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• Modifying risk factors to prevent RA
  Marie Falahee, Karim Raza
  Published on: 8 June 2021
• Correspondence on “Rheumatoid arthritis prevention: any takers?”
  Wilson Bautista-Molano
  Published on: 25 May 2021

• Published on: 8 June 2021

  Modifying risk factors to prevent RA

  • Marie Falahee, Lecturer in Behavioral Rheumatology University of Birmingham
  • Other Contributors:
    • Karim Raza, Professor of Rheumatology

  We would like to thank Prof Wilson Bautista-Molano for his interest in our Editorial and for his insightful comments on it. As Prof Bautista-Molano highlights, a number of risk factors for RA have been identified, including smoking, periodontitis and a high BMI. Data that modifying these will have major positive health benefits, including on cardiometabolic outcomes, are strong. It is also tempting to speculate that modifying these will reduce the likelihood of RA development in individuals at risk.

  In designing studies to assess this, it is important to consider when, during the development of RA, these risk factors may exert their effects. For example, data suggest that cigarette smoking may drive the development of ACPA, whereas the transition from ACPA positivity to RA may be dependent upon a different ‘second hit’ (1). If this is indeed the case, then smoking cessation would be relevant as a primary preventive strategy for RA but may be less useful (at least in the context of RA development) when employed as a secondary preventive strategy in ACPA positive individuals (2).

  Assessing the impact of lifestyle and environmental modification on RA development in seronegative first-degree relatives (FDRs) of RA patients (or seronegative individuals identified as being at high risk on the basis of specific genetic / environmental risk factors) will be challenging. A relatively low rate of RA development, and the fact that those who develop RA may not develop i...

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  We would like to thank Prof Wilson Bautista-Molano for his interest in our Editorial and for his insightful comments on it. As Prof Bautista-Molano highlights, a number of risk factors for RA have been identified, including smoking, periodontitis and a high BMI. Data that modifying these will have major positive health benefits, including on cardiometabolic outcomes, are strong. It is also tempting to speculate that modifying these will reduce the likelihood of RA development in individuals at risk.

  In designing studies to assess this, it is important to consider when, during the development of RA, these risk factors may exert their effects. For example, data suggest that cigarette smoking may drive the development of ACPA, whereas the transition from ACPA positivity to RA may be dependent upon a different ‘second hit’ (1). If this is indeed the case, then smoking cessation would be relevant as a primary preventive strategy for RA but may be less useful (at least in the context of RA development) when employed as a secondary preventive strategy in ACPA positive individuals (2).

  Assessing the impact of lifestyle and environmental modification on RA development in seronegative first-degree relatives (FDRs) of RA patients (or seronegative individuals identified as being at high risk on the basis of specific genetic / environmental risk factors) will be challenging. A relatively low rate of RA development, and the fact that those who develop RA may not develop it for many years, suggests that a trial would require a large sample size and/or a long follow-up duration. Furthermore, careful consideration would need to be given to the design of the intervention, for example to facilitate adherence to behavioural change, and also to the choice of an appropriate control group. Despite these challenges, qualitative data suggest that FDRs would be receptive to interventions focussed on changing lifestyle factors and that many would prefer this approach over pharmaceutical intervention (3). Whilst a qualitative study has identified challenges to the recruitment of patients with established RA to a trial assessing whether treatment of periodontitis improves RA outcomes (4) many of the issues identified (e.g. difficulty maintaining oral hygiene during episodes of RA flare) will be less relevant to individuals in the at risk stage. We thus agree with Prof Bautista-Molano that research to assess the impact of treating periodontitis, and of modifying other risk factors for RA, should be considered by the rheumatology community as part of an approach to reducing the risk of this common and debilitating disease.
  References
  1. Catrina A, Krishnamurthy A, Rethi B. Current view on the pathogenic role of anti-citrullinated protein antibodies in rheumatoid arthritis. RMD open. 2021;7.
  2. Raza K, Klareskog L, Holers VM. Predicting and preventing the development of rheumatoid arthritis. Rheumatology. 2016;2016 Jan; 55(1): 1–3.
  3. Simons G, Stack RJ, Stoffer-Marx M, Englbrecht M, Mosor E, Buckley CD, et al. Perceptions of first-degree relatives of patients with rheumatoid arthritis about lifestyle modifications and pharmacological interventions to reduce the risk of rheumatoid arthritis development: a qualitative interview study. BMC Rheumatol. 2018;2:31.
  4. Serban S, Dietrich T, Lopez-Oliva I, de Pablo P, Raza K, Filer A, et al. Attitudes towards Oral Health in Patients with Rheumatoid Arthritis: A Qualitative Study Nested within a Randomized Controlled Trial. JDR Clin Trans Res. 2019;4(4):360-70.

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  Conflict of Interest:
  KR has received research funding from AbbVie and Pfizer and and honoraria/consultancy fees from AbbVie, Sanofi, Lilly, Bristol-Myers Squibb,UCB, Pfizer, Janssen and Roche Chugai
  
  MF declares no competing interests

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• Published on: 25 May 2021

  Correspondence on “Rheumatoid arthritis prevention: any takers?”

  • Wilson Bautista-Molano, Rheumatologist 1. Rheumatology Section, University Hospital Fundación Santa Fe de Bogotá, Bogotá, Colombia 2. School of Dentistry, Universidad

  Correspondence on “Rheumatoid arthritis prevention: any takers?”
  We read with great and special interest the editorial recently published in Rheumatic and Musculoskeletal Diseases by Falahee and Raza. 1 The authors clearly and elegantly state the clinical context in relation to current and potential interventions aimed to delay the onset, reduce the likelihood, or mitigate the severity of rheumatoid arthritis (RA). In addition, the authors present some data based on the perspectives and preferences of individuals who had participated in clinical trials aimed to achieve RA prevention and, on the challenges, related to recruitment for the research community as well. 2
  Preventive strategies targeting RA—especially in the preclinical phases—have recently been developed. Currently, this is an exciting field of research on chronic diseases and more specifically in the field of rheumatology to delineate interventions to modify or at least to delay the onset of RA. There is information provided in the literature related to assessing therapeutic approaches based on pharmacological interventions, such as glucocorticoids, 3 methotrexate, 4 hydroxychloroquine, 5 statins, 6 B cell directed therapy 7 and T-cell co-stimulation modulation. 8
  In contrast, studies on non-pharmacological preventive strategies in high-risk populations for RA are scarce. Thus, some cohort studies are exploring the efficacy of the modification of risk factors previously established as potentia...

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  Correspondence on “Rheumatoid arthritis prevention: any takers?”
  We read with great and special interest the editorial recently published in Rheumatic and Musculoskeletal Diseases by Falahee and Raza. 1 The authors clearly and elegantly state the clinical context in relation to current and potential interventions aimed to delay the onset, reduce the likelihood, or mitigate the severity of rheumatoid arthritis (RA). In addition, the authors present some data based on the perspectives and preferences of individuals who had participated in clinical trials aimed to achieve RA prevention and, on the challenges, related to recruitment for the research community as well. 2
  Preventive strategies targeting RA—especially in the preclinical phases—have recently been developed. Currently, this is an exciting field of research on chronic diseases and more specifically in the field of rheumatology to delineate interventions to modify or at least to delay the onset of RA. There is information provided in the literature related to assessing therapeutic approaches based on pharmacological interventions, such as glucocorticoids, 3 methotrexate, 4 hydroxychloroquine, 5 statins, 6 B cell directed therapy 7 and T-cell co-stimulation modulation. 8
  In contrast, studies on non-pharmacological preventive strategies in high-risk populations for RA are scarce. Thus, some cohort studies are exploring the efficacy of the modification of risk factors previously established as potential contributors to disease initiation and progression. In this context, potential preventive strategies, such as control of body weight,9 nutritional habits,10 education11, and smoking cessation,12 have been proposed as potential targets. Clinical trials demonstrating a significant preventive effect for lifestyle or risk factor modification are difficult to perform. Therefore, more investigations in this area are needed to properly define preventive treatment options in high-risk populations to translate them into specific interventions.13
  In addition, to the potential strategies defined by Falahhe et al., there is a missing ‘taker’ in the room that may be a cost-effective and non-pharmacological intervention to be considered in this approach to potentially prevent the development of RA. Periodontitis is a chronic inflammatory condition characterised by the progressive destruction of the periodontal ligament and alveolar bone.14 Periodontal disease is a common worldwide and inflammatory condition that has been considered to be associated with other systemic diseases, such as diabetes mellitus and cardiovascular disease.15 In the repertoire of conditions potentially associated with periodontal diseases, there is ample data supporting the strong association between periodontitis as a factor associated with developing RA. Many studies have reported that the presence of RA has been associated not only with an increased prevalence of periodontitis but also with a significant inflammatory periodontal involvement even in the early phase of the disease.16 Similarly, periodontitis has been considered to be a condition influencing the risk of developing RA in first-degree relatives17 and to be related to the progression of inflammatory involvement in RA as well.18
  In an era of precision and personalised medicine, one could expect that targeting individuals in the preclinical phases of RA—either pharmacologically and/or through risk factor modifications—may optimise prevention. Hence, first-degree relatives of RA patients may constitute an interesting population to be targeted to evaluate the impact and/or favourable effect of preventive measures, including oral health interventions and periodontal treatment. Information is lacking in the literature in assessing the effectiveness of oral interventions and their impacts on the preclinical phases of RA. Therefore, it will be highly valuable for the academic community to consider the modulation of a periodontal inflammatory condition as a plausible and cost-effective measure to modulate the beginning and the development of RA.

  References

  1. Falahee M, Raza K. Rheumatoid arthritis prevention: any takers? RMD Open 2021;7:e001633. doi:10.1136/rmdopen-2021-001633
  2. van Boheemen L, van Schaardenburg D. Predicting rheumatoid arthritis in at risk individuals. Clin Ther 2019; 41:1286–98
  3. Bos WH, Dijkmans BA, Boers M, van de Stadt RJ, van Schaardenburg D. Effect of dexamethasone on autoantibody levels and arthritis development in patients with arthralgia: a randomised trial. Ann Rheum Dis 2010; 69:571–574
  4. van Dongen H, van Aken J, Lard LR, Visser K, Ronday HK, Hulsmans HM, et al. Efficacy of methotrexate treatment in patients with probable rheumatoid arthritis: a double-blind, randomized, placebo-controlled trial. Arthritis Rheum 2007; 56:1424–1432
  5. Strategy to prevent the onset of Clinically- Apparent rheumatoid arthritis (StopRA). Available: http://clinicaltrials.gov/ct2/show/
  NCT02603146
  6. Van Boheemen L, Turk SA, Van Beers - Tas MH, et al. AB0230 Statins to Prevent Rheumatoid Arthritis: Inconclusive Results of the STAPRA Trial. Ann Rheum Dis 2020; 79:1415-1416
  7. Gerlag DM, Safy M, Maijer KI, et al. Effects of B- cell directed therapy on the preclinical stage of rheumatoid arthritis: the PRAIRI study. Ann Rheum Dis 2019; 78:179–85.
  8. Al- Laith M, Jasenecova M, Abraham S, et al. Arthritis prevention in the pre-clinical phase of RA with abatacept (the APIPPRA study): a multi centre, randomised, double-blind, parallel group, placebo-controlled clinical trial protocol. Trials 2019; 20:429.
  9. Deane KD, Demoruelle MK, Kelmenson LB, Kuhn KA, Norris JM, Holers VM. Genetic and environmental risk factors for rheumatoid arthritis. Best Pract Res Clin Rheumatol 2017; 31:3-18
  10. Zaccardelli A, Friedlander HM, Ford JA, Sparks JA. Potential of lifestyle changes for reducing the risk of developing rheumatoid arthritis: is an ounce of prevention worth a pound of cure? Clin Ther 2019; 41:1323–1345
  11. Sparks JA, Iversen MD, Miller Kroouze R, Mahmoud TG, Triedman NA, Kalia SS, et al. Personalized risk estimator for rheumatoid arthritis (PRE-RA) family study: rationale and design for a randomized controlled trial evaluating rheumatoid arthritis risk education to first-degree relatives. Contemp Clin Trials 2014; 39:145–157.
  12. Liu X, Tedeschi SK, Barbhaiya M, Leatherwood CL, Speyer CB, Lu B, et al. Impact and timing of smoking cessation on reducing risk of rheumatoid arthritis among women in the nurses’ health studies. Arthritis Care Res 2019; 71:914–924
  13. Alpizar-Rodriguez D, Finckh A. Is the prevention of rheumatoid arthritis possible? Clin Rheumatol. 2020; 39:1383-1389
  14. Page RC, Kornman KS. The pathogenesis of human periodontitis: an introduction. Periodontol 2000 1997;14:9–11
  15. Qin X, Zhao Y, Guo Y. Periodontal disease and myocardial infarction risk: A meta-analysis of cohort studies. Am J Emerg Med. 2021; 8; 48:103-109
  16. Rovas A, Puriene A, Punceviciene E, Butrimiene I, Stuopelyte K, Jarmalaite S. Associations of periodontal status in periodontitis and rheumatoid arthritis patients. J Periodontal Implant Sci. 2021; 51:124-134
  17. Unriza-Puin S, Bautista-Molano W, Lafaurie GI, et al. Are obesity, ACPAs and periodontitis conditions that influence the risk of developing rheumatoid arthritis in first-degree relatives? Clin Rheumatol 2017;36:799–806
  18. Lundberg K, Wegner N, Yucel-Lindberg T, Venables PJ. Periodontitis in RA the citrullinated enolase connection. Nat Rev Rheumatol 2010; 6:727–730

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  Conflict of Interest:
  None declared.

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