To the Editor:
We have read with interest the results of the RITAZAREM trial showing that rituximab is superior to azathioprine for the prevention of relapse following RTX induction therapy in patients with relapsing antineutrophil cytoplasmic antibody-associated vasculitis (AAV).1 We would like to address several comments, in particular regarding hypogammaglobulinemia.
First, one unexpected finding of RITAZAREM comes from a multivariable model of predictors for the development of hypogammaglobulinemia showing that the use of RTX was not associated with a significant higher risk of hypogammaglobulinemia than AZA (OR 2.2, 95% CI 0.9 to 5.7 ; p=0.1). This finding is consistent with the lack of difference of immunoglobulins levels observed throughout MAINRISTAN 1 between patients receiving RTX or those receiving AZA as a maintenance treatment2. It is interesting to remind that in MAINRISTAN 1, cyclophosphamide was the immunosuppressant used for the induction treatment and that the cumulative dose of rituximab was far lower. Hence, those consistent results do not support the statement in recent EUVAS 2022 guidelines that a switch from RTX to AZA should be considered in case of severe hypogammaglobulinemia3.
Conversely, this multivariable model of predictors in RITAZAREM points the level of steroids exposure as a variable which significantly affects the risk of acquired hypogammaglobulinemia (OR 8.6, 95% CI 3 to 27.6; p<0.001). Indeed, in this trial, the i...
To the Editor:
We have read with interest the results of the RITAZAREM trial showing that rituximab is superior to azathioprine for the prevention of relapse following RTX induction therapy in patients with relapsing antineutrophil cytoplasmic antibody-associated vasculitis (AAV).1 We would like to address several comments, in particular regarding hypogammaglobulinemia.
First, one unexpected finding of RITAZAREM comes from a multivariable model of predictors for the development of hypogammaglobulinemia showing that the use of RTX was not associated with a significant higher risk of hypogammaglobulinemia than AZA (OR 2.2, 95% CI 0.9 to 5.7 ; p=0.1). This finding is consistent with the lack of difference of immunoglobulins levels observed throughout MAINRISTAN 1 between patients receiving RTX or those receiving AZA as a maintenance treatment2. It is interesting to remind that in MAINRISTAN 1, cyclophosphamide was the immunosuppressant used for the induction treatment and that the cumulative dose of rituximab was far lower. Hence, those consistent results do not support the statement in recent EUVAS 2022 guidelines that a switch from RTX to AZA should be considered in case of severe hypogammaglobulinemia3.
Conversely, this multivariable model of predictors in RITAZAREM points the level of steroids exposure as a variable which significantly affects the risk of acquired hypogammaglobulinemia (OR 8.6, 95% CI 3 to 27.6; p<0.001). Indeed, in this trial, the induction therapy consisted in RTX (4 doses of 375mg/m2/week) and oral prednisone/prednisolone commencing at either 1 mg/kg/day (high dose) or 0.5 mg/kg/day (low dose), both reducing to 10 mg/day or less at 4 months. Although the choice of glucocorticoid regimen was not randomized, and thus may have been subject to bias, these two regimens appeared similarly effective with the lower dose approach providing approximately two-thirds of the total oral glucocorticoid exposure, and thus reduced dose glucocorticoids can be recommended as a treatment option4.
This latter finding is consistent with the non-inferiority in LOVAS trial of reduced-dose glucocorticoid (initial dose 0.5 mg/kg/day) compared to high-dose glucocorticoid (initial dose 1 mg/kg/day) plus rituximab regimen (four doses of 375mg/m2 / week) with regard to induction of disease remission at 6 months5. Although the 2 arms of RITAZAREM and LOVAS are quite similar in terms of induction treatment, there are difference regarding the populations of AAV patients: indeed, RITAZAREM has only included relapsing patients, the majority of which having anti-PR3 ANCA whereas LOVAS has included only newly diagnosed patients, the majority of which having anti-MPO ANCA.
In a retrospective cohort study including 227 AAV patients treated with rituximab induction in 14 European centers, a multivariable logistic regression showed that factors associated with the risk of hypogammaglobulinemia were age and oral glucocorticoid dose at induction (OR : 1.5, 95% CI 1.2 to 1.9 per 10 mg prednisone, p< 0.001) 6.
Taken together, these results add to the amount of evidence supporting the concept of minimizing steroids exposure, notably in patients having received rituximab during the induction phase. Alongside their well-established benefits on the incidence of osteoporosis, diabetes and infection rates, lower steroids cumulative doses also have an impact on the occurrence of hypogammaglobulinemia, contrary to the choice of the immunosuppressant used in maintenance.
References
1. Smith RM, Jones RB, Specks U et al. Rituximab versus azathioprine for maintenance of remission for patients with ANCA-associated vasculitis and relapsing disease: an international randomized controlled trial, Ann Rheum Dis 2023; 0 : 1-8. doi: 10.1136/ard-2022-223559
2. Guillevin L, Pagnoux C, Karras et al. Rituximab versus azathioprine for maintenance in ANCA-associated vasculitis. N Engl J Med. 2014 Nov 6;371(19):1771-80. doi: 10.1056/NEJMoa1404231. PMID: 25372085.
3. Hellmich B, SanchezAlamo B, Schirmer JH, et al. EULAR recommandations for the management of ANCA-associated vasculitis : 2022 update. Ann Rheum Dis 2023;0:1–18. doi:10.1136/ ard-2022-223764
4. Smith RM, Jones RB, Specks U et al. Rituximab as therapy to induce remission after relapse in ANCA-associated vasculitis. Ann Rheum Dis. 2020 Sep;79(9):1243-1249. doi: 10.1136/annrheumdis-2019-216863. Epub 2020 Jun 24.PMID: 32581088
5. Furuta S, Nakagomi D, Kobayashi Y et al. Effect of Reduced-Dose vs High-Dose Glucocorticoids Added to Rituximab on Remission Induction in ANCA-Associated Vasculitis: A Randomized Clinical Trial. JAMA. 2021;325(21):2178–2187. doi:10.1001/jama.2021.6615
6. Podestà MA, Mescia F, Ricchiuto A et al. Predictors of hypogammaglobulinemia in ANCA-associated vasculitis after a rituximab-based induction: a multicentre study. Rheumatology (Oxford) 2022 dec 23, :keac716. doi: 10.1093/rheumatology/keac716
We read with great interest the article by Baker et al.,1 which reported an increased incidence of osteoarthritis in patients with asthma or atopic dermatitis, or a combination of both. They also noted that patients may benefit from the use of a drug. Drugs that inhibit mast cells and allergic cytokines are used to treat or prevent osteoarthritis. This study is a valuable addition to the literature. However, the authors must address some issues.
First, your results show that type 2 immune responses specifically contribute to the risk of developing osteoarthritis, which may offset the significant association between type 2 immune response diseases and osteoarthritis.1 Type 2 immune response diseases include asthma, chronic urticaria, atopic dermatitis, allergic rhinitis, chronic rhinosinusitis, food allergies, anaphylaxis, drug hypersensitivity, and allergen immunotherapy.2, 3 However, the baseline type 2 immune response diseases data of the two groups were unavailable in this study, except for asthma and atopic dermatitis. The confounding effect of these variables may have contributed to causing incident osteoarthritis. Omitting these confounding effects may make the results less valid.
Second, a family history of osteoarthritis is a strong risk factor that is independently associated with incident osteoarthritis.4, 5 Epidemiological studies have shown that genetic factors contribute 50% or more to the effect.5 Hence, a family history of osteoarthritis...
We read with great interest the article by Baker et al.,1 which reported an increased incidence of osteoarthritis in patients with asthma or atopic dermatitis, or a combination of both. They also noted that patients may benefit from the use of a drug. Drugs that inhibit mast cells and allergic cytokines are used to treat or prevent osteoarthritis. This study is a valuable addition to the literature. However, the authors must address some issues.
First, your results show that type 2 immune responses specifically contribute to the risk of developing osteoarthritis, which may offset the significant association between type 2 immune response diseases and osteoarthritis.1 Type 2 immune response diseases include asthma, chronic urticaria, atopic dermatitis, allergic rhinitis, chronic rhinosinusitis, food allergies, anaphylaxis, drug hypersensitivity, and allergen immunotherapy.2, 3 However, the baseline type 2 immune response diseases data of the two groups were unavailable in this study, except for asthma and atopic dermatitis. The confounding effect of these variables may have contributed to causing incident osteoarthritis. Omitting these confounding effects may make the results less valid.
Second, a family history of osteoarthritis is a strong risk factor that is independently associated with incident osteoarthritis.4, 5 Epidemiological studies have shown that genetic factors contribute 50% or more to the effect.5 Hence, a family history of osteoarthritis is a clinically significant risk factor. As family history data were not available in this study, there might be residual confounding bias because of unmeasured factors.
In conclusion, although we have some concerns about Baker et al.,1 we applaud the authors for their commendable work and hope that this study will benefit readers. We also look forward to the time when patients with asthma or atopic dermatitis will benefit from the use of drugs that inhibit mast cells and allergic cytokines to prevent osteoarthritis.
References:
1. Baker MC, Sheth K, Lu R, et al. Increased risk of osteoarthritis in patients with atopic disease. Ann Rheum Dis 2023;82:866-72.
2. Kato A, Schleimer RP, Bleier BS. Mechanisms and pathogenesis of chronic rhinosinusitis. J Allergy Clin Immunol. 2022;149:1491-503.
3. Gause WC, Rothlin C, Loke P. Heterogeneity in the initiation, development and function of type 2 immunity. Nat Rev Immunol. 2020;20:603-14.
4. Spector TD, MacGregor AJ. Risk factors for osteoarthritis: genetics. Osteoarthritis Cartilage. 2004;12 Suppl A:S39-44.
5. Forestier R, Francon A, Briole V, et al. Prevalence of generalized osteoarthritis in a population with knee osteoarthritis. Joint Bone Spine. 2011;78:275-8.
We read with great interest the recent paper by Baker et al.1 regarding the association between atopic diseases and the risk of osteoarthritis (OA). By using data from two retrospective cohorts, this study showed that patients with atopic diseases have a higher risk of developing OA compared with the general population. Although the authors made great efforts to address confounders by using propensity score matching and adjusting for important baseline characteristics, residual confounding is an unavoidable methodological weakness of conventional observational studies that hinders causal inference. Mendelian randomization (MR) can overcome this limitation by leveraging randomly assorted genetic variants as instruments to study causal relationships. Therefore, we performed a two-sample MR analysis to investigate the causal effect of atopic diseases on OA.
We extracted single-nucleotide polymorphisms (SNPs) significantly (P < 5×10−8) associated with atopic diseases including asthma (88,486 cases and 447,859 controls),2 atopic dermatitis (21,399 cases and 95,464 controls),3 allergic rhinitis (59,762 cases and 152,358 controls),4 and plasma total Immunoglobulin (IgE) concentrations (6,819 subjects)5 from previously published genome-wide association study (GWAS) meta-analyses. These SNPs were clumped for independence by linkage disequilibrium (r2 < 0.001 within 10,000 kb clumping distance), leaving 124 SNPs associated with asthma, 18 SNPs with atopic dermatitis, 32...
We read with great interest the recent paper by Baker et al.1 regarding the association between atopic diseases and the risk of osteoarthritis (OA). By using data from two retrospective cohorts, this study showed that patients with atopic diseases have a higher risk of developing OA compared with the general population. Although the authors made great efforts to address confounders by using propensity score matching and adjusting for important baseline characteristics, residual confounding is an unavoidable methodological weakness of conventional observational studies that hinders causal inference. Mendelian randomization (MR) can overcome this limitation by leveraging randomly assorted genetic variants as instruments to study causal relationships. Therefore, we performed a two-sample MR analysis to investigate the causal effect of atopic diseases on OA.
We extracted single-nucleotide polymorphisms (SNPs) significantly (P < 5×10−8) associated with atopic diseases including asthma (88,486 cases and 447,859 controls),2 atopic dermatitis (21,399 cases and 95,464 controls),3 allergic rhinitis (59,762 cases and 152,358 controls),4 and plasma total Immunoglobulin (IgE) concentrations (6,819 subjects)5 from previously published genome-wide association study (GWAS) meta-analyses. These SNPs were clumped for independence by linkage disequilibrium (r2 < 0.001 within 10,000 kb clumping distance), leaving 124 SNPs associated with asthma, 18 SNPs with atopic dermatitis, 32 SNPs with allergic rhinitis, and 5 SNPs with IgE levels as instruments for the MR analysis. Summary genetic associations for OA (177,517 cases and 649,173 controls) were obtained from the largest GWAS meta-analysis to date.6 As a secondary outcome, we examined OA subtypes, including OA of the knee (62,497 cases and 333,557 controls), hip (36,445 cases and 316,943 controls), hand (20,901 cases and 282,881 controls), and spine (28,372 cases and 305,578). Participants included in this study were of predominantly European ancestry.
The inverse-variance weighted (IVW) method was adopted as the main analysis, supplemented by pleiotropy-robust analyses, including weighted median, MR-Egger, MR-PRESSO (Pleiotropy RESidual Sum and Outlier), and multivariable MR additionally adjusting for body mass index. We assessed horizontal pleiotropy and heterogeneity across SNP effects using the MR-Egger intercept and the Cochran’s Q statistic, respectively.
The results of the IVW analysis revealed no significant association between genetic liability to the three examined atopic diseases or higher IgE levels and the risk of developing OA at any site (all P > 0.1). In the site-specific OA analysis, we found suggestive evidence that the genetic liability to asthma (odds ratio [OR] 1.06, 95% confidence interval [CI] 0.99 to 1.14, P = 0.080), atopic dermatitis (OR 1.05, 95% CI 1.00 to 1.10, P = 0.044), and allergic rhinitis (OR 1.08, 95% CI 1.00 to 1.17, P = 0.057) all were associated with an increased risk of knee OA, but not with OA of other sites. A directionally consistent effect of genetically predicted higher IgE levels on knee OA was observed, albeit with a wider CI (OR 1.06, 95% CI 0.95 to 1.18, P = 0.280). Results were broadly consistent across sensitivity analyses, including multivariate MR with adjustment for body mass index. Although heterogeneity was detected in some associations, there was no indication of horizontal pleiotropy (all P > 0.05).
Several prior studies have linked atopic diseases to OA1 7 8 as well as IgE levels and anti-IgE therapy to knee OA,9 10 but the observational nature of these studies limited their ability to draw conclusions about causality, and the association with different joint sites remains poorly understood. Our findings suggest that atopic diseases might specifically contribute to the development of knee OA, but not OA of other sites. Further replicating the site-specific association and clarifying its underlying pathways would be worthwhile, with relevance to the development of novel treatments for knee OA.
References
1. Baker MC, Sheth K, Lu R, et al. Increased risk of osteoarthritis in patients with atopic disease. Ann Rheum Dis 2023 doi: 10.1136/ard-2022-223640 [published Online First: 2023/03/30]
2. Han Y, Jia Q, Jahani PS, et al. Genome-wide analysis highlights contribution of immune system pathways to the genetic architecture of asthma. Nat Commun 2020;11(1):1776. doi: 10.1038/s41467-020-15649-3 [published Online First: 2020/04/17]
3. Paternoster L, Standl M, Waage J, et al. Multi-ancestry genome-wide association study of 21,000 cases and 95,000 controls identifies new risk loci for atopic dermatitis. Nat Genet 2015;47(12):1449-56. doi: 10.1038/ng.3424 [published Online First: 2015/10/21]
4. Waage J, Standl M, Curtin JA, et al. Genome-wide association and HLA fine-mapping studies identify risk loci and genetic pathways underlying allergic rhinitis. Nat Genet 2018;50(8):1072-80. doi: 10.1038/s41588-018-0157-1 [published Online First: 2018/07/18]
5. Granada M, Wilk JB, Tuzova M, et al. A genome-wide association study of plasma total IgE concentrations in the Framingham Heart Study. J Allergy Clin Immunol 2012;129(3):840-45 e21. doi: 10.1016/j.jaci.2011.09.029 [published Online First: 2011/11/15]
6. Boer CG, Hatzikotoulas K, Southam L, et al. Deciphering osteoarthritis genetics across 826,690 individuals from 9 populations. Cell 2021;184(18):4784-818 e17. doi: 10.1016/j.cell.2021.07.038 [published Online First: 2021/08/28]
7. Koo HK, Song P, Lee JH. Novel association between asthma and osteoarthritis: a nationwide health and nutrition examination survey. BMC Pulm Med 2021;21(1):59. doi: 10.1186/s12890-021-01425-6 [published Online First: 2021/02/18]
8. Liu J, Martin A, Thatiparthi A, et al. Association between atopic dermatitis and osteoarthritis among US adults in the 1999-2006 NHANES. J Eur Acad Dermatol Venereol 2021;35(6):e375-e77. doi: 10.1111/jdv.17147 [published Online First: 2021/02/05]
9. Park S, Choi NK. Association between serum immunoglobulin E levels and knee osteoarthritis in Korean adults. Osteoarthritis Cartilage 2020;28(4):462-67. doi: 10.1016/j.joca.2020.02.830 [published Online First: 2020/03/03]
10. Aquili A, Farinelli L, Bottegoni C, et al. The effect of anti-IgE therapy in knee osteoarthritis: a pilot observational study. J Biol Regul Homeost Agents 2017;31(4 Suppl. 1):1-5. [published Online First: 2017/11/28]
I am writing in regards to the article, "Risk factors for serious infections in ANCA-associated vasculitis" by Odler and colleagues, which published in the Annals of Rheumatic Diseases1. While the study provides valuable information on the risk factors for severe infections in patients with ANCA-associated vasculitis (AAV), there are certain limitations that must be taken into consideration when interpreting the results. One of the significant limitations of the study is the small sample size of only 197 patients. This limited sample size raises questions about the generalizability of the results and their statistical significance. The study results may only be applicable to the population represented in the sample and may not reflect the experiences of larger patient populations. Moreover, the small sample size may increase the likelihood of type I or type II errors and make it difficult to identify significant associations2. Another important limitation is that the study only includes participants from the RAVE trial, which is a specific population of AAV patients who meet certain inclusion criteria. Therefore, the results may not be generalizable to the broader population of AAV patients, who may have different risk factors, underlying comorbidities, and other factors that may impact the risk of severe infections3. Furthermore, the lack of a control group is another limitation of the study. The study only compared patients receiving rituximab or cyclophosphami...
I am writing in regards to the article, "Risk factors for serious infections in ANCA-associated vasculitis" by Odler and colleagues, which published in the Annals of Rheumatic Diseases1. While the study provides valuable information on the risk factors for severe infections in patients with ANCA-associated vasculitis (AAV), there are certain limitations that must be taken into consideration when interpreting the results. One of the significant limitations of the study is the small sample size of only 197 patients. This limited sample size raises questions about the generalizability of the results and their statistical significance. The study results may only be applicable to the population represented in the sample and may not reflect the experiences of larger patient populations. Moreover, the small sample size may increase the likelihood of type I or type II errors and make it difficult to identify significant associations2. Another important limitation is that the study only includes participants from the RAVE trial, which is a specific population of AAV patients who meet certain inclusion criteria. Therefore, the results may not be generalizable to the broader population of AAV patients, who may have different risk factors, underlying comorbidities, and other factors that may impact the risk of severe infections3. Furthermore, the lack of a control group is another limitation of the study. The study only compared patients receiving rituximab or cyclophosphamide/azathioprine and did not include a control group for comparison. The absence of a control group limits the ability to fully understand the effects of the treatments and make informed conclusions about their efficacy4. A comparison with a control group would provide a more comprehensive understanding of the effects of the treatments. Despite these limitations, the study does provide important information on the use of trimethoprim-sulfamethoxazole as a preventative measure against severe infections in patients with ANCA-associated vasculitis. However, it is important to consider the limitations of the study when interpreting the results. Further research with larger sample sizes and longer follow-up periods is needed to fully understand the long-term effects of the treatments and the best approach for reducing the risk of severe infections in patients with AAV.
REFERNECES
1 Odler B, Riedl R, Gauckler P, et al. Risk factors for serious infections in ANCA-associated vasculitis. Annals of the Rheumatic Diseases 2023
2 VanVoorhis CW, Morgan BL. Understanding power and rules of thumb for determining sample sizes. Tutorials in quantitative methods for psychology 2007;3:43-50.
3 Do H, Pyo JY, Song JJ, et al. Implication of Serious Infections in Patients With Antineutrophil Cytoplasmic Antibody-Associated Vasculitis for the First Cycle of Rituximab: A Pilot Study in a Single Korean Center. J Rheum Dis 2023;30:45-52.
4 Malay S, Chung KC. The choice of controls for providing validity and evidence in clinical research. Plastic and reconstructive surgery 2012;130:959.
We have some comments on the retrospective study that looked at risk factors for severe COVID-19 in people with axial spondyloarthritis (axSpA), psoriasis (PsO), and psoriatic arthritis (PsA).1
First, according to the findings of the study, the use of tumor necrosis factor (TNF) inhibitors was associated with decreased probabilities of severe COVID-19 outcomes. The author cites some previous studies using clinical database analysis to support the result. However, in recent research, Rebecca H Haberman et al obtained postvaccination blood samples from participants with immune-mediated inflammatory diseases and healthy controls and analyzed SARS-CoV-2-spike-specific antibody titers and neutralization capacity. Their results showed that TNF inhibitors might lead to a dampened humoral response to COVID-19 vaccinations, and the persistence of an adequate humoral response is significantly decreased by month 6. This finding supports the use of supplemental booster dosing in patients with immune-mediated inflammatory diseases, specifically for those being treated with TNF inhibitors. Larger basic research is required to clarify these contradictions and evaluate the impact of other immunomodulatory strategies, which will assist in determining the appropriate timing and method for COVID-19 vaccinations. 2
Second, based on the results of one sensitivity analysis, Janus kinase (JAK) inhibitor use was associated with a higher risk of death owing to COVID-19 (binary outco...
We have some comments on the retrospective study that looked at risk factors for severe COVID-19 in people with axial spondyloarthritis (axSpA), psoriasis (PsO), and psoriatic arthritis (PsA).1
First, according to the findings of the study, the use of tumor necrosis factor (TNF) inhibitors was associated with decreased probabilities of severe COVID-19 outcomes. The author cites some previous studies using clinical database analysis to support the result. However, in recent research, Rebecca H Haberman et al obtained postvaccination blood samples from participants with immune-mediated inflammatory diseases and healthy controls and analyzed SARS-CoV-2-spike-specific antibody titers and neutralization capacity. Their results showed that TNF inhibitors might lead to a dampened humoral response to COVID-19 vaccinations, and the persistence of an adequate humoral response is significantly decreased by month 6. This finding supports the use of supplemental booster dosing in patients with immune-mediated inflammatory diseases, specifically for those being treated with TNF inhibitors. Larger basic research is required to clarify these contradictions and evaluate the impact of other immunomodulatory strategies, which will assist in determining the appropriate timing and method for COVID-19 vaccinations. 2
Second, based on the results of one sensitivity analysis, Janus kinase (JAK) inhibitor use was associated with a higher risk of death owing to COVID-19 (binary outcome). In a recent meta-analysis, patients with COVID-19 who were hospitalized did not experience an increase in infections, adverse events, or secondary infections as a result of receiving JAK inhibitor treatment (RR = 0.62, 95% CI: 0.49-0.78).3 Although venous thromboembolism (VTE) risk warnings have restricted their use, JAK inhibitor treatments are still good options for treating immune-mediated inflammatory disorders (IMIDs).4 According to research by Saskia Middeldorp et al, there is a significant observed risk for VTE in COVID-19, especially in patients in the intensive care unit. 5 The usage of JAK inhibitors in IMID patients with COVID-19 requires more evaluation.
Third, the study did not standardize the number of shots of the COVID-19 vaccine, the brand of vaccine, whether there were associated complications after the shots, etc. This may affect the severe COVID-19 outcome of the study. Although the author has stated that in the limitation and explained that the model adjustment for pandemic calendar period used in this study may act as a surrogate for vaccination status, we felt that the impact of the outcome was underestimated. Joseph Fraiman et al pointed out that most of the serious adverse event (SAE)-affected findings are quite typical occurrences, such as ischemic stroke, acute coronary syndrome, and brain hemorrhage. While clinical suspicion of an adverse vaccination reaction following a clinically relevant occurrence will be lower than for SAEs, signal detection is made more difficult as a result. 6
References
1 Machado PM, Schafer M, Mahil SK et al. Characteristics associated with poor COVID-19 outcomes in people with psoriasis, psoriatic arthritis and axial spondyloarthritis: data from the COVID-19 PsoProtect and Global Rheumatology Alliance physician-reported registries. Ann Rheum Dis 2023.
2 Haberman RH, Um S, Axelrad JE et al. Methotrexate and TNF inhibitors affect long-term immunogenicity to COVID-19 vaccination in patients with immune-mediated inflammatory disease. Lancet Rheumatol 2022; 4 (6): e384-e387.
3 Zhang X, Shang L, Fan G et al. The Efficacy and Safety of Janus Kinase Inhibitors for Patients With COVID-19: A Living Systematic Review and Meta-Analysis. Front Med (Lausanne) 2021; 8: 800492.
4 Yates M, Mootoo A, Adas M et al. Venous Thromboembolism Risk With JAK Inhibitors: A Meta-Analysis. Arthritis Rheumatol 2021; 73 (5): 779-788.
5 Middeldorp S, Coppens M, van Haaps TF et al. Incidence of venous thromboembolism in hospitalized patients with COVID-19. J Thromb Haemost 2020; 18 (8): 1995-2002.
6 Fraiman J, Erviti J, Jones M et al. Serious adverse events of special interest following mRNA COVID-19 vaccination in randomized trials in adults. Vaccine 2022; 40 (40): 5798-5805.
Dear Editor,
We read with great interest the article by Christina Charles-Schoeman et al. recently published in Annals of the Rheumatic Diseases, reporting the results of a post-hoc analysis of the ORAL Surveillance trial . As it is widely known to the rheumatology community, ORAL surveillance failed to demonstrate noninferiority of tofacitinib versus TNF inhibitors (TNFi) with relation to the risk of major adverse cardiovascular events (MACE) and cancer in a population of rheumatoid arthritis (RA) patients enriched for baseline cardiovascular disease (CVD) risk factors.
In their analysis, Charles-Schoeman et al.1 stratified ORAL Surveillance participants in two main cohorts, with and without a past history of atherosclerotic cardiovascular disease (ASCVD), respectively; the latter cohort was further categorized in incremental CVD risk classes according to the ASCVD pooled cohort equations (PCE). Compared to TNFi, the risk of MACE in tofacitinib recipients at the dose currently licensed for RA (5 mg two-times-per-day) was significantly higher only in patients with a history of ASCVD (HR (95% CI): 1.96 (0.87 to 4.40)), while no statistical difference in MACE occurrence was evident in patients with no history of ASCVD, regardless the estimated 10-year ASCVD risk.
Besides providing a better description of the subpopulation of patients who may experience a clear increase in CVD risk, this stratification revealed some interesting clues that, in our opinion, d...
Dear Editor,
We read with great interest the article by Christina Charles-Schoeman et al. recently published in Annals of the Rheumatic Diseases, reporting the results of a post-hoc analysis of the ORAL Surveillance trial . As it is widely known to the rheumatology community, ORAL surveillance failed to demonstrate noninferiority of tofacitinib versus TNF inhibitors (TNFi) with relation to the risk of major adverse cardiovascular events (MACE) and cancer in a population of rheumatoid arthritis (RA) patients enriched for baseline cardiovascular disease (CVD) risk factors.
In their analysis, Charles-Schoeman et al.1 stratified ORAL Surveillance participants in two main cohorts, with and without a past history of atherosclerotic cardiovascular disease (ASCVD), respectively; the latter cohort was further categorized in incremental CVD risk classes according to the ASCVD pooled cohort equations (PCE). Compared to TNFi, the risk of MACE in tofacitinib recipients at the dose currently licensed for RA (5 mg two-times-per-day) was significantly higher only in patients with a history of ASCVD (HR (95% CI): 1.96 (0.87 to 4.40)), while no statistical difference in MACE occurrence was evident in patients with no history of ASCVD, regardless the estimated 10-year ASCVD risk.
Besides providing a better description of the subpopulation of patients who may experience a clear increase in CVD risk, this stratification revealed some interesting clues that, in our opinion, deserve further consideration.
As shown in Table 2 of the article, only about 50% of patients with a history of ASCVD events were treated with antiplatelet (53.9% in tofacitinib 5 mg, 55.9% in tofacitinib 10 mg, and 50.0% in TNFi) or lipid lowering therapy (52.5% in tofacitinib 5 mg, 57.2% in tofacitinib 10 mg, and 49.1% in TNFi).
This percentage is surprisingly low, especially in the light of the well documented tofacitinib-induced rise in cholesterol levels . Additionally, it appears contrasting with the most recent guidelines for secondary prevention of cardiovascular events , which urge treatment for all patients with a history of ASCVD.
Even though weak adherence is a common issue with cardioprotective molecules, large studies from the general population reveal that 75–85% - and 85–90%5-6 of individuals with prior cardiovascular events are treated with lipid lowering or antiplatelet drugs, respectively.
From the rheumatology perspective, despite the European Alliance of Associations for Rheumatology (EULAR) published its first set of recommendations 15 years ago , the management of CVD risk in inflammatory arthritis patients remains largely suboptimal as demonstrated in different studies - .
It is already widely acknowledged that inflammation in RA patients represents a driver of accelerated atherogenesis and, accordingly, the main focus of treatment is reducing disease activity in the expectation that this may significantly ameliorate cardiovascular outcomes. However, excessive emphasis on this aspect carries the danger of neglecting the role of traditional CVD risk factors, estimated to contribute for 70% of the overall risk. In this contest, even assuming an unequivocal causal effect between tofacitinib (or other Janus kinase inhibitors, JAKi) exposure and the development of MACE, many cardiovascular events could still be prevented by improving the global CVD risk control.
In conclusion, the findings of this post-hoc analysis of the ORAL surveillance trial could be read under a different light: the compelling need to really implement appropriate cardiovascular therapy in RA patients. In this scenario, even if confirmed in subsequent research, effective management of CVD risk factors may, at least in part, counterbalance the additional risk conferred by JAKi.
1 Charles-Schoeman C, Buch MH, Dougados M, et al. Risk of major adverse cardiovascular events with tofacitinib versus tumour necrosis factor inhibitors in patients with rheumatoid arthritis with or without a history of atherosclerotic cardiovascular disease: a post hoc analysis from ORAL Surveillance. Ann Rheum Dis 2023; 82: 119-129.
2 Ytterberg SR, Bhatt DL, Mikuls TR, et al. Cardiovascular and cancer risk with tofacitinib in rheumatoid arthritis. N Eng J Med 2022; 386:316-326.
3 Souto A, Salgado E, Maneiro JR, et al. Lipid profile changes in patients with chronic inflammatory arthritis treated with biologic agents and tofacitinib in randomized clinical trials: a systematic review and meta‐analysis. Arthritis Rheumato, 2015;67:117-127
4 Visseren FL, Mach F, Smulders YM, et al. 2021 ESC Guidelines on cardiovascular disease prevention in clinical practice: Developed by the Task Force for cardiovascular disease prevention in clinical practice with representatives of the European Society of Cardiology and 12 medical societies With the special contribution of the European Association of Preventive Cardiology (EAPC). Eu Heart J 2021; 42:3227-3337.
5 Cannon CP, Rhee KE, Califf RM, et al. Current use of aspirin and antithrombotic agents in the United States among outpatients with atherothrombotic disease (from the REduction of Atherothrombosis for Continued Health [REACH] Registry). Am J Cardiol 2010;105:445-452.
6 Kotseva K, Wood D, De Bacquer D, et al. EUROASPIRE IV: A European Society of Cardiology survey on the lifestyle, risk factor and therapeutic management of coronary patients from 24 European countries. Eur J Prev Cardiol 2016;23: 636-648.
7 Peters MJL, Symmons DPM, McCarey D, et al. EULAR evidence-based recommendations for cardiovascular risk management in patients with rheumatoid arthritis and other forms of inflammatory arthriti. Ann Rheum Dis 2010;69: 325-331.
8 van Breukelen-van der Stoep DF, van Zeben D, Klop B, et al. Marked underdiagnosis and undertreatment of hypertension and hypercholesterolaemia in rheumatoid arthritis. Rheumatology 2016;55: 1210-1216.
9 van den Oever IA, Heslinga M, Griep EN, et al. Cardiovascular risk management in rheumatoid arthritis patients still suboptimal: the Implementation of Cardiovascular Risk Management in Rheumatoid Arthritis project. Rheumatology 2017;56:1472-1478.
We read with interest the article by Conrad et al. [1] that advocated modification of cardiovascular risk (CVR) scores to incorporate risk multipliers for each rheumatic and musculoskeletal disease (RMD). The proposed multipliers were based on hazard ratios for incident cardiovascular diseases in a nationwide study of electronic medical records in the UK [2]. This proposal contradicts recent recommendations in the 2022 EULAR recommendations for CVR management in patients with RMDs [3]. Based on a review of the evidence, including data of elevated CVR in other nationwide studies, and appraisal by experts, these recommendations did not support use of CVR multipliers in RMDs [3]. It is therefore important to examine several issues raised by this proposal.
First, the objective of study from which the multipliers were derived [1] was not to assess the added predictive validity of CVR score modifiers, but rather to examine the incidence of cardiovascular disease in patients with autoimmune diseases. Confidence in the validity of the multipliers is not high, considering that data on blood pressure were missing in one-third of patients, while data on cholesterol and smoking were missing in two-thirds and almost one-half, respectively [2]. Also, whether these risk estimates apply in countries with baseline CVRs different from the UK is unclear [3].
Second, the suggested multipliers were based on risk estimates of a wide range of cardiac or vascular diseases, including p...
We read with interest the article by Conrad et al. [1] that advocated modification of cardiovascular risk (CVR) scores to incorporate risk multipliers for each rheumatic and musculoskeletal disease (RMD). The proposed multipliers were based on hazard ratios for incident cardiovascular diseases in a nationwide study of electronic medical records in the UK [2]. This proposal contradicts recent recommendations in the 2022 EULAR recommendations for CVR management in patients with RMDs [3]. Based on a review of the evidence, including data of elevated CVR in other nationwide studies, and appraisal by experts, these recommendations did not support use of CVR multipliers in RMDs [3]. It is therefore important to examine several issues raised by this proposal.
First, the objective of study from which the multipliers were derived [1] was not to assess the added predictive validity of CVR score modifiers, but rather to examine the incidence of cardiovascular disease in patients with autoimmune diseases. Confidence in the validity of the multipliers is not high, considering that data on blood pressure were missing in one-third of patients, while data on cholesterol and smoking were missing in two-thirds and almost one-half, respectively [2]. Also, whether these risk estimates apply in countries with baseline CVRs different from the UK is unclear [3].
Second, the suggested multipliers were based on risk estimates of a wide range of cardiac or vascular diseases, including pericarditis, atrial fibrillation, valve disorders, venous thromboembolism, and infective endocarditis, and not only incident atherosclerotic cardiovascular disease (ASCVD) events. In contrast, CVR scores (e.g. Framingham, SCORE, ASCVD, Globorisk) are used to predict ASCVD events specifically (heart attack and stroke). It would not be surprising that Systemic lupus erythematosus or Systemic sclerosis were associated with the highest risk since the outcome included pericarditis, valve disease, arrhythmias and heart failure, common disease features. The proposed risk multipliers were based on outcomes that were different from those predicted by generic CVR scores.
Third, a likely consequence of multipliers’ adoption would be to increase the number of patients eligible for statin treatment. Although this is an effective intervention to lower rates of ASCVD events in the general population, evidence that statins provide comparable benefit in the prevention of ASCVD events in patients with RMDs, or additional benefit at lower treatment thresholds than those used in the general population, is lacking ([3]; Systematic Literature review Supplementary material]), possibly because of a different pathophysiology of cardiovascular events in RMDs related to inflammation, disease-related mediators, and glucocorticoid use. In the 2021 European Society of Cardiology guidelines on cardiovascular disease prevention [4], the best evidence for chronic inflammation increasing CVR is available for rheumatoid arthritis, however the strength of evidence is less strong for other chronic inflammatory conditions, as is the independence of such increased risks from classical CVR factors.
Fourth, since clinical presentations are heterogeneous, universal use of the same risk multiplier for all patients with the same RMD diagnosis, without accounting for their specific disease features and treatments [5], may lead to over- or under-estimation of cardiovascular risk.
We agree with the motivation of Conrad and colleagues to develop better methods to combat high CVR in RMDs. Generally, we are not doing enough to help patients stop smoking, control hypertension and weight, and exercise more [6]. These practical steps and better management of disease-related factors can improve cardiovascular health in these patients. However, use of these risk multipliers for each RMD represents a jump from theory to policy, without support from the intervening step of evidence. We encourage additional studies dedicated to optimize CVR estimation that recognize the potentially unique pathophysiology of cardiovascular events in patients with RMDs.
References
1. Conrad N, McInnes IB, McMurray JJV, et al. Ann Rheum Dis Epub ahead of print: doi:10.1136/ard-2022-223315
2. Conrad N, Verbeke G, Molenberghs G, et al. Autoimmune diseases and cardiovascular risk: a population-based study on 19 autoimmune diseases and 12 cardiovascular diseases in 22 million individuals in the UK. Lancet 2022; 400:733–43.
3. Drosos GC, Vedder D, Houben E, et al. EULAR recommendations for cardiovascular risk management in rheumatic and musculoskeletal diseases, including systemic lupus erythematosus and antiphospholipid syndrome. Ann Rheum Dis 2022;81:768–79.
4. Visseren FLJ, Mach F, Smulders YM, et al. 2021 ESC Guidelines on cardiovascular disease prevention in clinical practice: Developed by the Task Force for cardiovascular disease prevention in clinical practice with representatives of the European Society of Cardiology and 12 medical societies with the special contribution of the European Association of Preventive Cardiology (EAPC). Eur Heart J 2021;42:3227-3337.
5. Petri MA, Barr E, Magder LS. Development of a systemic lupus erythematosus cardiovascular risk equation. Lupus Sci Med 2019;6:e000346.
6. Bartels CM, Roberts TJ, Hansen KE, et al. Rheumatologist and Primary Care Management of Cardiovascular Disease Risk in Rheumatoid Arthritis: Patient and Provider Perspectives. Arthritis Care Res 2016;68:415-23.
Although, several novel autoantibodies in idiopathic inflammatory myopathies (IIM) have been described, a serological gap persists which poses a diagnostic challenge. In this context, we read with interest the article by Vulsteke et al. [1]. The untargeted protein immunoprecipitation combined with gel-free liquid chromatography-tandem mass spectrometry (IP-MS) identified a novel autoantibody to cytoplasmic cysteinyl-tRNA-synthetase (CARS1, anti-Ly). In addition, rare ASA, such as anti-OJ, anti-Zo and anti-KS, and common ASA could also be identified by IP-MS. Consequently, Vulsteke et al. [1] concluded that IP-MS is a promising method for discovery detection of autoantibodies, especially autoantibodies that target complex autoantigens.
We agree that IP-MS represents a powerful discovery tool for novel autoantibodies. However, the gained knowledge is most valuable for more conventional in-vitro diagnostic platforms. Although the IP-MS method holds promise, due to the lack of standardization it is unlikely that it will be applicable for IVD solutions soon. Established alternative methods include ELISA [2], line immunoassay (LIA) and a recently developed particle-based multi-analyte technology (PMAT) that has been evaluated for the detection of MSA [3-5].
Due to the antigen complexity, anti-OJ are among the most difficult MSA to detect [6, 7]. According to an international survey, despite concern about its accuracy, LIA is commonly used for the detection of MSA inc...
Although, several novel autoantibodies in idiopathic inflammatory myopathies (IIM) have been described, a serological gap persists which poses a diagnostic challenge. In this context, we read with interest the article by Vulsteke et al. [1]. The untargeted protein immunoprecipitation combined with gel-free liquid chromatography-tandem mass spectrometry (IP-MS) identified a novel autoantibody to cytoplasmic cysteinyl-tRNA-synthetase (CARS1, anti-Ly). In addition, rare ASA, such as anti-OJ, anti-Zo and anti-KS, and common ASA could also be identified by IP-MS. Consequently, Vulsteke et al. [1] concluded that IP-MS is a promising method for discovery detection of autoantibodies, especially autoantibodies that target complex autoantigens.
We agree that IP-MS represents a powerful discovery tool for novel autoantibodies. However, the gained knowledge is most valuable for more conventional in-vitro diagnostic platforms. Although the IP-MS method holds promise, due to the lack of standardization it is unlikely that it will be applicable for IVD solutions soon. Established alternative methods include ELISA [2], line immunoassay (LIA) and a recently developed particle-based multi-analyte technology (PMAT) that has been evaluated for the detection of MSA [3-5].
Due to the antigen complexity, anti-OJ are among the most difficult MSA to detect [6, 7]. According to an international survey, despite concern about its accuracy, LIA is commonly used for the detection of MSA including anti-OJ [8]. Recently, a summary of studies analyzing the performance of LIA for the detection of anti-OJ antibodies concluded poor performance for anti-OJ by LIA [9]. This lack of performance was also observed in a very recent study by Preger et al. [10] as well as by Vulsteke et al. [1] detecting anti-OJ antibodies via IP-MS in a patient that was negative by LIA.
When Mimori et al. developed an anti-ARS ELISA (mixture of Jo-1, EJ, PL-7, PL-12, KS), they originally included IARS but removed the antigen because it did not agree with IP [2]. Similarly, the original studies using the PMAT MSA assay excluded anti-OJ form the analysis due to the lack of a reliable assay configuration. The most recent PMAT study included OJ based on IARS and KARS (two components of the OJ complex) [9]. This and another recent study, concluded that IARS and KARS represent promising antigens for anti-OJ detection [6]. Comparison with IP indicated that anti-KARS might show higher correlation with IP vs. anti-IARS antibodies. Since the commercial LIA uses IARS [9], which was also successfully used in ELISA [6], it is most likely that the protein construct or the immobilization of the analyte in the LIA are responsible for the remarkable difference in performance. Another reason might be the origin of the protein used by Muro et al. which derived from a cell free system (other proteins of the OJ complex could be present in the cell—free derived antigen).
Interestingly, Vulsteke et al. [1] showed that two samples contain anti-OJ had similar peaks in IP-MS for all OJ components except for LARS (Spearman=0.32, 95% CI -0.37-0.78). High correlation between samples for components of macromolecular complexes is expected since the entire complex is immunoprecipitated. However, different reactivity patterns in IP are frequently observed for anti-OJ (not all bands show comparable reactivity between samples) [7], potentially mediated by antibodies that dissociate the complex and affect the amount of precipitated proteins. Whether those differences are indicative of different reactivity to the individual components of OJ, remains unclear. However, before drawing definitive conclusions from the data, it is important to generate and review data on reproducibility of the IP-MS method (e.g. intra-, and inter-assay variability). In conclusion, we congratulate the authors on the discovery of anti-Ly and on the gain knowledge on anti-OJ.
References
1. Vulsteke JB, Derua R, Dubucquoi S, Coutant F, Sanges S, Goncalves D, et al. Mass spectrometry-based identification of new anti-Ly and known antisynthetase autoantibodies. Ann Rheum Dis. 2022.
2. Nakashima R, Imura Y, Hosono Y, Seto M, Murakami A, Watanabe K, et al. The multicenter study of a new assay for simultaneous detection of multiple anti-aminoacyl-tRNA synthetases in myositis and interstitial pneumonia. PLoS One. 2014;9(1):e85062.
3. Richards M, Garcia-De La Torre I, Gonzalez-Bello YC, Vazquez-Del MM, Andrade-Ortega L, Medrano-Ramirez G, et al. Autoantibodies to Mi-2 alpha and Mi-2 beta in patients with idiopathic inflammatory myopathy. Rheumatology (Oxford). 2019.
4. Mahler M, Betteridge Z, Bentow C, Richards M, Seaman A, Chinoy H, et al. Comparison of Three Immunoassays for the Detection of Myositis Specific Antibodies. Front Immunol. 2019;10:848.
5. Cavazzana I, Richards M, Bentow C, Seaman A, Fredi M, Giudizi MG, et al. Evaluation of a novel particle-based assay for detection of autoantibodies in idiopathic inflammatory myopathies. J Immunol Methods. 2019:112661.
6. Muro Y, Yamano Y, Yoshida K, Oto Y, Nakajima K, Mitsuma T, et al. Immune recognition of lysyl-tRNA synthetase and isoleucyl-tRNA synthetase by anti-OJ antibody-positive sera. J Autoimmun. 2021;122:102680.
7. Vulsteke JB, Satoh M, Malyavantham K, Bossuyt X, De Langhe E, Mahler M. Anti-OJ autoantibodies: Rare or underdetected? Autoimmun Rev. 2019;18(7):658-64.
8. Tansley SL, Snowball J, Pauling JD, Lissina A, Kuwana M, Rider LG, et al. The promise, perceptions, and pitfalls of immunoassays for autoantibody testing in myositis. Arthritis Res Ther. 2020;22(1):117.
9. Fritzler MJ, Bentow C, Satoh M, McHugh N, Ghirardello A, Mahler M. Deciphering the Autoantibody Response to the OJ Antigenic Complex. Diagnostics (Basel). 2023;13(1).
10. Preger C, Notarnicola A, Hellström C, Wigren E, Fernandes-Cerqueira C, Kvarnström M, et al. Autoantigenic properties of the aminoacyl tRNA synthetase family in idiopathic inflammatory myopathies. J Autoimmun. 2022;134:102951.
We are submitting a correspondence in regards to the paper "Individual patient data meta-analysis on continued use of glucocorticoids after their initiation as bridging therapy in patients with rheumatoid arthritis" by Lotte van Ouwerkerk et al.1 published in Ann Rheum Dis. 2022 Dec 16. The study is an important contribution to the field as it aimed to investigate the effectiveness of glucocorticoids (GC) as a bridging therapy for rheumatoid arthritis (RA) patients. The study combined data from 7 clinical trial arms that included GC bridging schedule in the initial treatment of RA, to investigate whether patients with RA can discontinue GC after GC 'bridging' and to identify factors that may affect this. The study has several strengths, such as the use of individual patient data meta-analysis which allows for a more comprehensive and detailed analysis. Additionally, the study's aim to investigate the effectiveness of GC as a bridging therapy is admirable, as it addresses an important question in the field of RA treatment2 3. However, the study also has some limitations that must be taken into account when interpreting the results. Firstly, the sample size of 1653 patients may not be representative of the general population of RA patients. This could limit the generalizability of the study's findings and may not fully capture the diversity of RA patients. Additionally, the study's short-term follow-up period of 18 months may not be enough...
We are submitting a correspondence in regards to the paper "Individual patient data meta-analysis on continued use of glucocorticoids after their initiation as bridging therapy in patients with rheumatoid arthritis" by Lotte van Ouwerkerk et al.1 published in Ann Rheum Dis. 2022 Dec 16. The study is an important contribution to the field as it aimed to investigate the effectiveness of glucocorticoids (GC) as a bridging therapy for rheumatoid arthritis (RA) patients. The study combined data from 7 clinical trial arms that included GC bridging schedule in the initial treatment of RA, to investigate whether patients with RA can discontinue GC after GC 'bridging' and to identify factors that may affect this. The study has several strengths, such as the use of individual patient data meta-analysis which allows for a more comprehensive and detailed analysis. Additionally, the study's aim to investigate the effectiveness of GC as a bridging therapy is admirable, as it addresses an important question in the field of RA treatment2 3. However, the study also has some limitations that must be taken into account when interpreting the results. Firstly, the sample size of 1653 patients may not be representative of the general population of RA patients. This could limit the generalizability of the study's findings and may not fully capture the diversity of RA patients. Additionally, the study's short-term follow-up period of 18 months may not be enough time to understand the long-term effects of GC bridging therapy. Long-term follow-up is essential to understand the durability of treatment effects and potential side effects. Furthermore, the study's focus on the specific GC bridging schedule used in the clinical trials may not be generalizable to other GC bridging schedules used in clinical practice. This could limit the applicability of the study's findings to clinical practice. The study also found that oral GC bridging studies only, the probabilities of later and continuous GC use and the cumulative GC doses were higher compared to the combined analyses with also parenteral GC bridging studies included. This finding may be misleading as the oral GC bridging studies only were not randomized, which could have introduced bias. Randomization is important to ensure that the groups being compared are similar and to reduce the likelihood of bias4. In conclusion, while this study provides some insights into the use of GC as a bridging therapy in RA, its results must be viewed with caution given its limitations. Further research with larger sample sizes, longer follow-up periods, and randomized controlled trial are needed to fully understand the effects of GC bridging therapy on RA patients and to determine if patients can discontinue GC after GC 'bridging.'
REFERNECES
1 van Ouwerkerk L, Boers M, Emery P, et al. Individual patient data meta-analysis on continued use of glucocorticoids after their initiation as bridging therapy in patients with rheumatoid arthritis. Annals of the Rheumatic Diseases 2022
2 Fraenkel L, Bathon JM, England BR, et al. 2021 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis & Rheumatology 2021;73:1108-23.
3 Hua C, Buttgereit F, Combe B. Glucocorticoids in rheumatoid arthritis: current status and future studies. RMD open 2020;6:e000536.
4 Akobeng AK. Understanding randomised controlled trials. Archives of disease in childhood 2005;90:840-4.
I am writing a correspondence on the article "Influence of active versus placebo control on treatment responses in randomised controlled trials in rheumatoid arthritis" by Kerschbaumer et al 1. The authors' systematic approach to comparing the treatment effects of pharmaceutical compounds in rheumatoid arthritis clinical trials with placebo and active treatment controls is commendable. The results of the study, showing significantly higher responses in active comparator trials compared to placebo controlled trials, provide valuable insights into the influence of control groups in RCTs. However, I have a few critical points to raise regarding the study's methodology and conclusions. Firstly, the matching of active treatment arms to comparable regimens, populations, background therapy, and outcome reporting was based solely on the nature of the control group, which is not an ideal approach. This method of matching could have led to unequal comparison groups and biased results 2. In order to ensure that the comparison between active treatment and control groups is fair and accurate, a more comprehensive and systematic approach to matching should have been employed. Secondly, the conclusion that placebo controlled trials lead to smaller effect sizes of active compounds in RCTs compared with the same compound in head-to-head trials may be an overgeneralization. The authors did not consider other potential confounding factors that could explain the difference...
I am writing a correspondence on the article "Influence of active versus placebo control on treatment responses in randomised controlled trials in rheumatoid arthritis" by Kerschbaumer et al 1. The authors' systematic approach to comparing the treatment effects of pharmaceutical compounds in rheumatoid arthritis clinical trials with placebo and active treatment controls is commendable. The results of the study, showing significantly higher responses in active comparator trials compared to placebo controlled trials, provide valuable insights into the influence of control groups in RCTs. However, I have a few critical points to raise regarding the study's methodology and conclusions. Firstly, the matching of active treatment arms to comparable regimens, populations, background therapy, and outcome reporting was based solely on the nature of the control group, which is not an ideal approach. This method of matching could have led to unequal comparison groups and biased results 2. In order to ensure that the comparison between active treatment and control groups is fair and accurate, a more comprehensive and systematic approach to matching should have been employed. Secondly, the conclusion that placebo controlled trials lead to smaller effect sizes of active compounds in RCTs compared with the same compound in head-to-head trials may be an overgeneralization. The authors did not consider other potential confounding factors that could explain the difference in response rates. For example, factors such as the placebo effect, patient expectations, and the impact of patient-provider interaction could all contribute to the difference in response rates between the two types of trials. The authors also should have discussed the potential impact of study design, population, and background therapy that could have influenced the results. The study design may have limitations such as sample size, randomization, or blinding that can affect the results 2. Moreover, the study population, including patient characteristics and co-morbidities, can also impact the results and generalizability of the findings to other populations 3. In conclusion, while the study provides valuable insights into the influence of control groups in RCTs in rheumatoid arthritis, the limitations discussed above should be considered when interpreting the results and drawing conclusions.
REFERNECES
1 Kerschbaumer A, Stimakovits NM, Smolen JS, et al. Influence of active versus placebo control on treatment responses in randomised controlled trials in rheumatoid arthritis. Annals of the Rheumatic Diseases 2023
2 Sella F, Raz G, Cohen Kadosh R. When randomisation is not good enough: Matching groups in intervention studies. Psychonomic Bulletin & Review 2021;28:2085-93.
3 Chidambaram AG, Josephson M. Clinical research study designs: The essentials. Pediatric investigation 2019;3:245-52.
To the Editor:
Show MoreWe have read with interest the results of the RITAZAREM trial showing that rituximab is superior to azathioprine for the prevention of relapse following RTX induction therapy in patients with relapsing antineutrophil cytoplasmic antibody-associated vasculitis (AAV).1 We would like to address several comments, in particular regarding hypogammaglobulinemia.
First, one unexpected finding of RITAZAREM comes from a multivariable model of predictors for the development of hypogammaglobulinemia showing that the use of RTX was not associated with a significant higher risk of hypogammaglobulinemia than AZA (OR 2.2, 95% CI 0.9 to 5.7 ; p=0.1). This finding is consistent with the lack of difference of immunoglobulins levels observed throughout MAINRISTAN 1 between patients receiving RTX or those receiving AZA as a maintenance treatment2. It is interesting to remind that in MAINRISTAN 1, cyclophosphamide was the immunosuppressant used for the induction treatment and that the cumulative dose of rituximab was far lower. Hence, those consistent results do not support the statement in recent EUVAS 2022 guidelines that a switch from RTX to AZA should be considered in case of severe hypogammaglobulinemia3.
Conversely, this multivariable model of predictors in RITAZAREM points the level of steroids exposure as a variable which significantly affects the risk of acquired hypogammaglobulinemia (OR 8.6, 95% CI 3 to 27.6; p<0.001). Indeed, in this trial, the i...
We read with great interest the article by Baker et al.,1 which reported an increased incidence of osteoarthritis in patients with asthma or atopic dermatitis, or a combination of both. They also noted that patients may benefit from the use of a drug. Drugs that inhibit mast cells and allergic cytokines are used to treat or prevent osteoarthritis. This study is a valuable addition to the literature. However, the authors must address some issues.
Show MoreFirst, your results show that type 2 immune responses specifically contribute to the risk of developing osteoarthritis, which may offset the significant association between type 2 immune response diseases and osteoarthritis.1 Type 2 immune response diseases include asthma, chronic urticaria, atopic dermatitis, allergic rhinitis, chronic rhinosinusitis, food allergies, anaphylaxis, drug hypersensitivity, and allergen immunotherapy.2, 3 However, the baseline type 2 immune response diseases data of the two groups were unavailable in this study, except for asthma and atopic dermatitis. The confounding effect of these variables may have contributed to causing incident osteoarthritis. Omitting these confounding effects may make the results less valid.
Second, a family history of osteoarthritis is a strong risk factor that is independently associated with incident osteoarthritis.4, 5 Epidemiological studies have shown that genetic factors contribute 50% or more to the effect.5 Hence, a family history of osteoarthritis...
We read with great interest the recent paper by Baker et al.1 regarding the association between atopic diseases and the risk of osteoarthritis (OA). By using data from two retrospective cohorts, this study showed that patients with atopic diseases have a higher risk of developing OA compared with the general population. Although the authors made great efforts to address confounders by using propensity score matching and adjusting for important baseline characteristics, residual confounding is an unavoidable methodological weakness of conventional observational studies that hinders causal inference. Mendelian randomization (MR) can overcome this limitation by leveraging randomly assorted genetic variants as instruments to study causal relationships. Therefore, we performed a two-sample MR analysis to investigate the causal effect of atopic diseases on OA.
Show MoreWe extracted single-nucleotide polymorphisms (SNPs) significantly (P < 5×10−8) associated with atopic diseases including asthma (88,486 cases and 447,859 controls),2 atopic dermatitis (21,399 cases and 95,464 controls),3 allergic rhinitis (59,762 cases and 152,358 controls),4 and plasma total Immunoglobulin (IgE) concentrations (6,819 subjects)5 from previously published genome-wide association study (GWAS) meta-analyses. These SNPs were clumped for independence by linkage disequilibrium (r2 < 0.001 within 10,000 kb clumping distance), leaving 124 SNPs associated with asthma, 18 SNPs with atopic dermatitis, 32...
I am writing in regards to the article, "Risk factors for serious infections in ANCA-associated vasculitis" by Odler and colleagues, which published in the Annals of Rheumatic Diseases1. While the study provides valuable information on the risk factors for severe infections in patients with ANCA-associated vasculitis (AAV), there are certain limitations that must be taken into consideration when interpreting the results. One of the significant limitations of the study is the small sample size of only 197 patients. This limited sample size raises questions about the generalizability of the results and their statistical significance. The study results may only be applicable to the population represented in the sample and may not reflect the experiences of larger patient populations. Moreover, the small sample size may increase the likelihood of type I or type II errors and make it difficult to identify significant associations2. Another important limitation is that the study only includes participants from the RAVE trial, which is a specific population of AAV patients who meet certain inclusion criteria. Therefore, the results may not be generalizable to the broader population of AAV patients, who may have different risk factors, underlying comorbidities, and other factors that may impact the risk of severe infections3. Furthermore, the lack of a control group is another limitation of the study. The study only compared patients receiving rituximab or cyclophosphami...
Show MoreWe have some comments on the retrospective study that looked at risk factors for severe COVID-19 in people with axial spondyloarthritis (axSpA), psoriasis (PsO), and psoriatic arthritis (PsA).1
First, according to the findings of the study, the use of tumor necrosis factor (TNF) inhibitors was associated with decreased probabilities of severe COVID-19 outcomes. The author cites some previous studies using clinical database analysis to support the result. However, in recent research, Rebecca H Haberman et al obtained postvaccination blood samples from participants with immune-mediated inflammatory diseases and healthy controls and analyzed SARS-CoV-2-spike-specific antibody titers and neutralization capacity. Their results showed that TNF inhibitors might lead to a dampened humoral response to COVID-19 vaccinations, and the persistence of an adequate humoral response is significantly decreased by month 6. This finding supports the use of supplemental booster dosing in patients with immune-mediated inflammatory diseases, specifically for those being treated with TNF inhibitors. Larger basic research is required to clarify these contradictions and evaluate the impact of other immunomodulatory strategies, which will assist in determining the appropriate timing and method for COVID-19 vaccinations. 2
Second, based on the results of one sensitivity analysis, Janus kinase (JAK) inhibitor use was associated with a higher risk of death owing to COVID-19 (binary outco...
Show MoreDear Editor,
Show MoreWe read with great interest the article by Christina Charles-Schoeman et al. recently published in Annals of the Rheumatic Diseases, reporting the results of a post-hoc analysis of the ORAL Surveillance trial . As it is widely known to the rheumatology community, ORAL surveillance failed to demonstrate noninferiority of tofacitinib versus TNF inhibitors (TNFi) with relation to the risk of major adverse cardiovascular events (MACE) and cancer in a population of rheumatoid arthritis (RA) patients enriched for baseline cardiovascular disease (CVD) risk factors.
In their analysis, Charles-Schoeman et al.1 stratified ORAL Surveillance participants in two main cohorts, with and without a past history of atherosclerotic cardiovascular disease (ASCVD), respectively; the latter cohort was further categorized in incremental CVD risk classes according to the ASCVD pooled cohort equations (PCE). Compared to TNFi, the risk of MACE in tofacitinib recipients at the dose currently licensed for RA (5 mg two-times-per-day) was significantly higher only in patients with a history of ASCVD (HR (95% CI): 1.96 (0.87 to 4.40)), while no statistical difference in MACE occurrence was evident in patients with no history of ASCVD, regardless the estimated 10-year ASCVD risk.
Besides providing a better description of the subpopulation of patients who may experience a clear increase in CVD risk, this stratification revealed some interesting clues that, in our opinion, d...
We read with interest the article by Conrad et al. [1] that advocated modification of cardiovascular risk (CVR) scores to incorporate risk multipliers for each rheumatic and musculoskeletal disease (RMD). The proposed multipliers were based on hazard ratios for incident cardiovascular diseases in a nationwide study of electronic medical records in the UK [2]. This proposal contradicts recent recommendations in the 2022 EULAR recommendations for CVR management in patients with RMDs [3]. Based on a review of the evidence, including data of elevated CVR in other nationwide studies, and appraisal by experts, these recommendations did not support use of CVR multipliers in RMDs [3]. It is therefore important to examine several issues raised by this proposal.
Show MoreFirst, the objective of study from which the multipliers were derived [1] was not to assess the added predictive validity of CVR score modifiers, but rather to examine the incidence of cardiovascular disease in patients with autoimmune diseases. Confidence in the validity of the multipliers is not high, considering that data on blood pressure were missing in one-third of patients, while data on cholesterol and smoking were missing in two-thirds and almost one-half, respectively [2]. Also, whether these risk estimates apply in countries with baseline CVRs different from the UK is unclear [3].
Second, the suggested multipliers were based on risk estimates of a wide range of cardiac or vascular diseases, including p...
Although, several novel autoantibodies in idiopathic inflammatory myopathies (IIM) have been described, a serological gap persists which poses a diagnostic challenge. In this context, we read with interest the article by Vulsteke et al. [1]. The untargeted protein immunoprecipitation combined with gel-free liquid chromatography-tandem mass spectrometry (IP-MS) identified a novel autoantibody to cytoplasmic cysteinyl-tRNA-synthetase (CARS1, anti-Ly). In addition, rare ASA, such as anti-OJ, anti-Zo and anti-KS, and common ASA could also be identified by IP-MS. Consequently, Vulsteke et al. [1] concluded that IP-MS is a promising method for discovery detection of autoantibodies, especially autoantibodies that target complex autoantigens.
Show MoreWe agree that IP-MS represents a powerful discovery tool for novel autoantibodies. However, the gained knowledge is most valuable for more conventional in-vitro diagnostic platforms. Although the IP-MS method holds promise, due to the lack of standardization it is unlikely that it will be applicable for IVD solutions soon. Established alternative methods include ELISA [2], line immunoassay (LIA) and a recently developed particle-based multi-analyte technology (PMAT) that has been evaluated for the detection of MSA [3-5].
Due to the antigen complexity, anti-OJ are among the most difficult MSA to detect [6, 7]. According to an international survey, despite concern about its accuracy, LIA is commonly used for the detection of MSA inc...
We are submitting a correspondence in regards to the paper "Individual patient data meta-analysis on continued use of glucocorticoids after their initiation as bridging therapy in patients with rheumatoid arthritis" by Lotte van Ouwerkerk et al.1 published in Ann Rheum Dis. 2022 Dec 16. The study is an important contribution to the field as it aimed to investigate the effectiveness of glucocorticoids (GC) as a bridging therapy for rheumatoid arthritis (RA) patients. The study combined data from 7 clinical trial arms that included GC bridging schedule in the initial treatment of RA, to investigate whether patients with RA can discontinue GC after GC 'bridging' and to identify factors that may affect this. The study has several strengths, such as the use of individual patient data meta-analysis which allows for a more comprehensive and detailed analysis. Additionally, the study's aim to investigate the effectiveness of GC as a bridging therapy is admirable, as it addresses an important question in the field of RA treatment2 3. However, the study also has some limitations that must be taken into account when interpreting the results. Firstly, the sample size of 1653 patients may not be representative of the general population of RA patients. This could limit the generalizability of the study's findings and may not fully capture the diversity of RA patients. Additionally, the study's short-term follow-up period of 18 months may not be enough...
Show MoreI am writing a correspondence on the article "Influence of active versus placebo control on treatment responses in randomised controlled trials in rheumatoid arthritis" by Kerschbaumer et al 1. The authors' systematic approach to comparing the treatment effects of pharmaceutical compounds in rheumatoid arthritis clinical trials with placebo and active treatment controls is commendable. The results of the study, showing significantly higher responses in active comparator trials compared to placebo controlled trials, provide valuable insights into the influence of control groups in RCTs. However, I have a few critical points to raise regarding the study's methodology and conclusions. Firstly, the matching of active treatment arms to comparable regimens, populations, background therapy, and outcome reporting was based solely on the nature of the control group, which is not an ideal approach. This method of matching could have led to unequal comparison groups and biased results 2. In order to ensure that the comparison between active treatment and control groups is fair and accurate, a more comprehensive and systematic approach to matching should have been employed. Secondly, the conclusion that placebo controlled trials lead to smaller effect sizes of active compounds in RCTs compared with the same compound in head-to-head trials may be an overgeneralization. The authors did not consider other potential confounding factors that could explain the difference...
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