We were intrigued by the recently published paper in the Annals of Rheumatic Diseases titled "HLA-B27, Axial Spondyloarthritis, and Survival" by Li et al.[1] This study explores the association between HLA-B27 carriage, axial spondyloarthritis (axSpA), and survival, offering valuable insights. By combining data from a 35-year follow-up study of Ankylosing Spondylitis (AS) and axSpA patients with the extensive UK Biobank dataset, the study significantly enhances our understanding of mortality patterns in AS/axSpA and the potential impact of HLA-B27 in the general population. We consider this study's implications important and look forward to critically examining its key findings and broader implications. However, there are some concerns that would better be clarified.
First and foremost, the observed gender-based differences in AS mortality are intriguing, with women generally exhibiting less severe sacroiliac joint damage.[2] However, an important consideration is the potential influence of HPV infection.[3] Surprisingly, the original study did not account for this factor, despite previous research linking HPV infection to autoimmune diseases, including AS, and suggesting a significantly elevated risk for AS development in HPV-infected individuals.[4] These findings underscore the complex interplay between infectious agents and autoimmune conditions. Additionally, prior research has indicated higher mortality in HPV-infected patients, emphasizing the...
We were intrigued by the recently published paper in the Annals of Rheumatic Diseases titled "HLA-B27, Axial Spondyloarthritis, and Survival" by Li et al.[1] This study explores the association between HLA-B27 carriage, axial spondyloarthritis (axSpA), and survival, offering valuable insights. By combining data from a 35-year follow-up study of Ankylosing Spondylitis (AS) and axSpA patients with the extensive UK Biobank dataset, the study significantly enhances our understanding of mortality patterns in AS/axSpA and the potential impact of HLA-B27 in the general population. We consider this study's implications important and look forward to critically examining its key findings and broader implications. However, there are some concerns that would better be clarified.
First and foremost, the observed gender-based differences in AS mortality are intriguing, with women generally exhibiting less severe sacroiliac joint damage.[2] However, an important consideration is the potential influence of HPV infection.[3] Surprisingly, the original study did not account for this factor, despite previous research linking HPV infection to autoimmune diseases, including AS, and suggesting a significantly elevated risk for AS development in HPV-infected individuals.[4] These findings underscore the complex interplay between infectious agents and autoimmune conditions. Additionally, prior research has indicated higher mortality in HPV-infected patients, emphasizing the need for a more in-depth investigation into the intricate relationship between infectious agents, autoimmune diseases, and mortality.
Second, understanding the factors contributing to high mortality in women with AS requires acknowledging the complex landscape of autoimmune diseases in this group. The study's female cohort likely included individuals with various autoimmune conditions, each impacting health and mortality differently. Additionally, the unique challenges related to reproductive health in women with AS, including the overlooked impact of pregnancy on disease outcomes, must be considered, given the higher prevalence of autoimmune diseases in women of childbearing age.[5] This highlights the importance of a holistic healthcare approach that accounts for the multifaceted aspects of women's health and the potential implications of pregnancy on both disease management and mortality in individuals with AS or other autoimmune conditions. While AS may indeed be linked to increased mortality, the confounding effect of coexisting autoimmune diseases should not be underestimated. The presence of multiple autoimmune conditions in the same study group complicates attributing mortality solely to AS or HLA-B27 status. To gain a more precise understanding of mortality patterns in AS, future studies may benefit from stratifying patients based on their autoimmune disease profiles and assessing mortality within more homogeneous subgroups.[6].
Third, the study appears to omit an examination of the impact of race, ethnicity, and social/lifestyle factors on mortality outcomes. These factors can affect disease susceptibility, severity, healthcare access, and social determinants of health, all of which shape mortality rates. Neglecting these variables can introduce bias and limit the study's generalizability.[7] Similarly, social and lifestyle factors, such as smoking, alcohol consumption, physical activity, diet, socioeconomic status, and more, can significantly impact health outcomes.[8] Future research on AS mortality should encompass the multifaceted influence of race, ethnicity, and social/lifestyle factors to gain a more comprehensive understanding of mortality contributors in this population.[9]
In conclusion, Li et al.'s paper offers a thought-provoking exploration of AS/axSpA mortality patterns and the role of HLA-B27 in survival. While its findings hold significant clinical and research implications, further investigation into nuanced mortality factors in AS/axSpA is warranted. As educators and researchers, we believe that ongoing research, with a focus on infectious agents, autoimmune comorbidities, reproductive health, and social determinants, will advance our understanding of these complexities and inform targeted patient care and public health interventions. We eagerly anticipate the field's continued evolution and its potential to improve the lives of those affected by AS/axSpA.
References:
1 Li Z, Khan MK, van der Linden SM, et al. HLA-B27, axial spondyloarthritis and survival. Ann Rheum Dis Published Online First: 7 September 2023. doi:10.1136/ard-2023-224434
2 Nam B, Jo S, Bang S-Y, et al. Clinical and genetic factors associated with radiographic damage in patients with ankylosing spondylitis. Ann Rheum Dis 2023;82:527–32.
3 Lichter K, Krause D, Xu J, et al. Adjuvant Human Papillomavirus Vaccine to Reduce Recurrent Cervical Dysplasia in Unvaccinated Women: A Systematic Review and Meta-analysis. Obstet Gynecol 2020;135:1070–83.
4 Wei C-Y, Lin J-Y, Wang Y-T, et al. Risk of ankylosing spondylitis following human papillomavirus infection: A nationwide, population-based, cohort study. J Autoimmun 2020;113:102482.
5 Meissner Y, Strangfeld A, Molto A, et al. Pregnancy and neonatal outcomes in women with axial spondyloarthritis: pooled data analysis from the European Network of Pregnancy Registries in Rheumatology (EuNeP). Ann Rheum Dis 2022;81:1524–33.
6 Singh AG, Chowdhary VR. Pregnancy-related issues in women with systemic lupus erythematosus. Int J Rheum Dis 2015;18:172–81.
7 GBD US Health Disparities Collaborators. Cause-specific mortality by county, race, and ethnicity in the USA, 2000-19: a systematic analysis of health disparities. Lancet 2023;402:1065–82.
8 Hosseini M, Rahimibarghani S, Ghorbanpour S, et al. The effects of supervision on the outcomes of exercise training in patients with ankylosing spondylitis: A single-blind randomized controlled trial. Int J Rheum Dis 2023;26:1120–8.
9 Inderjeeth CA, Boland E, Connor C, et al. Evaluation of an ankylosing spondylitis education and self-management program: Beneficial effects on ankylosing spondylitis specific outcomes. Int J Rheum Dis 2021;24:434–44.
To the Editor,
I am writing to address a recent article titled "Safety of colchicine and NSAID prophylaxis when initiating urate-lowering therapy for gout: propensity score-matched cohort studies in the UK Clinical Practice Research Datalink" (1). This study conducted two retrospective cohort studies to determine the risk of adverse events associated with colchicine or non-steroidal anti-inflammatory drug (NSAID) prophylaxis when initiating allopurinol for gout. The research presents valuable insights into the safety of these prophylactic measures, but it is essential to discuss both the limitations and strengths of this study.
The strengths of this study lie in its extensive sample size and its use of primary care consultation and prescription data linked to hospital records over a 20-year period. This approach provides a comprehensive and high-quality dataset, reflective of everyday clinical practice. The use of clinical diagnosis for gout, with a high positive predictive value, further reinforces the practical relevance of the study's findings. The researchers' recognition of limitations is commendable. It is essential to acknowledge that the observational design carries a risk of exposure status misclassification. Nevertheless, the study took measures to mitigate this risk through propensity score matching. Additionally, it should be noted that the study focused on adverse events severe enough to warrant consultation or hospitalization,...
To the Editor,
I am writing to address a recent article titled "Safety of colchicine and NSAID prophylaxis when initiating urate-lowering therapy for gout: propensity score-matched cohort studies in the UK Clinical Practice Research Datalink" (1). This study conducted two retrospective cohort studies to determine the risk of adverse events associated with colchicine or non-steroidal anti-inflammatory drug (NSAID) prophylaxis when initiating allopurinol for gout. The research presents valuable insights into the safety of these prophylactic measures, but it is essential to discuss both the limitations and strengths of this study.
The strengths of this study lie in its extensive sample size and its use of primary care consultation and prescription data linked to hospital records over a 20-year period. This approach provides a comprehensive and high-quality dataset, reflective of everyday clinical practice. The use of clinical diagnosis for gout, with a high positive predictive value, further reinforces the practical relevance of the study's findings. The researchers' recognition of limitations is commendable. It is essential to acknowledge that the observational design carries a risk of exposure status misclassification. Nevertheless, the study took measures to mitigate this risk through propensity score matching. Additionally, it should be noted that the study focused on adverse events severe enough to warrant consultation or hospitalization, potentially missing milder adverse events. Moreover, the inability to ascertain the use of over-the-counter NSAIDs or evaluate the effects of individual NSAIDs or colchicine dosing highlights areas for future research. Finally, the study's observational nature limits its ability to draw causal inferences.
The findings of this study provide valuable information to guide treatment decisions for people with gout and their clinicians. The increased occurrence of adverse events with prophylaxis when initiating allopurinol, particularly with colchicine, is noteworthy. While serious adverse events were rare, this study contributes to the ongoing discussion about the balance between the benefits and potential risks of prophylactic measures in gout treatment. Future research is warranted to determine which patients are at the greatest risk of adverse events and to explore the cardiovascular benefits of colchicine in gout patients.
In conclusion, the study serves as a valuable addition to the body of knowledge regarding gout treatment. Its limitations should be considered in interpreting the results, but the large dataset and real-world data sources make it a substantial contribution to the field. As further research is conducted, these findings will undoubtedly enhance the ability of patients and clinicians to make informed decisions about flare prophylaxis when initiating allopurinol, ultimately benefiting the well-being of individuals living with gout.
References
1. Roddy E, Bajpai R, Forrester H, et alSafety of colchicine and NSAID prophylaxis when initiating urate-lowering therapy for gout: propensity score-matched cohort studies in the UK Clinical Practice Research DatalinkAnnals of the Rheumatic Diseases Published Online First: 03 October 2023. doi: 10.1136/ard-2023-224154
We read with great interest the recent article by Roddy et al1 and commend their efforts to address a clinically relevant question using a large, generalizable database. However, we were surprised and concerned by their findings of notably increased absolute risks of serious adverse events with both colchicine and NSAID use, including neuropathy (4 excess cases/1000 person-years [PY]) and bone marrow suppression (10 excess cases/1000 PY) with colchicine and myocardial infarction (MI) with both colchicine (8 excess cases/1000 PY) and NSAIDs (6 excess cases/1000 PY). The corresponding HRs were 4.8, 3.3, 1.6, and 1.9, respectively. Together with the seriousness of these events, these data do not appear to support the authors’ conclusion that their findings provide reassurance for patients and clinicians. Conversely, if confirmed and true, these findings would raise safety concerns regarding the ACR/EULAR guideline recommendations, while being inconsistent with anecdotal clinical experience and recent randomized controlled trial (RCT) safety data.2,3 Indeed, the authors acknowledge that the higher MI risk with colchicine contradicts the RCT evidence4-6 demonstrating its cardiovascular benefit that resulted in FDA and EMA approval for MI prevention. All in all, we feel that additional analyses in the CPRD population and replications in different populations which consider the following would be critically important:
1. New user, active control design:...
We read with great interest the recent article by Roddy et al1 and commend their efforts to address a clinically relevant question using a large, generalizable database. However, we were surprised and concerned by their findings of notably increased absolute risks of serious adverse events with both colchicine and NSAID use, including neuropathy (4 excess cases/1000 person-years [PY]) and bone marrow suppression (10 excess cases/1000 PY) with colchicine and myocardial infarction (MI) with both colchicine (8 excess cases/1000 PY) and NSAIDs (6 excess cases/1000 PY). The corresponding HRs were 4.8, 3.3, 1.6, and 1.9, respectively. Together with the seriousness of these events, these data do not appear to support the authors’ conclusion that their findings provide reassurance for patients and clinicians. Conversely, if confirmed and true, these findings would raise safety concerns regarding the ACR/EULAR guideline recommendations, while being inconsistent with anecdotal clinical experience and recent randomized controlled trial (RCT) safety data.2,3 Indeed, the authors acknowledge that the higher MI risk with colchicine contradicts the RCT evidence4-6 demonstrating its cardiovascular benefit that resulted in FDA and EMA approval for MI prevention. All in all, we feel that additional analyses in the CPRD population and replications in different populations which consider the following would be critically important:
1. New user, active control design: A potential weakness of this study was that they compared active drug (colchicine or NSAID) with no drug. Despite their use of propensity score matching, this design is more susceptible to confounding, including confounding by indication. Furthermore, the covariates included in their propensity score model were relatively sparse and lacked key covariates such as rheumatology consultation, prior flare rates, and prior colchicine or NSAID use (before the preceding month). For example, comparing those who initiated colchicine vs. NSAIDs for gout flare prophylaxis would have better addressed this issue of potential confounding by indication, which can be otherwise intractable.
2. Follow-up duration: In this study, patients were followed up to 6 months or, in the case of the active drug groups, until the end of colchicine/NSAID treatment. As a result, the follow-up in both active drug groups was half that of unexposed groups (the mean follow-up duration = 3.1, 3.2, and 5.8 months in colchicine, NSAID, and no drug use group, respectively, based on the data from Tables 2 and 4). These large differences in follow-up carry major potential for selection bias associated with censoring, regardless of analytic adjustments. To this end, truncating follow-up properly and/or presenting an intention-to-treat analysis would help further evaluate the robustness of the findings.
3. Negative controls: Another way to ensure robustness of their findings would be to employ a negative control outcome. For example, one could examine certain NSAID-specific outcomes (expected to be null) in the colchicine group and vice versa. This is relevant as all study outcomes were positively associated, at least directionally. The study’s only overlapping outcome between colchicine and NSAID exposures was MI; both showed a positive association which was unexpected for colchicine as discussed above. As such, it appears critical to demonstrate that the analytic framework can validly discriminate null vs. genuine expected associations. If the analysis still finds an association with negative control outcomes, it may call into question the findings of the study at large.
In conclusion, while an important clinical question, further analyses and studies that consider the points above would be vital to validate the associations reported in this manuscript. We hope the study authors and others pursue these analyses to address these crucial clinical questions in gout care to be able to rigorously inform shared decision-making for patients.
1. Roddy E, Bajpai R, Forrester H, et al. Safety of colchicine and NSAID prophylaxis when initiating urate-lowering therapy for gout: propensity score-matched cohort studies in the UK Clinical Practice Research Datalink. Ann Rheum Dis 2023.
2. Mackenzie IS, Ford I, Nuki G, et al. Long-term cardiovascular safety of febuxostat compared with allopurinol in patients with gout (FAST): a multicentre, prospective, randomised, open-label, non-inferiority trial. Lancet 2020;396:1745-57.
3. O'Dell JR, Brophy MT, Pillinger MH, et al. Comparative Effectiveness of Allopurinol and Febuxostat in Gout Management. NEJM Evid 2022;1.
4. Nidorf SM, Eikelboom JW, Budgeon CA, Thompson PL. Low-dose colchicine for secondary prevention of cardiovascular disease. Journal of the American College of Cardiology 2013;61:404-10.
5. Tardif JC, Kouz S, Waters DD, et al. Efficacy and Safety of Low-Dose Colchicine after Myocardial Infarction. N Engl J Med 2019;381:2497-505.
6. Nidorf SM, Fiolet ATL, Mosterd A, et al. Colchicine in Patients with Chronic Coronary Disease. N Engl J Med 2020;383:1838-47.
This is a very interesting observational study on the cardiovascular risks of glucocorticoid therapy in RA. I particularly appreciate the balanced discussion, pointing to the problems of confounding by indication that were most likely not (completely) addressed by the analysis technique.
To further understand the findings I have a couple of requests:
1. Could the authors more clearly document how the exposure to GC developed over time? E.g., how many patients were on a mean dose of < 5mg/d, ≥ 5mg/d etc. for a set period of time? Were patterns of GC dosing visible? Previous studies (e.g. Michaud et al[1]) have documented that GC dosing can be dynamic with stops and starts over a period of time.
2. The primary analysis is based on a cut point of prednisolone 5 mg/d. Could the authors repeat the analysis where low dose is defined as ≤ 5mg/d, so including the 5 mg/d, to see whether the risk estimates (against intermediate dose defined as > 5 mg/d) change substantially? And perhaps even one where low dose is defined as ≤ 7.5 mg/d (in agreement with Buttgereit et al[2])? Such analyses would help inform clinicians, given that 5 and 7.5 mg/d dosing schedules are very frequently applied.
3. I have argued that current statistical analyses that adjust risk estimates for disease activity are suboptimal, because they obscure the fact that disease activity under treatment with GC is lower than it would be without treatment.[3] So, I would suggest that the r...
This is a very interesting observational study on the cardiovascular risks of glucocorticoid therapy in RA. I particularly appreciate the balanced discussion, pointing to the problems of confounding by indication that were most likely not (completely) addressed by the analysis technique.
To further understand the findings I have a couple of requests:
1. Could the authors more clearly document how the exposure to GC developed over time? E.g., how many patients were on a mean dose of < 5mg/d, ≥ 5mg/d etc. for a set period of time? Were patterns of GC dosing visible? Previous studies (e.g. Michaud et al[1]) have documented that GC dosing can be dynamic with stops and starts over a period of time.
2. The primary analysis is based on a cut point of prednisolone 5 mg/d. Could the authors repeat the analysis where low dose is defined as ≤ 5mg/d, so including the 5 mg/d, to see whether the risk estimates (against intermediate dose defined as > 5 mg/d) change substantially? And perhaps even one where low dose is defined as ≤ 7.5 mg/d (in agreement with Buttgereit et al[2])? Such analyses would help inform clinicians, given that 5 and 7.5 mg/d dosing schedules are very frequently applied.
3. I have argued that current statistical analyses that adjust risk estimates for disease activity are suboptimal, because they obscure the fact that disease activity under treatment with GC is lower than it would be without treatment.[3] So, I would suggest that the result of the disease activity measure (here, ESR or CRP) should be ‘corrected’ upwards before the adjustment procedure is applied. For DAS28 a correction of 0.6 could be applied for patients treated with doses around 5 mg. For other doses and disease activity measures the correction factor is not so clear, but simply applying a reasonable uniform correction in all GC treated patients would probably improve the model. Can the authors perform such an analysis?
1. Caplan L, Wolfe F, Russell AS, Michaud K. Corticosteroid use in rheumatoid arthritis: prevalence, predictors, correlates, and outcomes. J Rheumatol 2007;34:696-705.
2. Buttgereit F, Da Silva JA, Boers M, Burmester GR, Cutolo M, Jacobs J, et al. Standardised nomenclature for glucocorticoid dosages and glucocorticoid treatment regimens: current questions and tentative answers in rheumatology. Ann Rheum Dis 2002;61:718-22.
3. Boers M. Viewpoint: Glucocorticoids in the Treatment of Rheumatoid Arthritis: Points to (Re)consider. Rheumatology (Oxford) 2023.
The interesting paper by So et al.1 “Time and dose-dependent effect of systemic glucocorticoids on major adverse cardiovascular events in patients with rheumatoid arthritis” invites us to conduct an “artistic” dissection of glucocorticoids in our patients, remembering The Anatomy Lesson of Dr. Tulp by Rembrandt.
Rheumatoid arthritis (RA) is associated with CVD increased risk even before there is any clinical expression of RA, which continues to increase with the persistence and severity of the inflammatory process, making CVD the main cause of death particularly in seropositive patients.
The efficacy of glucocorticoids (GCs) is undeniable, including prevention or delay of structural changes, however, there is strong evidence that even “low doses” of GCs can increase the risk of CVD as well as other negative associations related to quality of life and survival. Additional to the risk of CVD associated to the systemic inflammatory nature of RA, 50% of the patients also have 1 or more other risk factors associated to major adverse cardiovascular events (MACE).1
The data presented emphasizes the potential presentation of MACE with GC-doses previously considered to be safe. Historically, the recommended therapeutic GC doses have been established based particularly on its efficacy, however, an increase of cardiovascular disease in 12 233 RA patients receiving more than 5 mg of prednisone per day has also been reported in this study, with reasonable follow up. 1...
The interesting paper by So et al.1 “Time and dose-dependent effect of systemic glucocorticoids on major adverse cardiovascular events in patients with rheumatoid arthritis” invites us to conduct an “artistic” dissection of glucocorticoids in our patients, remembering The Anatomy Lesson of Dr. Tulp by Rembrandt.
Rheumatoid arthritis (RA) is associated with CVD increased risk even before there is any clinical expression of RA, which continues to increase with the persistence and severity of the inflammatory process, making CVD the main cause of death particularly in seropositive patients.
The efficacy of glucocorticoids (GCs) is undeniable, including prevention or delay of structural changes, however, there is strong evidence that even “low doses” of GCs can increase the risk of CVD as well as other negative associations related to quality of life and survival. Additional to the risk of CVD associated to the systemic inflammatory nature of RA, 50% of the patients also have 1 or more other risk factors associated to major adverse cardiovascular events (MACE).1
The data presented emphasizes the potential presentation of MACE with GC-doses previously considered to be safe. Historically, the recommended therapeutic GC doses have been established based particularly on its efficacy, however, an increase of cardiovascular disease in 12 233 RA patients receiving more than 5 mg of prednisone per day has also been reported in this study, with reasonable follow up. 1
The ACR and EULAR guidelines continue to not clearly specify the time-length or dose of GCs, despite them being a therapeutic cornerstone.2,3 We recognize that GCs improve symptoms, although it is true that a few weeks may not be enough for optimal efficacy and modification of the natural course of RA. 4,5 Low-dose GC, defined as 5 mg of prednisone per day (pdn/d), modify the natural history of RA, unfortunately there are no studies comparing the difference on structural changes between <5 mg/d vs <10 mg/d,6 although similar efficacy achieved with <5 mg/d has been reported even after a decade of follow-up, without modifying adrenal function or suppressive response.7 Osteoporosis and infectious processes increase at doses greater than 5 mg/d of prednisone and the minimum reasonable safe length of time to avoid or restrict such effects is yet to be defined.8,9 Of transcendent interest is the fact that the requirements of low dose GCs are not limited to what we have called bridge-therapy and the adequate response is long-term maintained with very low doses of steroids. 10.11
The article by So et al, puts its finger on the sore point so as not to use more than 5 mg of pdn/d, because it monthly increases 7% of MACE. This important paper shows how the efficacy/safety index can be optimized with <5 mg pdn/day or equivalent, both to decrease CVD as a potential primary objective,1 and to prevent other comorbidities such as osteoporosis and infectious processes.8,9
We emphasize that these low doses can be left for long term to achieve the best response, and we must ask ourselves if the cardiovascular safety will be maintained over more years or decades.
Contrasting is the fact that despite the known accelerated atherosclerosis and increased MACE risk in RA patients, only a minority receive statins. Statins have demonstrated their immune-regulatory properties, showing efficacy in the activity of the disease and should be potentially prescribed in all of our patients, even without other CVD risk factors.
1. So H, Lam TO, Meng H, Lam SHM, Tam LS. Time and dose-dependent effect of systemic glucocorticoids on major adverse cardiovascular event in patients with rheumatoid arthritis: a population-based study. Ann Rheum Dis 2023;0: 1–7. doi:10.1136/ard-2023-224185
2. Fraenkel L, Bathon JM, England BR, et al. American college of rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken) 2021; 73: 924-39.
3. Smolen JS, Landewe RBM, Bergstra SA, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2022 update. Ann Rheum Dis 2022; 82: 3-18.
4. van Ouwerkerk L, Boers M, Emery P, de Jong PHP, Landewé RBM, Lems W et al. Individual patient data meta-analysis on continued use of glucocorticoids after their initiation as bridging therapy in patients with rheumatoid arthritis. Ann Rheum Dis 2023; 82: 468–475. doi:10.1136/ard-2022-223443
5. Doumen M, Pazmino S, Bertrand D, Westhovens R, Verschueren P. Glucocorticoids in rheumatoid arthritis: Balancing benefits and harm by leveraging the therapeutic window of opportunity. Joint Bone Spine 2023; 90: 105491. doi: 10.1016/j.jbspin.2022.105491.
6. Kirwan JR, Bijlsma JW, Boers M, Shea BJ. Effects of glucocorticoids on radiological progression in rheumatoid arthritis. Cochrane Database Syst Rev. 2007; 2007:CD006356. doi: 10.1002/14651858.CD006356.
7. Pincus T, Sokka T Castrejón I, Cutolo M. Decline of Mean Initial Prednisone Dosage From 10.3 to 3.6 mg/day to Treat Rheumatoid Arthritis Between 1980 and 2004 in One Clinical Setting, With Long-Term Effectiveness of Dosages Less Than 5 mg/day. Arthritis Care Res 2013; 65: 729-36. DOI 10.1002/acr.21899
8. Messina OD, Vidal LF, Wilman MV, Bultink IEM, Raterman HG, Lems W. Management of glucocorticoid-induced osteoporosis. Aging Clin Exp Res 2021; 33: 793-804. doi: 10.1007/s40520-021-01823-0.
9. George MD, Baker JF, Winthrop K, Hsu JY, Wu Q, Chen L, Xie F, Yun H, Curtis JR. Risk for serious infection with low-dose glucocorticoids in patients with rheumatoid arthritis : A cohort study. Ann Intern Med. 2020; 173: 870-8. doi: 10.7326/M20-1594.
10. Bergstra SA, Sepriano A, Kerschbaumer A, John Edwards C, van der Heijde D, Caporali R et al. Efficacy, duration of use and safety of glucocorticoids: a systematic literature review informing the 2022 update of the EULAR recommendations for the management of rheumatoid arthritis. Ann Rheum Dis.2022 Nov 21;ard-2022-223358. doi: 10.1136/ard-2022-223358.
11. Boers M, Hartman L, Opris-Belinski D, Bos R, Kok MR, Da Silva JAP et al. Low dose, add-on prednisolone in patients with rheumatoid arthritis aged 65+: the pragmatic randomised, double-blind placebo-controlled GLORIA trial. Ann Rheum Dis. 2022; 81: 925–936. doi: 10.1136/annrheumdis-2021-221957.
I wish to offer a comprehensive commentary on the article titled "Effect of Tapered versus Stable Treatment with Tumour Necrosis Factor Inhibitors on Disease Flares in Patients with Rheumatoid Arthritis in Remission: A Randomised, Open-Label, Non-Inferiority Trial"(1) authored by Lillegraven et al., published in Annals of the Rheumatic Diseases. This investigation is commendable for its rigorous scientific inquiry into the optimal management of patients with rheumatoid arthritis (RA) in prolonged remission, specifically addressing the contentious issue of tapering tumor necrosis factor inhibitors (TNFi) in this clinical context. I applaud the authors for their meticulous design, execution, and interpretation of the study's findings.
The authors' inquiry into the therapeutic approaches pertinent to patients with RA who have attained sustained remission is a timely and pertinent endeavor. Contemporary treatment paradigms have demonstrated that achieving remission necessitates the integration of TNFi therapy in patients exhibiting inadequate response or an inability to attain remission solely through methotrexate monotherapy. However, the broader clinical strategy concerning the tapering of TNFi in patients having achieved remission remains unresolved within the extant literature. The article under consideration offers a thoughtful exploration of this topic, effectively elucidating the consequences of tapering TNFi therapy to disc...
I wish to offer a comprehensive commentary on the article titled "Effect of Tapered versus Stable Treatment with Tumour Necrosis Factor Inhibitors on Disease Flares in Patients with Rheumatoid Arthritis in Remission: A Randomised, Open-Label, Non-Inferiority Trial"(1) authored by Lillegraven et al., published in Annals of the Rheumatic Diseases. This investigation is commendable for its rigorous scientific inquiry into the optimal management of patients with rheumatoid arthritis (RA) in prolonged remission, specifically addressing the contentious issue of tapering tumor necrosis factor inhibitors (TNFi) in this clinical context. I applaud the authors for their meticulous design, execution, and interpretation of the study's findings.
The authors' inquiry into the therapeutic approaches pertinent to patients with RA who have attained sustained remission is a timely and pertinent endeavor. Contemporary treatment paradigms have demonstrated that achieving remission necessitates the integration of TNFi therapy in patients exhibiting inadequate response or an inability to attain remission solely through methotrexate monotherapy. However, the broader clinical strategy concerning the tapering of TNFi in patients having achieved remission remains unresolved within the extant literature. The article under consideration offers a thoughtful exploration of this topic, effectively elucidating the consequences of tapering TNFi therapy to discontinuation.
The methodological stringency underpinning this study is noteworthy. Its randomized, open-label, non-inferiority design, executed across multiple rheumatology departments in Norway, bestows robustness upon the findings. The holistic assessment of patients through clinical and ultrasonographic examinations serves to enhance the reliability and granularity of the observed outcomes. Notwithstanding, the authors astutely acknowledge potential limitations such as the open-label nature of the trial and attendant biases stemming from patient expectations. This transparency is pivotal in contextualizing the findings within the broader landscape of rheumatological research.
Emanating from the study are cogent implications challenging the feasibility of tapering TNFi therapy to discontinuation in patients with RA in sustained remission. A notable disparity in disease flare rates between patients who underwent tapering and those subjected to stable therapy is delineated. This pronounced divergence corroborates the empirical notion that cessation of TNFi therapy is associated with an elevated risk of disease reactivation. Such findings, if corroborated across diverse cohorts, will invariably shape clinical practice by engendering a nuanced deliberation on therapeutic strategy among clinicians and their patients.
The article's thrust extends beyond the examination of clinical outcomes and merits consideration in light of existing literature. The authors astutely draw attention to the complex interplay between TNFi and other disease-modifying antirheumatic drugs (DMARDs) in the context of tapering strategies. This mechanistic insight underscores the multifaceted nature of therapeutic interventions and portends the necessity for tailored therapeutic approaches. Moreover, the article's discourse on the sustained remission outcomes among patients who experienced flares and subsequently regained remission following the reinstatement of full-dose treatment is germane to a holistic comprehension of therapeutic strategies in RA.
The scholarly discourse is further enriched through the discussion of methodological considerations and the juxtaposition of the study's outcomes against the broader literature. A lucid acknowledgment of the challenges posed by cross-study comparisons, consequent to disparate inclusion criteria and tapering protocols, evinces the authors' astute discernment. This salient insight underscores the need for standardized methodologies in future tapering studies. Additionally, the contemplation of the intricate interrelation between disease activity, TNFi administration, and radiographic joint damage, drawn from the extant literature, augments the study's depth and informs future research directions.
References
1. Siri L, Nina Paulshus S, Anna-Birgitte A, et al. Effect of tapered versus stable treatment with tumour necrosis factor inhibitors on disease flares in patients with rheumatoid arthritis in remission: a randomised, open label, non-inferiority trial. Annals of the Rheumatic Diseases. 2023:ard-2023-224476. doi: 10.1136/ard-2023-224476.
Dear Editor
Recently, we read an article entitled "Comparative safety and effectiveness of TNF inhibitors, IL6 inhibitors and methotrexate for the treatment of immune checkpoint inhibitor-associated arthritis." published by Bass, A. R. et al. contribution. The authors performed a retrospective analysis of outcomes in 147 patients with immune checkpoint inhibitor-associated inflammatory arthritis (ICI-IA) and compared tumor necrosis factor inhibitor (TNFi), interleukin-6 receptor inhibitor (IL6Ri) and/or methotrexate (MTX) on the efficacy and safety of this disease. The present study found that biologic disease-modifying antirheumatic drugs (DMARDs) brought arthritis under control more quickly than MTX for ICI-IA, but this may shorten the time to cancer progression. We are very grateful to the authors for their contributions, but some things still need to be addressed in this study.
First, in this study, doctors and patients were not blinded to treatment methods, so there may be an undiscovered selection or guidance bias. Zhang et al. 2 found that factors such as the beliefs and preferences of patients and doctors, disease monitoring requirements, and patient's compliance with treatment all impact the research results. Therefore, in this study, the author should fully consider the influence of the above factors on the research results. Second, the authors should also consider the effect of glucocorticoids on the efficacy of DMARDs. Studies have fo...
Dear Editor
Recently, we read an article entitled "Comparative safety and effectiveness of TNF inhibitors, IL6 inhibitors and methotrexate for the treatment of immune checkpoint inhibitor-associated arthritis." published by Bass, A. R. et al. contribution. The authors performed a retrospective analysis of outcomes in 147 patients with immune checkpoint inhibitor-associated inflammatory arthritis (ICI-IA) and compared tumor necrosis factor inhibitor (TNFi), interleukin-6 receptor inhibitor (IL6Ri) and/or methotrexate (MTX) on the efficacy and safety of this disease. The present study found that biologic disease-modifying antirheumatic drugs (DMARDs) brought arthritis under control more quickly than MTX for ICI-IA, but this may shorten the time to cancer progression. We are very grateful to the authors for their contributions, but some things still need to be addressed in this study.
First, in this study, doctors and patients were not blinded to treatment methods, so there may be an undiscovered selection or guidance bias. Zhang et al. 2 found that factors such as the beliefs and preferences of patients and doctors, disease monitoring requirements, and patient's compliance with treatment all impact the research results. Therefore, in this study, the author should fully consider the influence of the above factors on the research results. Second, the authors should also consider the effect of glucocorticoids on the efficacy of DMARDs. Studies have found that the use of glucocorticoids may impact the effectiveness of DMARDs3. This study should evaluate the relationship between glucocorticoids and DMARDs, which may affect the accuracy of the experimental results.
In this article, the authors wanted to compare further TNFi, IL6Ri and/or MTX efficacy and safety, but there is still some room for improvement. There is an inseparable relationship between the way of drug administration and drug efficacy. Bansback, N. et al. 4 studies found that different administration methods will produce different bioavailability, affecting DMARDs' efficacy. Therefore, this study should consider the bias brought about by administering the research results. Finally, we would like to thank the authors again for their contributions, which have greatly helped the treatment of ICI-IA.
Reference
1 Bass, A. R. et al. Comparative safety and effectiveness of TNF inhibitors, IL6 inhibitors and methotrexate for the treatment of immune checkpoint inhibitor-associated arthritis. Ann Rheum Dis 82, 920-926, doi:10.1136/ard-2023-223885 (2023).
2 Zhang, J. et al. Thresholds in disease activity for switching biologics in rheumatoid arthritis patients: experience from a large U.S. cohort. Arthritis Care Res (Hoboken) 63, 1672-1679, doi:10.1002/acr.20643 (2011).
3 Sebba, A. et al. Comparative effectiveness of TNF inhibitor vs IL-6 receptor inhibitor as monotherapy or combination therapy with methotrexate in biologic-experienced patients with rheumatoid arthritis: An analysis from the CorEvitas RA Registry. Clin Rheumatol 42, 2037-2051, doi:10.1007/s10067-023-06588-7 (2023).
4 Bansback, N., Trenaman, L. & Harrison, M. How important is mode of administration in treatments for rheumatic diseases and related conditions? Curr Rheumatol Rep 17, 514, doi:10.1007/s11926-015-0514-3 (2015).
I have read with great interest the study conducted by Zhu, et al. entitled Glucagon-like peptide-1 receptor agonists as a disease-modifying therapy for knee osteoarthritis mediated by weight loss: findings from the Shanghai Osteoarthritis Cohort. In this study, the authors found that regular use of GLP-1 RA was associated with a lower risk of future knee surgery among patients with knee osteoarthritis and type 2 diabetes. This association was partly mediated by weight loss (about 32.1%).
In this large cohort study, all the patients were enrolled at baseline from January 2011 to the end of 2016. A total of 233 patients were defined as regular users of GLP-RA (for at least 2 years) including liraglutide, dulaglutide, semaglutide, loxenatide, lisenatide and exenatide (see supplemental table S8 of the manuscript). However, concerns are thus raised that the series of cardiovascular outcome trials (CVOTs) of semaglutide (the SUSTAIN studies) was first published in November 2016 in the New England Journal of Medicine1 and was commercially available since 2017 in the US. In 2020, the phase I trial of semaglutide in China just got started2 and semaglutide was finally approved by NMPA in April 2021 in China. For loxenatide, the two most recent phase III clinical trials were published at the end of 20203 and in the early 2021.4 Loxenatide was finally commercially available in 2021.
Based on the above information, the timeline of the manuscript was rather confused. The...
I have read with great interest the study conducted by Zhu, et al. entitled Glucagon-like peptide-1 receptor agonists as a disease-modifying therapy for knee osteoarthritis mediated by weight loss: findings from the Shanghai Osteoarthritis Cohort. In this study, the authors found that regular use of GLP-1 RA was associated with a lower risk of future knee surgery among patients with knee osteoarthritis and type 2 diabetes. This association was partly mediated by weight loss (about 32.1%).
In this large cohort study, all the patients were enrolled at baseline from January 2011 to the end of 2016. A total of 233 patients were defined as regular users of GLP-RA (for at least 2 years) including liraglutide, dulaglutide, semaglutide, loxenatide, lisenatide and exenatide (see supplemental table S8 of the manuscript). However, concerns are thus raised that the series of cardiovascular outcome trials (CVOTs) of semaglutide (the SUSTAIN studies) was first published in November 2016 in the New England Journal of Medicine1 and was commercially available since 2017 in the US. In 2020, the phase I trial of semaglutide in China just got started2 and semaglutide was finally approved by NMPA in April 2021 in China. For loxenatide, the two most recent phase III clinical trials were published at the end of 20203 and in the early 2021.4 Loxenatide was finally commercially available in 2021.
Based on the above information, the timeline of the manuscript was rather confused. The authors should check the original data.
Ethics statements
Patient consent for publication
Not required.
References
1. Marso SP, Bain SC, Consoli A, et al. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2016;375(19):1834-1844.
2. Shi A, Xie P, Nielsen LL, Skjøth TV, He X, Haugaard SP. Pharmacokinetics, Safety and Tolerability of Once-Weekly Subcutaneous Semaglutide in Healthy Chinese Subjects: A Double-Blind, Phase 1, Randomized Controlled Trial. Adv Ther. 2021;38(1):550-561.
3. Gao F, Lv X, Mo Z, et al. Efficacy and safety of polyethylene glycol loxenatide as add-on to metformin in patients with type 2 diabetes: A multicentre, randomized, double-blind, placebo-controlled, phase 3b trial. Diabetes Obes Metab. 2020;22(12):2375-2383.
4. Shuai Y, Yang G, Zhang Q, et al. Efficacy and safety of polyethylene glycol loxenatide monotherapy in type 2 diabetes patients: A multicentre, randomized, double-blind, placebo-controlled phase 3a clinical trial. Diabetes Obes Metab. 2021;23(1):116-124.
We read with great interest the article by Zhu et al.1 entitled “Glucagon-like peptide-1 receptor agonists as a disease-modifying therapy for knee osteoarthritis mediated by weight loss: findings from the Shanghai Osteoarthritis Cohort”, which was a prospective cohort study to examine whether glucagon-like peptide-1 receptor agonists (GLP-1RAs) therapies could be disease-modifying for knee osteoarthritis (KOA) patients with comorbid type 2 diabetes mellitus (T2DM). Although we appreciate the work to pursue the potential effects of GLP-1RAs in KOA patients with T2DM, we would like to draw attention to three concerns that may affect the interpretation of the findings.
First, the authors used analytical methods that were suitable for randomized controlled trials, rather than cohorts, which may have underestimated the confounding effects (Table 2 and Table 4). Patients using GLP-1RAs often have better economic conditions, as well as possibly other indicators that could be potential confounders. Using real-world Chinese patient data, Wang et al2 reported that patients prescribed GLP-1RAs were generally younger, living in Tier 1 city and reported lower HbA1c, lower fasting plasma glucose measurements, and higher body mass index (BMI) than patients administered with insulin therapy. Although most of these variables were well-balanced except for sex (Table 1), it would be more convincing to use trial emulation methods, such as Propensity Score Matching (PSM) throughout the...
We read with great interest the article by Zhu et al.1 entitled “Glucagon-like peptide-1 receptor agonists as a disease-modifying therapy for knee osteoarthritis mediated by weight loss: findings from the Shanghai Osteoarthritis Cohort”, which was a prospective cohort study to examine whether glucagon-like peptide-1 receptor agonists (GLP-1RAs) therapies could be disease-modifying for knee osteoarthritis (KOA) patients with comorbid type 2 diabetes mellitus (T2DM). Although we appreciate the work to pursue the potential effects of GLP-1RAs in KOA patients with T2DM, we would like to draw attention to three concerns that may affect the interpretation of the findings.
First, the authors used analytical methods that were suitable for randomized controlled trials, rather than cohorts, which may have underestimated the confounding effects (Table 2 and Table 4). Patients using GLP-1RAs often have better economic conditions, as well as possibly other indicators that could be potential confounders. Using real-world Chinese patient data, Wang et al2 reported that patients prescribed GLP-1RAs were generally younger, living in Tier 1 city and reported lower HbA1c, lower fasting plasma glucose measurements, and higher body mass index (BMI) than patients administered with insulin therapy. Although most of these variables were well-balanced except for sex (Table 1), it would be more convincing to use trial emulation methods, such as Propensity Score Matching (PSM) throughout the main analysis to ensure more robust findings3,4.
Second, the authors focused on the impact of core exposure GLP-1RAs on the primary outcome of incident knee surgery after enrolment. Although this cohort was established from 2011 to 2017, dulaglutide was added to the Chinese market in 2019 and listed in the catalogue of medicines covered by the National Medical Insurance System (NMIS) in 2020, and semaglutide was approved for the Chinese market by the National Medical Products Administration in 20215. Therefore, the follow-up periods seem inadequate for outcomes such as joint replacement. In addition, it is worth noting that semaglutide resulted in greater weight loss when compared to liraglutide6. However, the author did not compare different administration methods (oral or injection), types of GLP-1RAs, and drug replacement during follow-up, which could have impacted the interpretation of the results.
Last, the sample size of the GLP-1RA group was much smaller than that of the non-GLP-1RA group, and there were only 4 endpoint events of knee surgery in the exposure group, indicating that the comparability between two groups was questionable and the results should be interpreted with caution.
References
1 Zhu H, Zhou L, Wang Q, et al. Glucagon-like peptide-1 receptor agonists as a disease-modifying therapy for knee osteoarthritis mediated by weight loss: findings from the Shanghai Osteoarthritis Cohort. Ann Rheum Dis Published Online First: 31 May 2023.
2 Wang K, Chen Y, Strizek A, et al. Comparison of Characteristics Between Chinese Patients Taking Glucagon-like Peptide 1 Receptor Agonists and Insulin: A Cross-sectional Database Analysis. Clin Ther. 2019 Oct;41(10):2057-2065.
3 Matthews AA, Danaei G, Islam N, et al. Target trial emulation: applying principles of randomised trials to observational studies. BMJ. 2022 Aug 30;378:e071108.
4 Hernán MA, Wang W, Leaf DE. Target Trial Emulation: A Framework for Causal Inference from Observational Data. JAMA. 2022 Dec 27;328(24):2446-2447.
5 Hu S, Gu S, Qi C, et al. Cost-utility analysis of semaglutide for type 2 diabetes after its addition to the National Medical Insurance System in China. Diabetes Obes Metab. 2023 Feb;25(2):387-397.
6 Jensterle M, Rizzo M, Haluzík M, et al. Efficacy of GLP-1 RA Approved for Weight Management in Patients with or Without Diabetes: A Narrative Review. Adv Ther. 2022 Jun;39(6):2452-2467.
*Corresponding Author
Z. Zhu. E-mail: zhaohua.zhu@utas.edu.au; Postal address: Clinical Research Centre, Zhujiang Hospital, Southern Medical University, Guangzhou, China, 510280; ORCiD iD: 0000-0003-3913-2564
Dear Editor,
We read with great interest the article by Bergstra et al., which demonstrated that residence at lower latitudes is associated with younger age of onset of rheumatoid arthritis (RA).[1] We are impressed by the in-depth explanation of how the level of socioeconomic welfare in different countries can contribute the results.[1] This contribution provides new insights into disease development and highlights the need for improving public health policies in many developing countries.
Geographical distribution, including latitude and altitude, is an important factor in several diseases. Previous studies revealed an association between geographical distribution and age of onset and severity of diseases such as systemic sclerosis and systemic lupus erythematosus.[2, 3] Furthermore, regional climate differences in similar latitude can lead different immune status in autoimmune disease.[4] The climate is influenced not only latitude or altitude but also other factors, such as ocean currents, prevailing winds, and vegetation cover. In previous studies, there is a possible association between climate factors and disease activity.[5, 6] On the other hand, for the evaluation of country-level factors, I thought that some index is more appropriate for the association survey, such as the human development index (HDI), the multidimensional poverty index (MPI), the social progress index (SPI).[7, 8]
In this study, the locations of each healthcare facility are cl...
Dear Editor,
We read with great interest the article by Bergstra et al., which demonstrated that residence at lower latitudes is associated with younger age of onset of rheumatoid arthritis (RA).[1] We are impressed by the in-depth explanation of how the level of socioeconomic welfare in different countries can contribute the results.[1] This contribution provides new insights into disease development and highlights the need for improving public health policies in many developing countries.
Geographical distribution, including latitude and altitude, is an important factor in several diseases. Previous studies revealed an association between geographical distribution and age of onset and severity of diseases such as systemic sclerosis and systemic lupus erythematosus.[2, 3] Furthermore, regional climate differences in similar latitude can lead different immune status in autoimmune disease.[4] The climate is influenced not only latitude or altitude but also other factors, such as ocean currents, prevailing winds, and vegetation cover. In previous studies, there is a possible association between climate factors and disease activity.[5, 6] On the other hand, for the evaluation of country-level factors, I thought that some index is more appropriate for the association survey, such as the human development index (HDI), the multidimensional poverty index (MPI), the social progress index (SPI).[7, 8]
In this study, the locations of each healthcare facility are clearly identified, allowing us to obtain clear information of climate classification and country-level socioeconomic or development index. Due to this strength, we have the following two suggestions:
First, we thought that the possible reasonable explanation that negligible results within the same country are that the correlation is not only due to the latitudes but also other climate factors, thus we suggest conducting correlation analysis using not only latitude but also considering climate classification, such as Köppen climate classification, and specific factors such as temperature variations and humidity to investigate the correlation between these factors and the onset age of RA if data available. This comprehensive analysis will help to further elucidate potential discrepancies and improve the accuracy of the correlation.
Second, considering the multidimensional perspective on socioeconomic status, HDI may be better for presentation than gross domestic product (GDP). Previous studies demonstrated the association between malignancy mortality, fatigue severity in RA patients and HDI, and we believed that such similar index is more appropriate to represent the socio-economic status of the country.[9, 10] Thus, I suggest that HDI, MPI, SPI or other similar index is executed to achieve a more accurate assessment of factors at the country level.
In conclusion, this article leads to a great contribution that latitude is a remarkable associated factor in the onset of age in rheumatoid arthritis, this highlighting the strong association between epidemiology and geography. To solve potential discrepancies and urge improvement of accuracy, we provide the suggestion mentioned in the article.
References
1. Bergstra, S.A., et al., Country-level socioeconomic status relates geographical latitude to the onset of RA: a worldwide cross-sectional analysis in the METEOR registry. Ann Rheum Dis, 2023.
2. Qian, G., et al., Systemic lupus erythematosus patients in the low-latitude plateau of China: altitudinal influences. Lupus, 2014. 23(14): p. 1537-1545.
3. Walker, U.A., et al., Geographical variation of disease manifestations in systemic sclerosis: a report from the EULAR Scleroderma Trials and Research (EUSTAR) group database. Ann Rheum Dis, 2009. 68(6): p. 856-62.
4. Kondo, Y., et al., Effect of climatic environment on immunological features of rheumatoid arthritis. Sci Rep, 2023. 13(1): p. 1304.
5. Rozin, A., A. Balbir-Gurman, and D. Schapira, Seasonal distribution of relapse onset in rheumatoid arthritis and spondyloarthropathy: the possible effect of the solar factor. Clinical and experimental rheumatology, 2003. 21(2): p. 161-170.
6. Yang, J., et al., Seasonal distribution of systemic lupus erythematosus activity and its correlation with climate factors. Rheumatol Int, 2012. 32(8): p. 2393-9.
7. Behera, D.K., Measuring socio-economic progress in India: issues and challenges. Revista Galega de Economia, 2016. 25(2): p. 117-132.
8. Kar, M., New Indicators and Measurement Methods for Welfare in the Global Economy Era, in Redefining Global Economic Thinking for the Welfare of Society. 2022, IGI Global. p. 8-32.
9. Hifinger, M., et al., In rheumatoid arthritis, country of residence has an important influence on fatigue: results from the multinational COMORA study. Rheumatology (Oxford), 2016. 55(4): p. 735-44.
10. Razi, S., et al., The incidence and mortality of ovarian cancer and their relationship with the Human Development Index in Asia. Ecancermedicalscience, 2016. 10: p. 628.
We were intrigued by the recently published paper in the Annals of Rheumatic Diseases titled "HLA-B27, Axial Spondyloarthritis, and Survival" by Li et al.[1] This study explores the association between HLA-B27 carriage, axial spondyloarthritis (axSpA), and survival, offering valuable insights. By combining data from a 35-year follow-up study of Ankylosing Spondylitis (AS) and axSpA patients with the extensive UK Biobank dataset, the study significantly enhances our understanding of mortality patterns in AS/axSpA and the potential impact of HLA-B27 in the general population. We consider this study's implications important and look forward to critically examining its key findings and broader implications. However, there are some concerns that would better be clarified.
First and foremost, the observed gender-based differences in AS mortality are intriguing, with women generally exhibiting less severe sacroiliac joint damage.[2] However, an important consideration is the potential influence of HPV infection.[3] Surprisingly, the original study did not account for this factor, despite previous research linking HPV infection to autoimmune diseases, including AS, and suggesting a significantly elevated risk for AS development in HPV-infected individuals.[4] These findings underscore the complex interplay between infectious agents and autoimmune conditions. Additionally, prior research has indicated higher mortality in HPV-infected patients, emphasizing the...
Show MoreTo the Editor,
Show MoreI am writing to address a recent article titled "Safety of colchicine and NSAID prophylaxis when initiating urate-lowering therapy for gout: propensity score-matched cohort studies in the UK Clinical Practice Research Datalink" (1). This study conducted two retrospective cohort studies to determine the risk of adverse events associated with colchicine or non-steroidal anti-inflammatory drug (NSAID) prophylaxis when initiating allopurinol for gout. The research presents valuable insights into the safety of these prophylactic measures, but it is essential to discuss both the limitations and strengths of this study.
The strengths of this study lie in its extensive sample size and its use of primary care consultation and prescription data linked to hospital records over a 20-year period. This approach provides a comprehensive and high-quality dataset, reflective of everyday clinical practice. The use of clinical diagnosis for gout, with a high positive predictive value, further reinforces the practical relevance of the study's findings. The researchers' recognition of limitations is commendable. It is essential to acknowledge that the observational design carries a risk of exposure status misclassification. Nevertheless, the study took measures to mitigate this risk through propensity score matching. Additionally, it should be noted that the study focused on adverse events severe enough to warrant consultation or hospitalization,...
Dear Editor,
We read with great interest the recent article by Roddy et al1 and commend their efforts to address a clinically relevant question using a large, generalizable database. However, we were surprised and concerned by their findings of notably increased absolute risks of serious adverse events with both colchicine and NSAID use, including neuropathy (4 excess cases/1000 person-years [PY]) and bone marrow suppression (10 excess cases/1000 PY) with colchicine and myocardial infarction (MI) with both colchicine (8 excess cases/1000 PY) and NSAIDs (6 excess cases/1000 PY). The corresponding HRs were 4.8, 3.3, 1.6, and 1.9, respectively. Together with the seriousness of these events, these data do not appear to support the authors’ conclusion that their findings provide reassurance for patients and clinicians. Conversely, if confirmed and true, these findings would raise safety concerns regarding the ACR/EULAR guideline recommendations, while being inconsistent with anecdotal clinical experience and recent randomized controlled trial (RCT) safety data.2,3 Indeed, the authors acknowledge that the higher MI risk with colchicine contradicts the RCT evidence4-6 demonstrating its cardiovascular benefit that resulted in FDA and EMA approval for MI prevention. All in all, we feel that additional analyses in the CPRD population and replications in different populations which consider the following would be critically important:
Show More1. New user, active control design:...
This is a very interesting observational study on the cardiovascular risks of glucocorticoid therapy in RA. I particularly appreciate the balanced discussion, pointing to the problems of confounding by indication that were most likely not (completely) addressed by the analysis technique.
Show MoreTo further understand the findings I have a couple of requests:
1. Could the authors more clearly document how the exposure to GC developed over time? E.g., how many patients were on a mean dose of < 5mg/d, ≥ 5mg/d etc. for a set period of time? Were patterns of GC dosing visible? Previous studies (e.g. Michaud et al[1]) have documented that GC dosing can be dynamic with stops and starts over a period of time.
2. The primary analysis is based on a cut point of prednisolone 5 mg/d. Could the authors repeat the analysis where low dose is defined as ≤ 5mg/d, so including the 5 mg/d, to see whether the risk estimates (against intermediate dose defined as > 5 mg/d) change substantially? And perhaps even one where low dose is defined as ≤ 7.5 mg/d (in agreement with Buttgereit et al[2])? Such analyses would help inform clinicians, given that 5 and 7.5 mg/d dosing schedules are very frequently applied.
3. I have argued that current statistical analyses that adjust risk estimates for disease activity are suboptimal, because they obscure the fact that disease activity under treatment with GC is lower than it would be without treatment.[3] So, I would suggest that the r...
The interesting paper by So et al.1 “Time and dose-dependent effect of systemic glucocorticoids on major adverse cardiovascular events in patients with rheumatoid arthritis” invites us to conduct an “artistic” dissection of glucocorticoids in our patients, remembering The Anatomy Lesson of Dr. Tulp by Rembrandt.
Show MoreRheumatoid arthritis (RA) is associated with CVD increased risk even before there is any clinical expression of RA, which continues to increase with the persistence and severity of the inflammatory process, making CVD the main cause of death particularly in seropositive patients.
The efficacy of glucocorticoids (GCs) is undeniable, including prevention or delay of structural changes, however, there is strong evidence that even “low doses” of GCs can increase the risk of CVD as well as other negative associations related to quality of life and survival. Additional to the risk of CVD associated to the systemic inflammatory nature of RA, 50% of the patients also have 1 or more other risk factors associated to major adverse cardiovascular events (MACE).1
The data presented emphasizes the potential presentation of MACE with GC-doses previously considered to be safe. Historically, the recommended therapeutic GC doses have been established based particularly on its efficacy, however, an increase of cardiovascular disease in 12 233 RA patients receiving more than 5 mg of prednisone per day has also been reported in this study, with reasonable follow up. 1...
Dear Editor,
I wish to offer a comprehensive commentary on the article titled "Effect of Tapered versus Stable Treatment with Tumour Necrosis Factor Inhibitors on Disease Flares in Patients with Rheumatoid Arthritis in Remission: A Randomised, Open-Label, Non-Inferiority Trial"(1) authored by Lillegraven et al., published in Annals of the Rheumatic Diseases. This investigation is commendable for its rigorous scientific inquiry into the optimal management of patients with rheumatoid arthritis (RA) in prolonged remission, specifically addressing the contentious issue of tapering tumor necrosis factor inhibitors (TNFi) in this clinical context. I applaud the authors for their meticulous design, execution, and interpretation of the study's findings.
Show MoreThe authors' inquiry into the therapeutic approaches pertinent to patients with RA who have attained sustained remission is a timely and pertinent endeavor. Contemporary treatment paradigms have demonstrated that achieving remission necessitates the integration of TNFi therapy in patients exhibiting inadequate response or an inability to attain remission solely through methotrexate monotherapy. However, the broader clinical strategy concerning the tapering of TNFi in patients having achieved remission remains unresolved within the extant literature. The article under consideration offers a thoughtful exploration of this topic, effectively elucidating the consequences of tapering TNFi therapy to disc...
Dear Editor
Show MoreRecently, we read an article entitled "Comparative safety and effectiveness of TNF inhibitors, IL6 inhibitors and methotrexate for the treatment of immune checkpoint inhibitor-associated arthritis." published by Bass, A. R. et al. contribution. The authors performed a retrospective analysis of outcomes in 147 patients with immune checkpoint inhibitor-associated inflammatory arthritis (ICI-IA) and compared tumor necrosis factor inhibitor (TNFi), interleukin-6 receptor inhibitor (IL6Ri) and/or methotrexate (MTX) on the efficacy and safety of this disease. The present study found that biologic disease-modifying antirheumatic drugs (DMARDs) brought arthritis under control more quickly than MTX for ICI-IA, but this may shorten the time to cancer progression. We are very grateful to the authors for their contributions, but some things still need to be addressed in this study.
First, in this study, doctors and patients were not blinded to treatment methods, so there may be an undiscovered selection or guidance bias. Zhang et al. 2 found that factors such as the beliefs and preferences of patients and doctors, disease monitoring requirements, and patient's compliance with treatment all impact the research results. Therefore, in this study, the author should fully consider the influence of the above factors on the research results. Second, the authors should also consider the effect of glucocorticoids on the efficacy of DMARDs. Studies have fo...
I have read with great interest the study conducted by Zhu, et al. entitled Glucagon-like peptide-1 receptor agonists as a disease-modifying therapy for knee osteoarthritis mediated by weight loss: findings from the Shanghai Osteoarthritis Cohort. In this study, the authors found that regular use of GLP-1 RA was associated with a lower risk of future knee surgery among patients with knee osteoarthritis and type 2 diabetes. This association was partly mediated by weight loss (about 32.1%).
In this large cohort study, all the patients were enrolled at baseline from January 2011 to the end of 2016. A total of 233 patients were defined as regular users of GLP-RA (for at least 2 years) including liraglutide, dulaglutide, semaglutide, loxenatide, lisenatide and exenatide (see supplemental table S8 of the manuscript). However, concerns are thus raised that the series of cardiovascular outcome trials (CVOTs) of semaglutide (the SUSTAIN studies) was first published in November 2016 in the New England Journal of Medicine1 and was commercially available since 2017 in the US. In 2020, the phase I trial of semaglutide in China just got started2 and semaglutide was finally approved by NMPA in April 2021 in China. For loxenatide, the two most recent phase III clinical trials were published at the end of 20203 and in the early 2021.4 Loxenatide was finally commercially available in 2021.
Based on the above information, the timeline of the manuscript was rather confused. The...
Show MoreWe read with great interest the article by Zhu et al.1 entitled “Glucagon-like peptide-1 receptor agonists as a disease-modifying therapy for knee osteoarthritis mediated by weight loss: findings from the Shanghai Osteoarthritis Cohort”, which was a prospective cohort study to examine whether glucagon-like peptide-1 receptor agonists (GLP-1RAs) therapies could be disease-modifying for knee osteoarthritis (KOA) patients with comorbid type 2 diabetes mellitus (T2DM). Although we appreciate the work to pursue the potential effects of GLP-1RAs in KOA patients with T2DM, we would like to draw attention to three concerns that may affect the interpretation of the findings.
First, the authors used analytical methods that were suitable for randomized controlled trials, rather than cohorts, which may have underestimated the confounding effects (Table 2 and Table 4). Patients using GLP-1RAs often have better economic conditions, as well as possibly other indicators that could be potential confounders. Using real-world Chinese patient data, Wang et al2 reported that patients prescribed GLP-1RAs were generally younger, living in Tier 1 city and reported lower HbA1c, lower fasting plasma glucose measurements, and higher body mass index (BMI) than patients administered with insulin therapy. Although most of these variables were well-balanced except for sex (Table 1), it would be more convincing to use trial emulation methods, such as Propensity Score Matching (PSM) throughout the...
Show MoreDear Editor,
Show MoreWe read with great interest the article by Bergstra et al., which demonstrated that residence at lower latitudes is associated with younger age of onset of rheumatoid arthritis (RA).[1] We are impressed by the in-depth explanation of how the level of socioeconomic welfare in different countries can contribute the results.[1] This contribution provides new insights into disease development and highlights the need for improving public health policies in many developing countries.
Geographical distribution, including latitude and altitude, is an important factor in several diseases. Previous studies revealed an association between geographical distribution and age of onset and severity of diseases such as systemic sclerosis and systemic lupus erythematosus.[2, 3] Furthermore, regional climate differences in similar latitude can lead different immune status in autoimmune disease.[4] The climate is influenced not only latitude or altitude but also other factors, such as ocean currents, prevailing winds, and vegetation cover. In previous studies, there is a possible association between climate factors and disease activity.[5, 6] On the other hand, for the evaluation of country-level factors, I thought that some index is more appropriate for the association survey, such as the human development index (HDI), the multidimensional poverty index (MPI), the social progress index (SPI).[7, 8]
In this study, the locations of each healthcare facility are cl...
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