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 invol...
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.
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...
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.
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...
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
The small randomized clinical trial by Lopes MI et al. has shown a meaningful benefit of colchicine in COVID- 19 patients. However, there are ambiguities in the written study design including the techniques opted for allocation concealment, blinding, and sample size calculations with six primary endpoints. Investigators were not able to analyze four major endpoints including mortality rate, causes of mortality, admission to ICU, and length of stay in ICU [1]. These results became hard to compare with other major studies such as preliminary findings of the RECOVERY trial where investigators have closed the recruitment of colchicine arm. There was no convincing evidence of mortality benefit in the colchicine group. Final results will show more data on secondary outcomes such as length of hospital stay and need for invasive mechanical ventilation [2].
This may not be the end of the road for colchicine as 26 study groups have been registered with clinicaltrial.gov to prove the beneficial effects of colchicine in COVID patients. At least four of these studies have already been completed. Preprint data from the COLCORONA trial shows a controversial conclusion of reduction in composite rate of death or hospitalization with colchicine in PCR confirmed non hospitalized patients [3]. Another small size COLORIT trial by Mareev V.Yu. et al. showed the median SHOCS score decreased from 8 to 2, i.e., from a moderate to a mild degree in the colchicine group. The...
The small randomized clinical trial by Lopes MI et al. has shown a meaningful benefit of colchicine in COVID- 19 patients. However, there are ambiguities in the written study design including the techniques opted for allocation concealment, blinding, and sample size calculations with six primary endpoints. Investigators were not able to analyze four major endpoints including mortality rate, causes of mortality, admission to ICU, and length of stay in ICU [1]. These results became hard to compare with other major studies such as preliminary findings of the RECOVERY trial where investigators have closed the recruitment of colchicine arm. There was no convincing evidence of mortality benefit in the colchicine group. Final results will show more data on secondary outcomes such as length of hospital stay and need for invasive mechanical ventilation [2].
This may not be the end of the road for colchicine as 26 study groups have been registered with clinicaltrial.gov to prove the beneficial effects of colchicine in COVID patients. At least four of these studies have already been completed. Preprint data from the COLCORONA trial shows a controversial conclusion of reduction in composite rate of death or hospitalization with colchicine in PCR confirmed non hospitalized patients [3]. Another small size COLORIT trial by Mareev V.Yu. et al. showed the median SHOCS score decreased from 8 to 2, i.e., from a moderate to a mild degree in the colchicine group. The change in the SHOCS-COVID score was minimal and statistically insignificant in the control group. SHOCS-COVID score includes the assessment of the patient’s clinical condition, CT score of pulmonary lesions, CRP, and D-dimer values [4]. Preprint results from one observational cross-sectional study from Columbia with analysis of 301 patients also found treatment with corticosteroids and colchicine for managing patients with severe COVID-19 pneumonia was associated with low mortality [5]. Although this study had a moderate risk of bias due to study design. Many more studies are on their way to completion and publication. A comprehensive meta-analysis will provide conclusive evidence if colchicine can be included in the standard of care for COVID-19 patients.
1- Lopes MI, Bonjorno LP, Giannini MC, et al Beneficial effects of colchicine for moderate to severe COVID-19: a randomised, double-blinded, placebo-controlled clinical trial. RMD Open 2021;7:e001455. https://doi.org/10.1136/rmdopen-2020-001455
2- RECOVERY trial closes recruitment to colchicine treatment for patients hospitalised with COVID-19 — RECOVERY Trial. (n.d.). Retrieved March 21, 2021, from https://www.recoverytrial.net/news/recovery-trial-closes-recruitment-to-...
3- Tardif, J.-C., Bouabdallaoui, N., L’allier, P. L., et al Efficacy of Colchicine in Non-Hospitalized Patients with COVID-19. MedRxiv, 2021.01.26.21250494. https://doi.org/10.1101/2021.01.26.21250494
4- Mareev V.Yu., Orlova Y.A., Plisyk A.G. et al Proactive anti-inflammatory therapy with colchicine in the treatment of advanced stages of new coronavirus infection. The first results of the COLORIT study. Kardiologiia. 2021;61(2):15-27. https://doi.org/10.18087/cardio.2021.2.n1560
5- Miguel Alejandro Pinzón, Doris Cardona Arango, Juan Felipe Betancur et al. Clinical Outcome of Patients with COVID-19 Pneumonia Treated with Corticosteroids and Colchicine in Colombia, 23 October 2020, PREPRINT (Version 1) available at Research Square [https://doi.org/10.21203/rs.3.rs-94922/v1]
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 e...
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.
I read with interest the results of the C-View study (1). In the study it is reported that 17 patients (19%) were on systemic glucocorticoids in the 48-week pre-baseline period, and 6 patients (7%) used systemic glucocorticoid in the certolizumab (CZP) treatment period. The report does not elaborate on the median dose used by each of these groups of people. Adverse events are increase with increasing doses of systemic glucocorticoid and reporting these doses would be of value to help assess the results of the trial.
High doses in the pre-baseline period and low doses in the treatment period could have the effect of reducing the estimated treatment effect of CZP on acute anterior uveitis (AAU). Low doses in the pre-baseline period and high doses in the treatment period could have the opposite effect.
In addition, it was reported that five patients (6%) entered the CZP treatment period with an AAU flare. It was not reported how these patients were assessed for the outcome. Were these flares on entry assumed to be a flare in the CZP treatment period or were only new onset flares in the CZP treatment period counted towards flares in the CZP treatment period?
Philip C. Robinson
University of Queensland, Brisbane, Australia
1. van der Horst-Bruinsma I, van Bentum R, Verbraak FD, Rath T, Rosenbaum JT, Misterska-Skora M, et al. The impact of certolizumab pegol treatment on the incidence of anterior uveitis flares in patients w...
I read with interest the results of the C-View study (1). In the study it is reported that 17 patients (19%) were on systemic glucocorticoids in the 48-week pre-baseline period, and 6 patients (7%) used systemic glucocorticoid in the certolizumab (CZP) treatment period. The report does not elaborate on the median dose used by each of these groups of people. Adverse events are increase with increasing doses of systemic glucocorticoid and reporting these doses would be of value to help assess the results of the trial.
High doses in the pre-baseline period and low doses in the treatment period could have the effect of reducing the estimated treatment effect of CZP on acute anterior uveitis (AAU). Low doses in the pre-baseline period and high doses in the treatment period could have the opposite effect.
In addition, it was reported that five patients (6%) entered the CZP treatment period with an AAU flare. It was not reported how these patients were assessed for the outcome. Were these flares on entry assumed to be a flare in the CZP treatment period or were only new onset flares in the CZP treatment period counted towards flares in the CZP treatment period?
Philip C. Robinson
University of Queensland, Brisbane, Australia
1. van der Horst-Bruinsma I, van Bentum R, Verbraak FD, Rath T, Rosenbaum JT, Misterska-Skora M, et al. The impact of certolizumab pegol treatment on the incidence of anterior uveitis flares in patients with axial spondyloarthritis: 48-week interim results from C-VIEW. RMD Open. 2020;6(1).
Dear Editor,
Jean W. Liew and collaborators recently reported a systematic literature review and meta-analysis comprising the association of body mass index (BMI) on disease activity in axial spondyloarthritis (axSpA) [1]. We consider these data very interesting, as BMI is a modifiable factor. The inclusion criteria defined by the authors were based on the following issues: 1) ankylosing spondylitis, non-radiographic axSpA or all spondyloarthropathies; 2) BMI as primary exposure; 3) a validated measure of disease activity or treatment response, measured by BASDAI or ASDAS as the primary outcome. The search date was 15th December 2019. The authors selected 20 articles for full-text review but then excluded 7 articles, three for not having the primary exposure or outcome of interest, three for not reporting disease activity stratified by BMI at baseline and one for incomplete reporting results (no references provided). Finally, the authors included 13 observational studies in the qualitative analysis and 12 studies in the quantitative meta-analysis. In spite of the broad literature search strategy employed by the authors, at least one article is missed in the included studies, which may reduce the strength of the final conclusions.
Our research group published a manuscript, last February 2019 in the journal Arthritis Research and Therapy, attending this issue [2]. This reported the results of a prospective observational study including a total of 180 patients wit...
Dear Editor,
Jean W. Liew and collaborators recently reported a systematic literature review and meta-analysis comprising the association of body mass index (BMI) on disease activity in axial spondyloarthritis (axSpA) [1]. We consider these data very interesting, as BMI is a modifiable factor. The inclusion criteria defined by the authors were based on the following issues: 1) ankylosing spondylitis, non-radiographic axSpA or all spondyloarthropathies; 2) BMI as primary exposure; 3) a validated measure of disease activity or treatment response, measured by BASDAI or ASDAS as the primary outcome. The search date was 15th December 2019. The authors selected 20 articles for full-text review but then excluded 7 articles, three for not having the primary exposure or outcome of interest, three for not reporting disease activity stratified by BMI at baseline and one for incomplete reporting results (no references provided). Finally, the authors included 13 observational studies in the qualitative analysis and 12 studies in the quantitative meta-analysis. In spite of the broad literature search strategy employed by the authors, at least one article is missed in the included studies, which may reduce the strength of the final conclusions.
Our research group published a manuscript, last February 2019 in the journal Arthritis Research and Therapy, attending this issue [2]. This reported the results of a prospective observational study including a total of 180 patients with axSpA treated with TNF inhibitors (TNFi) (infliximab or adalimumab) that investigated the influence of conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) and BMI on clinical response to TNF inhibitors, measured by BASDAI and ASDAS. For this purpose, descriptive analysis and regression logistics models were employed considering the presence of possible interactions and confounding covariates. The presence of interactions can have important implications for the interpretation of statistical models. Therefore, when a possible interaction terms is to be considered in the regression model, this needs always to be assessed before confounding. Using an overall adjusted summary estimate is advised only if no significant interaction is present [3]. Interestingly, we found a significant interaction between BMI and DMARDs. The use of concomitant csDMARDs with TNFi increased the probability of achieving clinical response in overweight/obese axSpA patients (OR: 7.86, 95%CI: 2.39–25.78) but no association was found for normal-weight patients (OR: 1.10, 95%CI: 0.33-3.58). According to these results, we wonder whether BMI is just an independent factor of poor treatment response or if this in fact acts as an effect modifier for other factors influencing on this. In addition, disease activity at baseline stratified by BMI groups is also reported in our manuscript. Therefore, after reviewing the inclusion criteria proposed by Liew et al., we consider our work fulfilled all of them and its inclusion in the present review could contribute to reward it.
References
[1] Liew JW, Huang IJ, Louden DN, et al. Association of body mass index on disease activity in axial spondyloarthritis: systematic review and meta-analysis. RMD Open 2020;6:e001225.
[2]Hernández-Breijo B, Plasencia-Rodríguez C, Navarro-Compán V, et al. Association between concomitant csDMARDs and clinical response to TNF inhibitors in overweight patients with axial spondyloarthritis. Arthritis Res Ther. 2019;21:66.
[3] Pearce N., Greenland S. Confounding and Interaction. In: Ahrens W, Pigeot I, eds. Handbook of Epidemiology. New York, NY: Springer 2014: 659-84.
I read the article by Hua et al.1 that was published in this journal with great interest. The authors provided an excellent review of the literature regarding the clinical efficacy and toxicity of glucocorticoids (GCs) in rheumatoid arthritis (RA). The review included comprehensive discussion about the efficacy of GCs as a bridging therapy in addition to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) based on the rapid onset of action of these drugs.1 The authors advocate that because even low-doses of GCs might have adverse effects, administration of these drugs should be restricted to the lowest dose for the shortest time.1 The first part about the effectiveness of GCs was well documented and convincing; however, the second part about the safety of these drugs seemed a little less convincing. This might be attributed to the fact that a small number of studies on the safety of GCs have been published. In particular, little evidence regarding bone-related adverse effects has been presented. We have obtained very preliminary data in our hospital about the effects of GCs on bone health, including fractures and osteoporosis, and would like to contribute these as a comment.
We retrospectively reviewed the medical records of 883 patients with RA who visited our hospital in 2018. Of these, 364 patients (41.2%, Figure 1A) were prescribed GCs. At the last visits in 2018, appro...
I read the article by Hua et al.1 that was published in this journal with great interest. The authors provided an excellent review of the literature regarding the clinical efficacy and toxicity of glucocorticoids (GCs) in rheumatoid arthritis (RA). The review included comprehensive discussion about the efficacy of GCs as a bridging therapy in addition to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) based on the rapid onset of action of these drugs.1 The authors advocate that because even low-doses of GCs might have adverse effects, administration of these drugs should be restricted to the lowest dose for the shortest time.1 The first part about the effectiveness of GCs was well documented and convincing; however, the second part about the safety of these drugs seemed a little less convincing. This might be attributed to the fact that a small number of studies on the safety of GCs have been published. In particular, little evidence regarding bone-related adverse effects has been presented. We have obtained very preliminary data in our hospital about the effects of GCs on bone health, including fractures and osteoporosis, and would like to contribute these as a comment.
We retrospectively reviewed the medical records of 883 patients with RA who visited our hospital in 2018. Of these, 364 patients (41.2%, Figure 1A) were prescribed GCs. At the last visits in 2018, approximately 80% of the patients who were receiving GCs used 5 mg/day or less of GCs; the mean dosage was 4.1 mg/day (Figure 1B). Vertebral fractures were more frequently observed in patients who were receiving GCs than in those not receiving them (p = 0.028, Figure 1C). The incidence of non-vertebral fractures was the same regardless of GC use (Figure 1D). Osteoporosis, defined as <80% of the young-adult mean bone mineral density of the lumber spine or left femoral neck, was diagnosed in 195 patients (22.1%). The incidence of osteoporosis was twice as high among patients who were receiving GCs compared with those who were not receiving them (Figure 1E). The effect of GCs on osteoporosis was observed in both male and female patients (Figure 1F).
Figure is available upon request.
Patients with RA are at a high risk of fracture, and the use of GCs for more than 3 months is associated with an increased risk of vertebral fracture regardless of the dosage.2,3 Our data were very preliminary, and thus, it had several limitations. For example, we did not consider differences in patient backgrounds. However, this simplified retrospective study supports, at least in part, the concept that GCs should be used at minimal dosage and for the shortest duration possible.1
References
Hua C, Buttgereit F, Cobe B. Glucocorticoids in rheumatoid arthritis: current status and future studies. RMD Open 2020;6(1):e000536.
Xue AL, Wu SY, Jiang L, Feng AM, Guo HF, Zhao P. Bone fracture risk in patients with rheumatoid arthritis: A meta-analysis. Medicine (Baltimore) 2017;96:e6983.
Ozen G, Pedro S, Wolfe F, Michaud K. Medications associated with fracture risk in patients with rheumatoid arthritis. Ann Rheum Dis 2019;78:1041–1047.
Acknowledgments
The study protocol was approved by the Ethics Committee of the Osaki Citizen Hospital (No. 20190822-25) and performed in accordance with the Declaration of Helsinki.
This survey demonstrated that a significant proportion of clinicians
use smartphones to share clinical information. While this rightly raises
concerns over confidentiality and makes headlines in the press it is
important to question why this situation has arisen. As Mobasheri and
colleagues demonstrated, ownership is near ubiquitous among medical staff
and this affords availability and immediacy of access. It is hardly...
This survey demonstrated that a significant proportion of clinicians
use smartphones to share clinical information. While this rightly raises
concerns over confidentiality and makes headlines in the press it is
important to question why this situation has arisen. As Mobasheri and
colleagues demonstrated, ownership is near ubiquitous among medical staff
and this affords availability and immediacy of access. It is hardly
surprising that medics should choose to use tools which improve their
efficiency and the care they deliver to their patients. If there is a
faster or easier way to answer a clinical question than using the legacy
IT systems and software that many trusts provide then many will use it.
It would appear that the NHS lags behind the private sector in having
the appropriate software tools and as a result many individuals find their
own solutions. There is an abundance of software available, much of it
free, which enhances productivity. Rather than limiting staff to safe but
basic tools, hospital IT departments would do well to explore these
available options and facilitate the use of modern collaborative software
to optimise workflow and improve patient care.
Thank you for your interest in our work. Your letter allows us to
further explain aspects that could possibly be misunderstood. We stressed
in the title and in the conclusion that depression was a predictor of the
"risk to consider applying for work disability pension". The key messages
could, however, be interpreted differently.
Firstly, we decided to use a composite endpoint of obtaining work
disability pens...
Thank you for your interest in our work. Your letter allows us to
further explain aspects that could possibly be misunderstood. We stressed
in the title and in the conclusion that depression was a predictor of the
"risk to consider applying for work disability pension". The key messages
could, however, be interpreted differently.
Firstly, we decided to use a composite endpoint of obtaining work
disability pension plus considering to apply for a disability pension due
to peculiarites of the German health insurance system: Before receiving a
work disability pension, chronically ill persons usually receive sick
leave compensation for up to 78 weeks. The patients in our cohort had less
than six months symptoms at inclusion. Therefore, only a minority of them
had a chance to have already completed the application process of work
disability pension at two years of follow-up. However, considering to
apply for work disability leads to definite work disability in the vast
majoritiy of cases. In our data, only 12 patients who had considered
disability pension changed their minds during follow-up.
Secondly, we reported that depression was a stronger predictor than
disease activity. Choing and Attia are right that this statement cannot be
made by means of the comparison of odds ratios referring to different
scales. Our statement was based on the comparion of models by means of the
likelihood score statistic which is not scale dependent.
When areas under the ROC curve were compared, the model including age,
FFbH, days of sick leave and PHQ-9 had an area under the curve of 0.80.
The model including age, FFbH, days of sick leave and DAS28 had an area
under the curve of 0.77 (p-value for comparison: 0.09).
Thirdly, the numbers presented in the baseline table are percent
values. In fact, 5% of all patients in the analysis and 22% of the
patients who did consider applying for (or had already applied) disability
pension had severe depression. These numbers are large enough to calculate
an odds ratio. We would like to point out that the lower margin of the 95%
confidence interval of this odds ratio was 3.4 which is still a
considerable effect.
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.
Show MoreSuch 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 invol...
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...
Show MoreCorrespondence on “Rheumatoid arthritis prevention: any takers?”
Show MoreWe 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...
Dear Editor
The small randomized clinical trial by Lopes MI et al. has shown a meaningful benefit of colchicine in COVID- 19 patients. However, there are ambiguities in the written study design including the techniques opted for allocation concealment, blinding, and sample size calculations with six primary endpoints. Investigators were not able to analyze four major endpoints including mortality rate, causes of mortality, admission to ICU, and length of stay in ICU [1]. These results became hard to compare with other major studies such as preliminary findings of the RECOVERY trial where investigators have closed the recruitment of colchicine arm. There was no convincing evidence of mortality benefit in the colchicine group. Final results will show more data on secondary outcomes such as length of hospital stay and need for invasive mechanical ventilation [2].
Show MoreThis may not be the end of the road for colchicine as 26 study groups have been registered with clinicaltrial.gov to prove the beneficial effects of colchicine in COVID patients. At least four of these studies have already been completed. Preprint data from the COLCORONA trial shows a controversial conclusion of reduction in composite rate of death or hospitalization with colchicine in PCR confirmed non hospitalized patients [3]. Another small size COLORIT trial by Mareev V.Yu. et al. showed the median SHOCS score decreased from 8 to 2, i.e., from a moderate to a mild degree in the colchicine group. The...
Dear Editor,
Show MoreWe 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 e...
Dear Editor,
I read with interest the results of the C-View study (1). In the study it is reported that 17 patients (19%) were on systemic glucocorticoids in the 48-week pre-baseline period, and 6 patients (7%) used systemic glucocorticoid in the certolizumab (CZP) treatment period. The report does not elaborate on the median dose used by each of these groups of people. Adverse events are increase with increasing doses of systemic glucocorticoid and reporting these doses would be of value to help assess the results of the trial.
High doses in the pre-baseline period and low doses in the treatment period could have the effect of reducing the estimated treatment effect of CZP on acute anterior uveitis (AAU). Low doses in the pre-baseline period and high doses in the treatment period could have the opposite effect.
In addition, it was reported that five patients (6%) entered the CZP treatment period with an AAU flare. It was not reported how these patients were assessed for the outcome. Were these flares on entry assumed to be a flare in the CZP treatment period or were only new onset flares in the CZP treatment period counted towards flares in the CZP treatment period?
Philip C. Robinson
University of Queensland, Brisbane, Australia
1. van der Horst-Bruinsma I, van Bentum R, Verbraak FD, Rath T, Rosenbaum JT, Misterska-Skora M, et al. The impact of certolizumab pegol treatment on the incidence of anterior uveitis flares in patients w...
Show MoreDear Editor,
Show MoreJean W. Liew and collaborators recently reported a systematic literature review and meta-analysis comprising the association of body mass index (BMI) on disease activity in axial spondyloarthritis (axSpA) [1]. We consider these data very interesting, as BMI is a modifiable factor. The inclusion criteria defined by the authors were based on the following issues: 1) ankylosing spondylitis, non-radiographic axSpA or all spondyloarthropathies; 2) BMI as primary exposure; 3) a validated measure of disease activity or treatment response, measured by BASDAI or ASDAS as the primary outcome. The search date was 15th December 2019. The authors selected 20 articles for full-text review but then excluded 7 articles, three for not having the primary exposure or outcome of interest, three for not reporting disease activity stratified by BMI at baseline and one for incomplete reporting results (no references provided). Finally, the authors included 13 observational studies in the qualitative analysis and 12 studies in the quantitative meta-analysis. In spite of the broad literature search strategy employed by the authors, at least one article is missed in the included studies, which may reduce the strength of the final conclusions.
Our research group published a manuscript, last February 2019 in the journal Arthritis Research and Therapy, attending this issue [2]. This reported the results of a prospective observational study including a total of 180 patients wit...
To the Editor,
I read the article by Hua et al.1 that was published in this journal with great interest. The authors provided an excellent review of the literature regarding the clinical efficacy and toxicity of glucocorticoids (GCs) in rheumatoid arthritis (RA). The review included comprehensive discussion about the efficacy of GCs as a bridging therapy in addition to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) based on the rapid onset of action of these drugs.1 The authors advocate that because even low-doses of GCs might have adverse effects, administration of these drugs should be restricted to the lowest dose for the shortest time.1 The first part about the effectiveness of GCs was well documented and convincing; however, the second part about the safety of these drugs seemed a little less convincing. This might be attributed to the fact that a small number of studies on the safety of GCs have been published. In particular, little evidence regarding bone-related adverse effects has been presented. We have obtained very preliminary data in our hospital about the effects of GCs on bone health, including fractures and osteoporosis, and would like to contribute these as a comment.
We retrospectively reviewed the medical records of 883 patients with RA who visited our hospital in 2018. Of these, 364 patients (41.2%, Figure 1A) were prescribed GCs. At the last visits in 2018, appro...
Show MoreThis survey demonstrated that a significant proportion of clinicians use smartphones to share clinical information. While this rightly raises concerns over confidentiality and makes headlines in the press it is important to question why this situation has arisen. As Mobasheri and colleagues demonstrated, ownership is near ubiquitous among medical staff and this affords availability and immediacy of access. It is hardly...
Thank you for your interest in our work. Your letter allows us to further explain aspects that could possibly be misunderstood. We stressed in the title and in the conclusion that depression was a predictor of the "risk to consider applying for work disability pension". The key messages could, however, be interpreted differently.
Firstly, we decided to use a composite endpoint of obtaining work disability pens...
Pages