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.
Dear Editor,
We read with great interest the paper published by Perez-Garcia et al [1] on ‘Is methotrexate safe for men with an immune-mediated inflammatory disease and an active desire to become a father? Results of a prospective cohort study (iFAME-MTX)’. The authors bring original data to address an important and controversial topic regarding the use of MTX in men with immune-mediated inflammatory diseases (IMIDs) who desire to father a child. They prospectively evaluated the testicular toxicity profile of MTX through quantitative and qualitative study of the sperm from treated patients. The strength of this study lies in its prospective design and comprehensive evaluation of various fertility markers in men exposed to MTX such as semen parameters, reproductive hormone levels, sperm DNA fragmentation index, and the presence of MTX-polyglutamates (MTX-PG) in spermatozoa. The author included three distinct groups, namely MTX-starters, MTX-chronic, and healthy controls, to provide a comparative analysis and highlight the impact of both short-term and long-term MTX exposure on male fertility. They observe that MTX exposure in men with IMIDs does not significantly affect conventional semen parameters, reproductive endocrine markers, or sperm DNA fragmentation index. These results provide reassurance regarding the start or continuation of MTX therapy in men planning to father a child, which align with the recent recommendations from the American College of Rheumatology...
Dear Editor,
We read with great interest the paper published by Perez-Garcia et al [1] on ‘Is methotrexate safe for men with an immune-mediated inflammatory disease and an active desire to become a father? Results of a prospective cohort study (iFAME-MTX)’. The authors bring original data to address an important and controversial topic regarding the use of MTX in men with immune-mediated inflammatory diseases (IMIDs) who desire to father a child. They prospectively evaluated the testicular toxicity profile of MTX through quantitative and qualitative study of the sperm from treated patients. The strength of this study lies in its prospective design and comprehensive evaluation of various fertility markers in men exposed to MTX such as semen parameters, reproductive hormone levels, sperm DNA fragmentation index, and the presence of MTX-polyglutamates (MTX-PG) in spermatozoa. The author included three distinct groups, namely MTX-starters, MTX-chronic, and healthy controls, to provide a comparative analysis and highlight the impact of both short-term and long-term MTX exposure on male fertility. They observe that MTX exposure in men with IMIDs does not significantly affect conventional semen parameters, reproductive endocrine markers, or sperm DNA fragmentation index. These results provide reassurance regarding the start or continuation of MTX therapy in men planning to father a child, which align with the recent recommendations from the American College of Rheumatology and the British Society for Rheumatology [2]. While this study provides significant insights, it is important to acknowledge some limitations, and mitigate the authors conclusions.
First, the sample size, particularly in the MTX-chronic group, is small (n = 5), which may affect the generalizability of the findings and inadequately represent the diversity of IMID patients receiving chronic MTX therapy. Importantly, small groups lead to insufficient statistical powers and an inability to demonstrate statistical differences. As an example, median spermatozoa concentration is 37x106/mL of sperm in chronic MTX users, whereas it is 60x106/mL in healthy donors or 57x106/mL in IMIDs patients not treated. These numerical differences (38% and 35% decreases, respectively) may reach statistical significance with bigger groups. The study did not provide detailed information on the MTX dosage and treatment duration for the participants. Chronic MTX users may have been on different doses and treatment durations, leading to varying cumulative exposure levels. This information is crucial as the effects on fertility may depend on the total amount of MTX received over time. Without considering cumulative exposure, the conclusion may not accurately reflect the potential impact of long-term MTX use on fertility.
Second, the authors use biological surrogates (concentration of MTX-PG, spermatozoa quantity and morphology, DNA fragmentation index) to evaluate MTX impact on semen. The use of these biological surrogates, although reassuring, cannot replace the evaluation of clinically relevant endpoints that are live birth, birth defect, and developmental abnormality of the child. While MTX-PG is relatively low in spermatozoa, it is high in the seminal fluid, which could impact the newly fertilized egg. A recent meta-analysis graded the evidence on the impact paternal exposure of MTX from “low” to “very low” [3], and a small cohort study has reported birth defect after paternal exposure [4]. Therefore, although the current study brings forward important and reassuring data, we believe that the study abstract conclusion stating that MTX therapy can be safely started or continued in men with a wish to conceive is incompletely supported by the authors data and the current literature. The precautionary principle should be used while good quality clinical data are not available to keep our oath, “Primum non nocere”.
REFERENCES
1 Perez-Garcia LF, Röder E, Krijthe BP, et al. Is methotrexate safe for men with an immune-mediated inflammatory disease and an active desire to become a father? Results of a prospective cohort study (iFAME-MTX). Ann Rheum Dis Published Online First: 1 June 2023. doi:10.1136/ard-2023-224032
2 Russell MD, Dey M, Flint J, et al. British Society for Rheumatology guideline on prescribing drugs in pregnancy and breastfeeding: immunomodulatory anti-rheumatic drugs and corticosteroids. Rheumatology 2023;62:e48–88. doi:10.1093/rheumatology/keac551
3 Mouyis M, Flint JD, Giles IP. Safety of anti-rheumatic drugs in men trying to conceive: A systematic review and analysis of published evidence. Semin Arthritis Rheum 2019;48:911–20. doi:10.1016/j.semarthrit.2018.07.011
4 Saougou I, Markatseli TE, Papagoras C, et al. Fertility in male patients with seronegative spondyloarthropathies treated with infliximab. Joint Bone Spine 2013;80:34–7. doi:10.1016/j.jbspin.2012.03.004
Dear Editors,
I read with great interest the report by Bergstra et al. (2023) on a cross-sectional analysis of rheumatoid arthritis patients from the worldwide METEOR registry1. The study is commendable for its sample size and geographical distribution of rheumatoid patients from 17 countries and 93 hospitals. Latitude has been defined as a potential underlying associative factor of early onset of rheumatoid arthritis among individuals living near the equator, which could be explained with socioeconomic status and accessibility to social welfare.
I have a few questions regarding the outcome measures and patient distribution. First, from which 17 countries were patients included, and how many patients were presented from each country along with the corresponding hospitals' latitudes? Second, were the included hospitals and countries were stratified to lower, middle, and higher latitudes, considering the disparities in socioeconomic status among low- and middle-income (LCMI) countries? These LCMI countries often have wider socioeconomic gaps, creating a complex scenario where diagnostic and treatment modalities for rheumatoid arthritis, as well as healthcare awareness, may not be uniform across rural and urban settings. This could potentially impact patient representation in the study. Third, were the included patients from low and middle socioeconomic statuses primarily presented from metro cities? It is worth noting that a majority of the patients in thi...
Dear Editors,
I read with great interest the report by Bergstra et al. (2023) on a cross-sectional analysis of rheumatoid arthritis patients from the worldwide METEOR registry1. The study is commendable for its sample size and geographical distribution of rheumatoid patients from 17 countries and 93 hospitals. Latitude has been defined as a potential underlying associative factor of early onset of rheumatoid arthritis among individuals living near the equator, which could be explained with socioeconomic status and accessibility to social welfare.
I have a few questions regarding the outcome measures and patient distribution. First, from which 17 countries were patients included, and how many patients were presented from each country along with the corresponding hospitals' latitudes? Second, were the included hospitals and countries were stratified to lower, middle, and higher latitudes, considering the disparities in socioeconomic status among low- and middle-income (LCMI) countries? These LCMI countries often have wider socioeconomic gaps, creating a complex scenario where diagnostic and treatment modalities for rheumatoid arthritis, as well as healthcare awareness, may not be uniform across rural and urban settings. This could potentially impact patient representation in the study. Third, were the included patients from low and middle socioeconomic statuses primarily presented from metro cities? It is worth noting that a majority of the patients in this study are from India, with unequal distribution of hospitals with rheumatoid care facilities.
Fourth, how participating hospitals and included patients in India and countries nearing to equators were stratified by latitude beyond the Tropic of Cancer? Apart from latitude, air pollution and vitamin D deficiency are also considered potent risk factors for the onset of autoimmune diseases. The Italian cohort (n = 81,363) demonstrates that long-term exposure to air pollution increases the risk of autoimmune disease. Specifically, exposure to particulate matter of 10PM increases the risk of rheumatoid arthritis, while exposure to particles of size 2.5PM or less increases the risk of multiple autoimmune diseases2. The relationship between vitamin D deficiency and the prevalence of autoimmune diseases, including rheumatoid arthritis, remains debatable3. If vitamin D deficiency is not a surrogate marker and a plausible cause of rheumatoid arthritis, environmental triggers should be stratified by latitude.
It is important to note that latitude and socioeconomic status are not direct causes but rather indirect factors contributing to autoimmune diseases and rheumatoid arthritis. Considering the influence of air pollution, sunlight exposure, access to and awareness of healthcare services, demographics, age, sex, and genetic makeup, it is intriguing to consider latitude as a risk factor for rheumatoid arthritis and other autoimmune diseases1. Therefore, large-scale cohorts investigating risk factors for autoimmune diseases should be widely stratified.
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, doi:10.1136/ard-2023-224080 (2023).
2 Adami, G. et al. Association between long-term exposure to air pollution and immune-mediated diseases: a population-based cohort study. RMD Open 8, doi:10.1136/rmdopen-2021-002055 (2022).
3 Clasen, J. L., Cole, R., Aune, D., Sellon, E. & Heath, A. K. Vitamin D status and risk of rheumatoid arthritis: systematic review and meta-analysis. BMC Rheumatol 7, 3, doi:10.1186/s41927-023-00325-y (2023).
We would like to thank dr. Mahla for his interest in our paper and respond to the questions asked. The first question relates to the included patients, hospitals and countries. We were able to analyze 37,981 patients from 93 hospitals in 17 countries. Information on the included countries, and the number of patients and hospitals per country is provided in the original manuscript in table 1. Hospital latitudes are displayed in figure 1.
As we mentioned in the discussion section, one of the main limitations of our paper is that the number of patients per hospital/country strongly differs and it is impossible to determine to what extent these patients are representative of all patients with RA in a country. Especially in lower- and middle income economies, healthcare disparities may be significant and we were unable to include individual patients’ socioeconomic data . As an example, dr. Mahla mentions India, the country with the largest contribution of patients to our study. We performed a sensitivity analysis excluding India, and found very similar results.
Most countries were represented by only a limited number of hospitals. These were primarily located in cities. Whereas especially in lower income countries these hospitals serve a large area, this may have led to an underrepresentation of patients living in rural areas. We can only speculate on how this may have influenced our findings, which may not only depend on regional and personal socioeconomic circumst...
We would like to thank dr. Mahla for his interest in our paper and respond to the questions asked. The first question relates to the included patients, hospitals and countries. We were able to analyze 37,981 patients from 93 hospitals in 17 countries. Information on the included countries, and the number of patients and hospitals per country is provided in the original manuscript in table 1. Hospital latitudes are displayed in figure 1.
As we mentioned in the discussion section, one of the main limitations of our paper is that the number of patients per hospital/country strongly differs and it is impossible to determine to what extent these patients are representative of all patients with RA in a country. Especially in lower- and middle income economies, healthcare disparities may be significant and we were unable to include individual patients’ socioeconomic data . As an example, dr. Mahla mentions India, the country with the largest contribution of patients to our study. We performed a sensitivity analysis excluding India, and found very similar results.
Most countries were represented by only a limited number of hospitals. These were primarily located in cities. Whereas especially in lower income countries these hospitals serve a large area, this may have led to an underrepresentation of patients living in rural areas. We can only speculate on how this may have influenced our findings, which may not only depend on regional and personal socioeconomic circumstances and access to healthcare, but also on intangible factors that we were unable to measure.
Dr. Mahla gives a few examples: healthcare awareness, air pollution, vitamin D deficiency and genetic make-up. Unfortunately, reliable data on these factors were not available at either the patient or hospital level. Other factors such as demographics, age and sex were included in our model but did not satisfactorily explain the association between latitude and age at disease onset.
The final question relates to a stratification of latitude, for countries nearing the equator and for countries with a different socioeconomic status. We used a structural equation model, to assess the association between latitude and age at onset. In this model, we treated latitude as a continuous variable. Only some of the patient factors (ACPA, rheumatoid factor, ever smoking and sex) were included as dichotomous variables. All other variables, including indicators of country level socioeconomic status (e.g. GDP per capita) were treated as continuous variables. No stratified analyses were performed. We also refer to figures 2 and 3 in our original manuscript.
Only 8 hospitals are located in the southern hemisphere, at negative latitude. Since we observed no interaction between latitude and hemisphere (i.e. the association between latitude and age at onset was similar at the northern and southern hemisphere), all negative latitudes were artificially converted into positive latitudes.
We hope this response will contribute to further clarification of our results and conclusion.
The article says that "At the end of the inclusion consultation, rheumatologists initiated a first targeted therapy: 8.6% by bDMARDs etc.". That number is actually wrong, probably because a typing issue. The actual number would be 89.6%.
Recently, we have been very interested in the article: "Increased risk of osteoarthritis in patients with atopic disease" by Baker et al. [1]. In this article, the author analyzed the incidence of OA in patients with atopic disease in two databases, suggesting that the immune response to atopic illness contributes to the increased incidence of OA. This study provides a new direction for immunotherapy against OA.
Overall, the authors' research design is meticulous. In two different databases, the author divided the idiopathic disease exposure group and the non-exposed group. The author strictly stipulated the sequence of idiopathic diseases and OA to ensure the impact of idiopathic diseases on OA. Matching was performed for age, sex, race/ethnicity, education level, Charlson comorbidity score, follow-up time, and clinic visit frequency, effectively reducing these factors influence. Furthermore, OA risk was reduced after adjusting for BMI in the STARR cohort, confirming that BMI is an independent confounding factor. However, although the authors analyzed various limitations of this study in the Discussion section, there are still some unmentioned issues worth considering.
First, to reduce the influence of confounding factors, the author matched and adjusted multiple independent factors, including age, gender, and BMI. In addition, the impact of factors such as history of joint trauma and physical activity level were mentioned in the discussion sect...
Recently, we have been very interested in the article: "Increased risk of osteoarthritis in patients with atopic disease" by Baker et al. [1]. In this article, the author analyzed the incidence of OA in patients with atopic disease in two databases, suggesting that the immune response to atopic illness contributes to the increased incidence of OA. This study provides a new direction for immunotherapy against OA.
Overall, the authors' research design is meticulous. In two different databases, the author divided the idiopathic disease exposure group and the non-exposed group. The author strictly stipulated the sequence of idiopathic diseases and OA to ensure the impact of idiopathic diseases on OA. Matching was performed for age, sex, race/ethnicity, education level, Charlson comorbidity score, follow-up time, and clinic visit frequency, effectively reducing these factors influence. Furthermore, OA risk was reduced after adjusting for BMI in the STARR cohort, confirming that BMI is an independent confounding factor. However, although the authors analyzed various limitations of this study in the Discussion section, there are still some unmentioned issues worth considering.
First, to reduce the influence of confounding factors, the author matched and adjusted multiple independent factors, including age, gender, and BMI. In addition, the impact of factors such as history of joint trauma and physical activity level were mentioned in the discussion section. However, the pathogenesis of OA is complex. In addition to the factors mentioned in the article, the patient's smoking history, drinking history, and other living habits are essential factors affecting OA [2]. These confounding factors may affect the accuracy of the results. In another study, the author mentioned that in sedentary patients, the relationship between atopic dermatitis and osteoarthritis might be closer [3], which suggests that our occupation-related living habits also affect idiopathic diseases and the incidence of OA rate factor.
Second, recall bias is a problem that any retrospective study has to face. The author uses the International Classification of Disease (ICD) code 9 or 10 as the inclusion criteria for the disease. One of the problems here is the need for clinical experience in diagnosing the disease, and there may be differences in the results due to the diagnostic criteria of different ages and the diagnosis of other doctors.
Third, for idiopathic diseases, the authors discuss the contribution of idiopathic dermatitis and asthma to the increased incidence of OA. Idiopathic disease is an immune disease with elevated IgE levels. In addition to idiopathic dermatitis and asthma, joint diseases include hay fever [4]. The article does not discuss hay fever, which may include omitting objectives.
Also, we mentioned some suggestions. To exclude the influence of general lung diseases, the author compared the prevalence of OA in COPD patients and asthma patients, confirmed that COPD and other prevalent lung diseases do not affect the incidence of OA, and further confirmed that OA causes asthma through an immune response. We believe that the comparison between COPD patients and patients with non-idiopathic diseases can be increased, and it can be more directly explained that widespread lung diseases such as COPD do not affect the occurrence of OA. In this study, the impact of pre-existing idiopathic conditions on the event of OA was explored. In the future, whether patients with pre-existing OA will lead to the occurrence of idiopathic diseases is also a direction worthy of research.
We thank the authors again for their contributions and look forward to their responses.
Reference:
[1] M.C. Baker, K. Sheth, R. Lu, D. Lu, E.P. von Kaeppler, A. Bhat, D.T. Felson, W.H. Robinson, Increased risk of osteoarthritis in patients with atopic disease, Ann Rheum Dis 82(6) (2023) 866-872.
[2] J.M. Gwinnutt, M. Wieczorek, A. Balanescu, H.A. Bischoff-Ferrari, A. Boonen, G. Cavalli, S. de Souza, A. de Thurah, T.E. Dorner, R.H. Moe, P. Putrik, J. Rodriguez-Carrio, L. Silva-Fernandez, T. Stamm, K. Walker-Bone, J. Welling, M.I. Zlatkovic-Svenda, F. Guillemin, S.M.M. Verstappen, 2021 EULAR recommendations regarding lifestyle behaviours and work participation to prevent progression of rheumatic and musculoskeletal diseases, Ann Rheum Dis 82(1) (2023) 48-56.
[3] J. Liu, A. Martin, A. Thatiparthi, J.J. Wu, Association between atopic dermatitis and osteoarthritis among US adults in the 1999-2006 NHANES, J Eur Acad Dermatol Venereol 35(6) (2021) e375-e377.
[4] M. Rudwaleit, B. Andermann, R. Alten, H. Sorensen, J. Listing, A. Zink, J. Sieper, J. Braun, Atopic disorders in ankylosing spondylitis and rheumatoid arthritis, Ann Rheum Dis 61(11) (2002) 968-74.
We thank Dr Bitoun et al for their careful reading of our manuscript. We acknowledge that the small number of patients experiencing cancer progression in our study is a limitation as it reduced the number of covariates that could be analyzed. However, in individual unadjusted Cox models analyses we did not find that age, sex, cancer type, cancer stage, ICI type, ICI discontinuation, concomitant irAE or steroid duration were associated with progression free survival suggesting that inclusion of these covariates in a larger study might not have influenced our findings.
We do agree that arthritis disease activity is an important confounder of DMARD choice. However, in our cohort, arthritis grade at the time of presentation was similar across the groups (p=0.67). Unfortunately, other measures of disease activity such as DAS28 were not available in this retrospective study. In addition, to address potential bias arising from biologic DMARD-treated patients’ being treated earlier because of more severe arthritis, we included the time-dependent variable “time from ICI initiation to DMARD initiation” into our model (an analysis in which there was no censoring at the time of DMARD switch). With this covariate included, our results favoring methotrexate in comparison to a TNF inhibitor became if anything, stronger (HR 3.27, 95% CI 1.21-8.84, p=0.019). The two methods commonly used to account for immortal time bias are landmark models and time dependent covariates. We chos...
We thank Dr Bitoun et al for their careful reading of our manuscript. We acknowledge that the small number of patients experiencing cancer progression in our study is a limitation as it reduced the number of covariates that could be analyzed. However, in individual unadjusted Cox models analyses we did not find that age, sex, cancer type, cancer stage, ICI type, ICI discontinuation, concomitant irAE or steroid duration were associated with progression free survival suggesting that inclusion of these covariates in a larger study might not have influenced our findings.
We do agree that arthritis disease activity is an important confounder of DMARD choice. However, in our cohort, arthritis grade at the time of presentation was similar across the groups (p=0.67). Unfortunately, other measures of disease activity such as DAS28 were not available in this retrospective study. In addition, to address potential bias arising from biologic DMARD-treated patients’ being treated earlier because of more severe arthritis, we included the time-dependent variable “time from ICI initiation to DMARD initiation” into our model (an analysis in which there was no censoring at the time of DMARD switch). With this covariate included, our results favoring methotrexate in comparison to a TNF inhibitor became if anything, stronger (HR 3.27, 95% CI 1.21-8.84, p=0.019). The two methods commonly used to account for immortal time bias are landmark models and time dependent covariates. We chose to use time dependent covariates because landmark methods are dependent on the choice of landmark, which might be incorrect, and can be prone to bias.1
While clinical trial emulation could be very informative, we did not have a study population with similar enough pre-DMARD characteristics to accurately simulate a trial population. Of course, we also agree that a prospective clinical trial would ultimately best answer the important questions posed on how DMARDs may impact cancer progression while optimizing arthritis control and quality of life.
Finally, we do recognize that there are patients with very severe ICI arthritis who require fast acting treatment such as with a biologic DMARD, and we are not suggesting that effective therapy should be withheld in these cases. However, there may be other situations where there is clinical equipoise regarding DMARD choice, and in those situations our study suggests that methotrexate is a safer approach.
1Jones M, Fowler R. Immortal time bias in observational studies of time-to-event outcomes. J Crit Care. 2016 Dec; 36:195-199. PMID: 27546771.
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...
Dear Editor,
Show MoreWe read with great interest the paper published by Perez-Garcia et al [1] on ‘Is methotrexate safe for men with an immune-mediated inflammatory disease and an active desire to become a father? Results of a prospective cohort study (iFAME-MTX)’. The authors bring original data to address an important and controversial topic regarding the use of MTX in men with immune-mediated inflammatory diseases (IMIDs) who desire to father a child. They prospectively evaluated the testicular toxicity profile of MTX through quantitative and qualitative study of the sperm from treated patients. The strength of this study lies in its prospective design and comprehensive evaluation of various fertility markers in men exposed to MTX such as semen parameters, reproductive hormone levels, sperm DNA fragmentation index, and the presence of MTX-polyglutamates (MTX-PG) in spermatozoa. The author included three distinct groups, namely MTX-starters, MTX-chronic, and healthy controls, to provide a comparative analysis and highlight the impact of both short-term and long-term MTX exposure on male fertility. They observe that MTX exposure in men with IMIDs does not significantly affect conventional semen parameters, reproductive endocrine markers, or sperm DNA fragmentation index. These results provide reassurance regarding the start or continuation of MTX therapy in men planning to father a child, which align with the recent recommendations from the American College of Rheumatology...
Dear Editors,
I read with great interest the report by Bergstra et al. (2023) on a cross-sectional analysis of rheumatoid arthritis patients from the worldwide METEOR registry1. The study is commendable for its sample size and geographical distribution of rheumatoid patients from 17 countries and 93 hospitals. Latitude has been defined as a potential underlying associative factor of early onset of rheumatoid arthritis among individuals living near the equator, which could be explained with socioeconomic status and accessibility to social welfare.
I have a few questions regarding the outcome measures and patient distribution. First, from which 17 countries were patients included, and how many patients were presented from each country along with the corresponding hospitals' latitudes? Second, were the included hospitals and countries were stratified to lower, middle, and higher latitudes, considering the disparities in socioeconomic status among low- and middle-income (LCMI) countries? These LCMI countries often have wider socioeconomic gaps, creating a complex scenario where diagnostic and treatment modalities for rheumatoid arthritis, as well as healthcare awareness, may not be uniform across rural and urban settings. This could potentially impact patient representation in the study. Third, were the included patients from low and middle socioeconomic statuses primarily presented from metro cities? It is worth noting that a majority of the patients in thi...
Show MoreWe would like to thank dr. Mahla for his interest in our paper and respond to the questions asked. The first question relates to the included patients, hospitals and countries. We were able to analyze 37,981 patients from 93 hospitals in 17 countries. Information on the included countries, and the number of patients and hospitals per country is provided in the original manuscript in table 1. Hospital latitudes are displayed in figure 1.
Show MoreAs we mentioned in the discussion section, one of the main limitations of our paper is that the number of patients per hospital/country strongly differs and it is impossible to determine to what extent these patients are representative of all patients with RA in a country. Especially in lower- and middle income economies, healthcare disparities may be significant and we were unable to include individual patients’ socioeconomic data . As an example, dr. Mahla mentions India, the country with the largest contribution of patients to our study. We performed a sensitivity analysis excluding India, and found very similar results.
Most countries were represented by only a limited number of hospitals. These were primarily located in cities. Whereas especially in lower income countries these hospitals serve a large area, this may have led to an underrepresentation of patients living in rural areas. We can only speculate on how this may have influenced our findings, which may not only depend on regional and personal socioeconomic circumst...
The article says that "At the end of the inclusion consultation, rheumatologists initiated a first targeted therapy: 8.6% by bDMARDs etc.". That number is actually wrong, probably because a typing issue. The actual number would be 89.6%.
Recently, we have been very interested in the article: "Increased risk of osteoarthritis in patients with atopic disease" by Baker et al. [1]. In this article, the author analyzed the incidence of OA in patients with atopic disease in two databases, suggesting that the immune response to atopic illness contributes to the increased incidence of OA. This study provides a new direction for immunotherapy against OA.
Show MoreOverall, the authors' research design is meticulous. In two different databases, the author divided the idiopathic disease exposure group and the non-exposed group. The author strictly stipulated the sequence of idiopathic diseases and OA to ensure the impact of idiopathic diseases on OA. Matching was performed for age, sex, race/ethnicity, education level, Charlson comorbidity score, follow-up time, and clinic visit frequency, effectively reducing these factors influence. Furthermore, OA risk was reduced after adjusting for BMI in the STARR cohort, confirming that BMI is an independent confounding factor. However, although the authors analyzed various limitations of this study in the Discussion section, there are still some unmentioned issues worth considering.
First, to reduce the influence of confounding factors, the author matched and adjusted multiple independent factors, including age, gender, and BMI. In addition, the impact of factors such as history of joint trauma and physical activity level were mentioned in the discussion sect...
We thank Dr Bitoun et al for their careful reading of our manuscript. We acknowledge that the small number of patients experiencing cancer progression in our study is a limitation as it reduced the number of covariates that could be analyzed. However, in individual unadjusted Cox models analyses we did not find that age, sex, cancer type, cancer stage, ICI type, ICI discontinuation, concomitant irAE or steroid duration were associated with progression free survival suggesting that inclusion of these covariates in a larger study might not have influenced our findings.
We do agree that arthritis disease activity is an important confounder of DMARD choice. However, in our cohort, arthritis grade at the time of presentation was similar across the groups (p=0.67). Unfortunately, other measures of disease activity such as DAS28 were not available in this retrospective study. In addition, to address potential bias arising from biologic DMARD-treated patients’ being treated earlier because of more severe arthritis, we included the time-dependent variable “time from ICI initiation to DMARD initiation” into our model (an analysis in which there was no censoring at the time of DMARD switch). With this covariate included, our results favoring methotrexate in comparison to a TNF inhibitor became if anything, stronger (HR 3.27, 95% CI 1.21-8.84, p=0.019). The two methods commonly used to account for immortal time bias are landmark models and time dependent covariates. We chos...
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