Dear Editor:
We read with great interest the editorial by Felson et al. on definitions of remission in rheumatoid arthritis (RA).[1] It gives a comprehensive and historical overview of the development of remission criteria, and provides a well-founded critique of remission criteria based on the 28-joint Disease Activity Score (DAS28). DAS28 has been primarily developed and validated for evaluations at the group level, i.e. for measuring effects in clinical trials. However, in almost forgotten earlier times, when patient remission was rarely achieved, there was a need for a single index, expressing disease activity of the individual patient, and the only instrument available was the 44-joint Disease Activity Score (DAS).[2] When biologicals become available, in many countries of Europe, use of DAS28 as single index of disease activity was also stimulated by health authorities and insurance companies, requiring DAS28 proof of active RA and documented previous treatment failure (or contra-indication) of conventional synthetic DMARDs, before allowing reimbursement of an (expensive) biological drug. Since then, remission has proved to be an achievable goal, and for clinical trials and for individual patients, DAS28 cut-offs have been used for this purpose, especially in Europe, although their limitations for evaluations at the individual patient level have indeed been recognised.[3]
Moreover, we agree with Felson et al. that patient global assessment (PGA) is a valuable assessment. However, we feel compelled to clarify the misunderstanding that seems to persist regarding our relatively simple proposal. We do not suggest merely eliminating PGA from the definitions of remission; we suggest that a second target, based on valid and discriminative patient-reported measures of disease impact, is adopted, in parallel but separated from the existing target for (inflammatory) disease activity, which, we believe, could be refined by the exclusion of PGA. Although Felson et al. cite our paper,[4] they do not depict our proposal for this “Dual Target Strategy” and its conceptual framework, summarized in the conclusions of that paper. Following our proposal, the patient’s perspective would become more valued, rather than being ignored.
We disagree with the interpretation of the evidence provided by Felson et al. to support the concept that PGA should be kept as a component of the ACR/EULAR definitions of remission. Although PGA and measures of clinical disease activity are correlated at high levels of disease activity, contributing to the ability of PGA to distinguish active treatment from placebo in the context of clinical trials, they are only poorly, if at all, correlated at low levels of disease activity,[5, 6] precisely when the practising clinician needs to make difficult decisions regarding escalating or maintaining immunosuppressive/immunomodulatory therapy. Thus, while the inclusion of PGA may facilitate the distinction between treatments in clinical trials, we are concerned regarding the implications of including PGA as an element of composite definitions of remission used to tailor immunosuppressive/immunomodulatory therapy in clinical practice and the potential risk of overtreatment that this entails. As many as 45 to 61% of all patients with RA (in clinical trials[4] and cohort studies,[7] respectively) who are otherwise in remission fail to meet the Boolean definition of remission, solely because of a too high PGA score. These patients, in so-called “PGA-near-remission”, are exposed to the risk of overtreatment, because their disease cannot be improved by additional immunosuppression/immunomodulation. However, they still endure significant impact of non-disease activity manifestations and outcomes of the disease,[8] which were recently touched upon in the EULAR points to consider for the management of difficult-to-treat RA.[9] The use of the ACR/EULAR remission definitions in clinical practice was explicitly predicted in the original 2011 report,[10] and has been extensively adopted as part of the Treat-to-Target strategy. Thus, the implications of these definitions are more extensive than those for clinical trials only.
The assertion that PGA reflects subclinical inflammation is, in our view, unsupported by evidence. We, and in fact, some of the authors of the editorial themselves, have shown no correlation between PGA and joint damage accrual.[11] We have also demonstrated that in patients that are in PGA-near-remission there is no evidence of inflammation in other joints or synovial structures, through extensive ultrasonography assessment.[12] It is difficult to envisage what room is left for the consideration in the editorial that “…the patient global assessment reflects components of disease activity that are otherwise not captured, …as inflammation in joints not included in a 28-joint count, such as the feet and ankles.” This is, therefore, not the reason “why high patient global assessment scores, even when 28-joint counts are low, identify patients at high risk of later functional loss.”[1] This may be simply and better explained by the fact that function is a major determinant of PGA, irrespective of (inflammatory) disease activity, as repeatedly reported.[5, 6, 8, 13] These publications are the basis of our “Dual Target Strategy” proposal, which we hypothesize, may result in more accurate and comprehensive definitions of remission. We proposed the “Dual Target” to comprise (i) biologic remission, which will be sharper and more sensitive to help guide immunosuppressive/immunomodulatory therapy in individual patients in clinical practice, and (ii) patient remission, addressing also all other important aspects of non-disease activity manifestations, outcomes of the disease, and of medication adverse effects (disease impact); thus, more informative than the current one-item PGA. Surely, this approach highlights the importance of patients’ perspective as it ensures that clinicians address both the disease activity and the disease impact aspects accordingly.
In summary, we agree with many of the points made in the editorial by Felson et al., but we feel that it distorts our proposal by omitting to mention the patient remission aspect, which is what makes it a “Dual Target”: a holistic strategy that empowers patients and promotes health by allowing patients to gain greater control over decisions and actions affecting their health, a World Health Organization recommendation, since the Ottawa conference in 1986.

References
1. Felson D, Lacaille D, LaValley MP, et al. Re-examining remission definitions in rheumatoid arthritis: considering the 28-Joint Disease Activity Score, C-reactive protein level and patient global assessment. RMD Open. 2021; dx.doi.org/10.1136/rmdopen-2021-002034.
2. van der Heijde DM, van 't Hof MA, van Riel PL, et al. Judging disease activity in clinical practice in rheumatoid arthritis: first step in the development of a disease activity score. Ann Rheum Dis. 1990;49:916-20.
3. Jacobs JW, Ten Cate DF, van Laar JM. Monitoring of rheumatoid arthritis disease activity in individual patients: still a hurdle when implementing the treat-to-target principle in daily clinical practice. Rheumatology (Oxford). 2015;54:959-61.
4. Ferreira RJO, Welsing PMJ, Jacobs JWG, et al. Revisiting the use of remission criteria for rheumatoid arthritis by excluding patient global assessment: an individual meta-analysis of 5792 patients. Ann Rheum Dis. 2020;80:293-303.
5. Ferreira RJO, Duarte C, Ndosi M, et al. Suppressing Inflammation in Rheumatoid Arthritis: Does Patient Global Assessment Blur the Target? A Practice-Based Call for a Paradigm Change. Arthritis Care Res (Hoboken). 2018;70:369-78.
6. Ferreira RJO, Carvalho PD, Ndosi M, et al. Impact of Patient's Global Assessment on Achieving Remission in Patients With Rheumatoid Arthritis: A Multinational Study Using the METEOR Database. Arthritis Care Res (Hoboken). 2019;71:1317-25.
7. Ferreira RJO, Santos E, Gossec L, et al. The patient global assessment in RA precludes the majority of patients otherwise in remission to reach this status in clinical practice. Should we continue to ignore this? Semin Arthritis Rheum. 2020;50:583-5.
8. Ferreira RJO, Dougados M, Kirwan JR, et al. Drivers of patient global assessment in patients with rheumatoid arthritis who are close to remission: an analysis of 1588 patients. Rheumatology (Oxford). 2017;56:1573-8.
9. Nagy G, Roodenrijs NMT, Welsing PMJ, et al. EULAR points to consider for the management of difficult-to-treat rheumatoid arthritis. Ann Rheum Dis. 2021;10.1136/annrheumdis-2021-220973.
10. Felson DT, Smolen JS, Wells G, et al. American College of Rheumatology/European League against Rheumatism provisional definition of remission in rheumatoid arthritis for clinical trials. Ann Rheum Dis. 2011;70:404-13.
11. Studenic P, Felson D, de Wit M, et al. Testing different thresholds for patient global assessment in defining remission for rheumatoid arthritis: are the current ACR/EULAR Boolean criteria optimal? Ann Rheum Dis. 2020;10.1136/annrheumdis-2019-216529.
12. Brites L, Rovisco J, Costa F, et al. High patient global assessment scores in patients with rheumatoid arthritis otherwise in remission do not reflect subclinical inflammation. Joint Bone Spine. 2021;88:105242.
13. Craig ET, Perin J, Zeger S, et al. What Does the Patient Global Health Assessment in Rheumatoid Arthritis Really Tell Us? Contribution of Specific Dimensions of Health-Related Quality of Life. Arthritis Care Res (Hoboken). 2020;72:1571-8.

Some of the most compelling clinical questions are hardly amenable to experimentation in randomized controlled trials (RCTs). ‘Does vertebroplasty improve health-related quality of life in elderly patients with an acute osteoporotic fracture?’ is one of those questions that was nevertheless challenged in not less than four RCTs recently. The outcome of this challenge was a disappointment for believers in vertebroplasty (VP): one-to-three against VP, and the invasive intervention was discarded from guidelines, as Christian Roux and colleagues have beautifully explained in a recent opinionated review in RMDOpen. [1] Obviously, an unmet need remained and Roux et al. broke a lance for reconsidering VP as a treatment option in highly selected vertebral fracture (VF)-patients with a bad prognosis. They solicited proposals for clinical studies.
Such studies should not necessarily have an RCT-design. Indisputably, RCTs provide the most unbiased results, but always at the expense of external validity. This is why clinical epidemiologists keep recalling that the absence of evidence (that VP works) does not imply that there is evidence for the absence of efficacy (of VP).
Roux et al have a point when they claim that the trials may have focused on the wrong population, that the choice of the trials’ primary outcome was not ideal, and that the duration of follow up was too short to detect clinically meaningful effects beyond pain resolution alone. All these objections involve limitations of the rigid RCT-design template. If Roux et al’s hypothesis is right, and VP indeed reduces mortality and improves health related quality of life among these selected elderly at high risk to die, perhaps different study designs with longer follow up, in different patients and with different outcomes, should be pursued. Proponents of RCTs will immediately object that such studies cannot provide the required level of unbiasedness that RCTs may provide, eg. because of the absence of a proper control group, the likelihood of bias by indication and the room for obscuring co-interventions. But as said some clinical research questions are simply not ‘made for trials’, and sometimes the medical community should better appreciate second-best, in order to avoid throwing the child with the bathwater.
Recently, we have applied principles of causal inference to two compelling research questions that were not suited well for RCTs; the first was whether intense short-term immunosuppression reduces mortality in patients with hyperinflammatory COVID-19. In a non-randomized study with untreated historic controls, and a proper mediator variable, we have construed the evidence that immunosuppressive treatment is indeed effective, [2] half a year before the RCTs and the guideline committees arrived at the same conclusion.
Whether or not bDMARDs can inhibit syndesmophyte formation in patients with axial spondyloarthritis is a matter of endless scientific debate. RCTs are (ethically) difficult to perform because of slow progression-rates warranting long-term trials, but many non-randomized studies have been done in the past. We have tackled the issue by categorizing the available evidence in the literature according to criteria of causality proposed by Gvozdenovic et al. [3] While this exercise has not provided final evidence, it gave important direction to a question that will likely never be unequivocally answered in an RCT. [4]
We invite Roux et al. to do a similar exercise in their carefully built database of studies to the efficacy of VP. They may bring some order of causation in the existing body of literature, as we did in the example of axial SpA. By doing so, they may propose a potential mediator-variable, or perhaps an instrumental-variable, that can be used in future clinical studies and shed more light on research questions that go beyond the level of pain-resolution by VP alone.

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

Dear Editor,
We have read with interest the paper written by Dr. Keisuke Ono et al [1] whose title is “Reactive arthritis after COVID-19 infection” and we would like to share some medical thoughts we have concerning its content.
In this paper, a male patient was admitted with COVID-19 pneumonia. On day 21, he developed an acute bilateral arthritis in his ankles, with mild enthesitis in his right Achilles tendon; given the circumstances and having excluded all the other plausible factors that might be related with this onset, the authors stated that such elements were given by a reactive arthritis whose primer was SARS-CoV-2.
Regarding the definition of reactive arthritis (ReA), we would like to highlight some doubts and we belive that this element is contradicts the nature of ReA itself; first of all, as of today, ReA is to be given by bacterial infections only, should they be STDs-related or gastrointestinal. No viral agent has ever been either directly or indirectly linked to such element due to its pathogenesis. As Dr. Rebanta K. et al. properly stated in their papers, when ReA- associated invasive bacteria reach the systemic circulation, T lymphocytes are induced by bacterial fragments such as lipopolysaccharide and nucleic acids; These elements activate cytotoxic-T cells then attack the synovium and other self-antigens through molecular mimicry. It is believed that anti-bacterial cytokine response is also impaired in ReA, resulting in the decreased elimination of the bacteria. Therefore, since SARSCoV-2 is not capable of expressing nor producing bacteria-like fragments, it appears to be incompatible with ReA-inducing mechanisms. [2]
The American College of Rheumatology, as well as Dr. Selmi and colleagues, clearly support the need for bacterial agents for the diagnosis of Reactive Arthritis [3]. The clinical description of the patient (acute bilateral arthritis in his ankles, with mild enthesitis in his right Achilles tendon, without rash, conjunctivitis, or preceding diarrhoea or urethritis, HLA B27 negativity and clinical response to NSAIDs) is undoubtedly compatible with a diagnosis of viral arthritis [4] as per its criteria. Moreover It would appear that the references that Dr. Keisuke Ono et al. put at the end of the paper not support their theory; on the other hand, all the quoted papers specify the need for a bacterial infection [5].
Given these elements, in our opinion it would be better to reconsider the statement of COVID-19- induced ReA and to re-classify this case as it is supposed to b: a Viral Arthritis. We have recently published a case report with some considerations to support our thesis on SARS-COV2 viral
arthritis [6].
We believe that the debate on this topic is very important in order to standardize the definitions.
Best Regards

References

1. Ono K, Kishimoto M, Shimasaki T, et al Reactive arthritis after COVID-19 infection RMD Open 2020;6:e001350.
2. Cheeti A, Chakraborty RK, Ramphul K. Reactive Arthritis (Reiter Syndrome) [Updated
2020 Mar 13]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020
Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK499831/
3. Selmi C, Gershwin ME. Diagnosis and classification of reactive arthritis. Autoimmun Rev.
2014 Apr-May;13(4-5):546-9. doi: 10.1016/j.autrev.2014.01.005. Epub 2014 Jan 10. PMID:
24418301.
4. Marks M, Marks JL. Viral arthritis. Clin Med (Lond). 2016;16(2):129-134.
doi:10.7861/clinmedicine.16-2-129
5. T. E. W. Feltkamp (1995) Factors Involved in the Pathogenesis of HLA-B27 Associated
Arthritis, Scandinavian Journal of Rheumatology, 24:sup101, 213-217, DOI:
10.3109/03009749509100931
6. Parisi S, Borrelli R, Bianchi S, Fusaro E. Viral arthritis and COVID-19. Lancet Rheumatol.
2020 Oct 5. doi: 10.1016/S2665-9913(20)30348-9. Epub ahead of print. PMID: 33043303;
PMCID: PMC7535796.