reinforces the hypothesized sequence that P gingivalis induces PD with anti-CCP development in patients with preclinical RA.5 Accordingly, Mankia et al3 suggested that the right time to target PD to prevent the occurrence of RA should be when PD is associated with anti-CCP in preclinical RA. This should be the right time to reduce the periodontal pathogenic load followed by a reduction or clearing of anti-CCP. However, it will likely be too late if effects of anti-CCP have already occurred.

The best solution to explore may be to directly target P gingivalis, for example, through vaccination. However, an easier method to test would be to improve oral hygiene and care worldwide to prevent PD and RA. Preventing PD could also prevent a spectrum of systemic diseases associated with PD, including Alzheimer disease.10

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Article Information

Published: June 7, 2019. doi:10.1001/jamanetworkopen.2019.5358

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2019 Marotte H. JAMA Network Open.

Corresponding Author: Hubert Marotte, MD, PhD, Department of Rheumatology, Hôpital Nord, University Hospital Saint-Etienne, 42055 Saint-Etienne Cedex 02, France (

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