We read with interest Dr Pisetsky’s review of the role of autoantibodies in rheumatic diseases in which he states ‘neither the amount nor specificity of ACPAs appears to demarcate a transition from arthralgia to arthritis. Similarly, ACPA responses appear stable with remission and persist despite decreases in synovitis’ [1]. While we appreciate Dr. Pisetsky’s review is restricted to papers published in ARD, we do believe there is evidence to suggest the contrary view.
It is well established that the presence of circulating ACPA confers a greater risk of RA development and furthermore, that ACPA seropositive RA subjects have a more aggressive disease course with an increased risk of joint damage as detected by radiographic erosions [2]. The duration in which ACPA and rheumatoid factor (RF) are detectable before clinically apparent or classifiable RA develops varies greatly, and there is some evidence that this relates to age, with younger individuals having a shorter duration of seropositivity before development of RA when compared to older individuals [3]. It has been suggested that less than 50% of seropositive individuals will develop RA in a median follow-up time of 28 months, but this duration of follow up appears too short to accurately define the risk conferred by seropositivity [4].
ACPA titres may rise over time and higher titres are associated with development of clinically suspect arthralgia (CSA) before frank RA [5]. ACPA-positive individuals wi...
We read with interest Dr Pisetsky’s review of the role of autoantibodies in rheumatic diseases in which he states ‘neither the amount nor specificity of ACPAs appears to demarcate a transition from arthralgia to arthritis. Similarly, ACPA responses appear stable with remission and persist despite decreases in synovitis’ [1]. While we appreciate Dr. Pisetsky’s review is restricted to papers published in ARD, we do believe there is evidence to suggest the contrary view.
It is well established that the presence of circulating ACPA confers a greater risk of RA development and furthermore, that ACPA seropositive RA subjects have a more aggressive disease course with an increased risk of joint damage as detected by radiographic erosions [2]. The duration in which ACPA and rheumatoid factor (RF) are detectable before clinically apparent or classifiable RA develops varies greatly, and there is some evidence that this relates to age, with younger individuals having a shorter duration of seropositivity before development of RA when compared to older individuals [3]. It has been suggested that less than 50% of seropositive individuals will develop RA in a median follow-up time of 28 months, but this duration of follow up appears too short to accurately define the risk conferred by seropositivity [4].
ACPA titres may rise over time and higher titres are associated with development of clinically suspect arthralgia (CSA) before frank RA [5]. ACPA-positive individuals with CSA have a tendency to higher ACPA and rheumatoid factor (RF) titres compared to lower risk arthralgia patients [6]. Higher titres imply recognition of more citrullinated epitopes recognised by several immunoglobulin subtypes including IgG, IgM, IgA and IgE. The increase in ACPA subtypes have been shown to correlate with an increase in cytokine levels such as TNF-, IL-6, IL-12 and interferon- [7,8]. It appears that maturation of this response occurs prior to the conversion of CSA to RA. Several studies have observed that higher ACPA titres in CSA are associated with development of RA [4,9]. Our group has shown that seropositive arthralgia patients at risk for developing RA had greater than 50% macroscopic synovitis or vascularity scores at knee arthroscopy and that an ACPA titre of >340IU (the upper limit of sensitivity at our laboratory), was associated with progression to RA [10].
Another clinical area where ACPA and RF titres are relevant in RA is when selecting a therapeutic agent. Seropositive patients are more likely to respond to abatacept and rituximab [7,11–14]. Those with higher ACPA titres had a better clinical response to abatacept compared to adalimumab in the AMPLE trial [7]. Significant reductions in both ACPA and RF titres have been observed in RA patients after 3 months on abatacept and the reduction in ACPA has been shown to be an independent predictor of abatacept persistence at 12 months, possibly attributable to sustained therapeutic response [11]. B-cell depletion with rituximab has also been shown to reduce ACPA levels and improve disease activity in RA [15]. However, not all seropositive patients respond to these agents, constituting a significant unmet need
Despite the work to date, it is clear that further large prospective studies are needed to improve risk prediction models in the pre-clinical RA phase to allow for better identification of these individuals “at risk” and to develop new preventative strategies, as well as more and improved treatment options.
References
1 Pisetsky DS. Annals of the Rheumatic Diseases collection on autoantibodies in the rheumatic diseases: new insights into pathogenesis and the development of novel biomarkers. Ann Rheum Dis. 2023;82:1243–7.
2 Van Der Woude D, Syversen SW, Van Der Voort EIH, et al. The ACPA isotype profile reflects long-term radiographic progression in rheumatoid arthritis. Ann Rheum Dis. 2010;69:1110–6.
3 Majka DS, Deane KD, Parrish LA, et al. Duration of preclinical rheumatoid arthritis-related autoantibody positivity increases in subjects with older age at time of disease diagnosis. Annals of the Rheumatic Diseases. 2008;67:801–7.
4 Bos WH, Wolbink GJ, Boers M, et al. Arthritis development in patients with arthralgia is strongly associated with anti-citrullinated protein antibody status: a prospective cohort study. Ann Rheum Dis. 2010;69:490–4.
5 Nielen MMJ, Van Schaardenburg D, Reesink HW, et al. Specific autoantibodies precede the symptoms of rheumatoid arthritis: A study of serial measurements in blood donors. Arthritis & Rheumatism. 2004;50:380–6.
6 Westra J, Brouwer E, Raveling-Eelsing E, et al. Arthritis autoantibodies in individuals without rheumatoid arthritis: follow-up data from a Dutch population-based cohort (Lifelines). Rheumatology. 2021;60:658–66.
7 Sokolove J, Schiff M, Fleischmann R, et al. Impact of baseline anti-cyclic citrullinated peptide-2 antibody concentration on efficacy outcomes following treatment with subcutaneous abatacept or adalimumab: 2-year results from the AMPLE trial. Ann Rheum Dis. 2016;75:709–14.
8 Suwannalai P, Van De Stadt LA, Radner H, et al. Avidity maturation of anti-citrullinated protein antibodies in rheumatoid arthritis. Arthritis & Rheumatism. 2012;64:1323–8.
9 Van De Stadt LA, Van Der Horst AR, De Koning MHMT, et al. The extent of the anti-citrullinated protein antibody repertoire is associated with arthritis development in patients with seropositive arthralgia. Annals of the Rheumatic Diseases. 2011;70:128–33.
10 Gorman A, Flynn K, Turk M, et al. Predicting Progression to RA in Patients with Seropositive Arthralgia. Arthritis Rheumatol. 2021;73.
11 Endo Y, Koga T, Kawashiri S-Y, et al. Anti-citrullinated protein antibody titre as a predictor of abatacept treatment persistence in patients with rheumatoid arthritis: a prospective cohort study in Japan. Scandinavian Journal of Rheumatology. 2020;49:13–7.
12 Sellam J, Hendel-Chavez H, Rouanet S, et al. B cell activation biomarkers as predictive factors for the response to rituximab in rheumatoid arthritis: A six-month, national, multicenter, open-label study. Arthritis & Rheumatism. 2011;63:933–8.
13 Chatzidionysiou K, Lie E, Nasonov E, et al. Highest clinical effectiveness of rituximab in autoantibody-positive patients with rheumatoid arthritis and in those for whom no more than one previous TNF antagonist has failed: pooled data from 10 European registries. Annals of the Rheumatic Diseases. 2011;70:1575–80.
14 Isaacs JD, Cohen SB, Emery P, et al. Effect of baseline rheumatoid factor and anticitrullinated peptide antibody serotype on rituximab clinical response: a meta-analysis. Ann Rheum Dis. 2013;72:329–36.
15 Teng YO, Wheater G, Hogan VE, et al. Induction of long-term B-cell depletion in refractory rheumatoid arthritis patients preferentially affects autoreactive more than protective humoral immunity. Arthritis Res Ther. 2012;14:R57.
We have carefully reviewed the study by Mark D. Russell et al., titled "JAK Inhibitors and the Risk of Malignancy: A Meta-Analysis Across Disease Indications."[1].This meta-analysis, which compares JAK inhibitors with methotrexate, placebo, and TNF inhibitors (TNFi), suggests a heightened risk of tumors associated with JAK inhibitors. We commend the authors for their work and would like to offer several observations.
Firstly, the study indicates a higher tumor risk with JAK inhibitors compared to
TNFi. However, considering methotrexate's known anti-tumor properties[2], and the
lack of significant difference in tumor risk between methotrexate and JAK inhibitors
observed in this study, it raises a question: Is the tumor risk associated with JAK
inhibitors comparable to that of methotrexate? Additionally, the study does not
compare the tumor risk between methotrexate and TNFi, which could have provided a
clearer perspective on the relative risk associated with JAK inhibitors.
Secondly, the study's scope in terms of types of tumors and risk factors[3], such
as smoking, BMI, and alcohol consumption, appears limited. Including more
comprehensive baseline information could enhance the study's persuasiveness. Thirdly, as meta-analyses typically involve subgroup analyses based on factors
like age, gender, and disease type to address heterogeneity, the absence of such
analyses in this st...
We have carefully reviewed the study by Mark D. Russell et al., titled "JAK Inhibitors and the Risk of Malignancy: A Meta-Analysis Across Disease Indications."[1].This meta-analysis, which compares JAK inhibitors with methotrexate, placebo, and TNF inhibitors (TNFi), suggests a heightened risk of tumors associated with JAK inhibitors. We commend the authors for their work and would like to offer several observations.
Firstly, the study indicates a higher tumor risk with JAK inhibitors compared to
TNFi. However, considering methotrexate's known anti-tumor properties[2], and the
lack of significant difference in tumor risk between methotrexate and JAK inhibitors
observed in this study, it raises a question: Is the tumor risk associated with JAK
inhibitors comparable to that of methotrexate? Additionally, the study does not
compare the tumor risk between methotrexate and TNFi, which could have provided a
clearer perspective on the relative risk associated with JAK inhibitors.
Secondly, the study's scope in terms of types of tumors and risk factors[3], such
as smoking, BMI, and alcohol consumption, appears limited. Including more
comprehensive baseline information could enhance the study's persuasiveness. Thirdly, as meta-analyses typically involve subgroup analyses based on factors
like age, gender, and disease type to address heterogeneity, the absence of such
analyses in this study is notable. We suggest that further subgroup analysis could
strengthen the study's conclusions.
This article highlights the use of methotrexate, TNFi, and JAK inhibitors in
treating rheumatoid arthritis (RA) and discusses the evolving role of JAK inhibitors in
RA treatment[4]. Recent studies, including this one, suggest an increased tumor risk
associated with JAK inhibitors, warranting caution among rheumatologists[5].
In summary, while this meta-analysis underscores a potential increased tumor
risk with JAK inhibitors, the limited number and scope of studies due to the relatively
recent introduction of these drugs suggest that these findings are preliminary. We
appreciate the authors' efforts in highlighting these risks, which serve as an important
caution for clinicians.
References:
[1] Russell MD, Stovin C, Alveyn E, et al. JAK inhibitors and the risk of malignancy: a
meta-analysis across disease indications. Ann Rheum Dis. 2023;82(8):1059-1067. [2] Mishra P, Ali Ahmad MF, Al-Keridis LA, et al. Methotrexate-conjugated zinc oxide
nanoparticles exert a substantially improved cytotoxic effect on lung cancer cells by inducing
apoptosis. Front Pharmacol. 2023;14:1194578. [3] Crepeau PK, Sutton W, Sahli Z, et al. Prevalence and risk factors for dysphagia in older adults
after thyroid and parathyroid surgery. Surgery. 2023. [4] Harrington R, Al Nokhatha SA, Conway R. JAK inhibitors in rheumatoid arthritis: an
evidence-based review on the emerging clinical data. J Inflamm Res. 2020;14(13):519-531. [5] Yoshida S, Miyata M, Suzuki E, et al. Safety of JAK and IL-6 inhibitors in patients with
rheumatoid arthritis: a multicenter cohort study. Front Immunol. 2023;14:1267749.
Dear editorial team,
I recently had the opportunity to read the article titled "Disease activity drives transcriptomic heterogeneity in early untreated rheumatoid synovitis," and I wanted to express my appreciation for the insightful research you and your team have conducted in the field of rheumatoid arthritis (RA). Your study utilized RNASeq to analyze synovial tissue samples from patients with early, untreated RA, and I was particularly intrigued by your use of unbiased, data-driven approaches to identify clinically relevant subgroups. The application of principal components analysis (PCA) and unsupervised clustering to define patient clusters based on the expression of the most variable genes provided valuable insights into the disease's heterogeneity.
The identification of two patient clusters, PtC1 and PtC2, based on the expression of key genes associated with disease activity was a significant finding. The differentiation of these clusters in terms of disease activity and the probability of response to methotrexate therapy sheds light on the potential clinical implications of transcriptomic profiles. The observed upregulation of immune system genes in PtC1 and lipid metabolism genes in PtC2 provides important clues into the underlying pathophysiology of these subgroups. Additionally, I found your investigation of M2-like and M1-like macrophage ratios in relation to disease activity and synovial inflammation to be especially intriguing. The...
Dear editorial team,
I recently had the opportunity to read the article titled "Disease activity drives transcriptomic heterogeneity in early untreated rheumatoid synovitis," and I wanted to express my appreciation for the insightful research you and your team have conducted in the field of rheumatoid arthritis (RA). Your study utilized RNASeq to analyze synovial tissue samples from patients with early, untreated RA, and I was particularly intrigued by your use of unbiased, data-driven approaches to identify clinically relevant subgroups. The application of principal components analysis (PCA) and unsupervised clustering to define patient clusters based on the expression of the most variable genes provided valuable insights into the disease's heterogeneity.
The identification of two patient clusters, PtC1 and PtC2, based on the expression of key genes associated with disease activity was a significant finding. The differentiation of these clusters in terms of disease activity and the probability of response to methotrexate therapy sheds light on the potential clinical implications of transcriptomic profiles. The observed upregulation of immune system genes in PtC1 and lipid metabolism genes in PtC2 provides important clues into the underlying pathophysiology of these subgroups. Additionally, I found your investigation of M2-like and M1-like macrophage ratios in relation to disease activity and synovial inflammation to be especially intriguing. The inverse correlation between M2:M1 macrophage ratios and disease activity scores suggests a potential protective role for tissue-resident macrophages in RA. This could have profound implications for understanding disease progression and identifying novel therapeutic targets.
However, I acknowledge the limitations you discussed in your study. The observational nature of the cohort and the lack of controlled steroid treatment may introduce confounding factors that could be addressed in a controlled, prospective setting. Moreover, your suggestion of longer-term follow-up and repeat biopsies to validate the clinical relevance of your findings seems promising and may offer deeper insights into the disease's dynamics.
I appreciate your transparency in discussing the limitations, especially regarding intra-joint heterogeneity. I agree that spatial single-cell transcriptomic profiling could provide a powerful perspective in examining the subphenotypes of synovial tissue macrophages and their interactions with synoviocytes. However, there are some other issues with the methodologies of the study that I would like to mention. The number of patients included in this study was low and the authors did not justify why they conducted their study with lower than what actually needed for robust statistical analyses. The relatively low number of patients included and the absence of justification for the sample size might raise questions about the robustness of the statistical analyses.
Besides, the authors did not give any information regarding the recruitment of the patient; therefore, the timespan of patient selection, the setting of recruitment, and the method of sampling are not clear in this study. The lack of these details could limit the study's reproducibility and comparability.
Overall, your research contributes significantly to our understanding of early, untreated RA and highlights the importance of transcriptomic heterogeneity in disease activity and treatment response. The findings of your study hold great potential to impact the management and therapeutic approaches for RA patients.
Once again, thank you for your invaluable contribution to the field of rheumatoid arthritis research. I look forward to witnessing how your work progresses in the future and how it will potentially shape clinical practice and patient outcomes.
Mascaro and colleagues1 have nicely described a cohort of 30 Spanish cases of VEXAS syndrome from a group of 42 patients with adult-onset undiagnosed autoinflammatory disease. The authors showcase features of VEXAS in line with previous reports2,3 with regards to clinical characteristic and therapeutic responses. However, they also produce new evidence on the presence of UBA1 mosaicism, by detecting pathogenic variants in this gene in both hematopoietic and non-hematopoietic tissues. This piece of information questions the data of the original study by Beck et al4 whereby UBA1 variants were demonstrated to be somatic and largely restricted to the myeloid lineage. It must be noted that Mascaro et al replicated such findings in sorted peripheral blood (PB) populations showing the near absence (<1% of variant allele frequency -VAF) of the UBA1 variant in T and B lymphocytes, which instead was found at a mean VAF of 60.5% (14.6%-86.3%) in DNA samples extracted from whole PB or bone marrow (BM). The authors then used nails as a source of “an ectodermic tissue that may be easily and repetitively collected with no risk of blood contamination” and showed the presence of the respective UBA1 variants found in PB/BM samples at a mean VAF 24.2% (range 2.7%–73.7%). By this virtue, they conclude that such mosaicism may be due to the occurrence of UBA1 mutations during embryonic development, thereby questioning the ontogenesis of the disease so far accepted.4
We believe that som...
Mascaro and colleagues1 have nicely described a cohort of 30 Spanish cases of VEXAS syndrome from a group of 42 patients with adult-onset undiagnosed autoinflammatory disease. The authors showcase features of VEXAS in line with previous reports2,3 with regards to clinical characteristic and therapeutic responses. However, they also produce new evidence on the presence of UBA1 mosaicism, by detecting pathogenic variants in this gene in both hematopoietic and non-hematopoietic tissues. This piece of information questions the data of the original study by Beck et al4 whereby UBA1 variants were demonstrated to be somatic and largely restricted to the myeloid lineage. It must be noted that Mascaro et al replicated such findings in sorted peripheral blood (PB) populations showing the near absence (<1% of variant allele frequency -VAF) of the UBA1 variant in T and B lymphocytes, which instead was found at a mean VAF of 60.5% (14.6%-86.3%) in DNA samples extracted from whole PB or bone marrow (BM). The authors then used nails as a source of “an ectodermic tissue that may be easily and repetitively collected with no risk of blood contamination” and showed the presence of the respective UBA1 variants found in PB/BM samples at a mean VAF 24.2% (range 2.7%–73.7%). By this virtue, they conclude that such mosaicism may be due to the occurrence of UBA1 mutations during embryonic development, thereby questioning the ontogenesis of the disease so far accepted.4
We believe that some caveats must be highlighted concerning the possible contamination of nails with PB monocytes. Indeed, while having a good negative predictive power, namely to exclude the presence of germline variants in case of no detection, the positive predictive value of using DNA from nails when dealing with a variant present in myeloid-derived clones is highly contentious. Hematologists and geneticists dealing with studies of germline predisposition to myeloid neoplasia are aware of such problematics. In fact, for this reason, experts’ panels indicate that cultured fibroblasts from skin biopsy are a reliable source of germline DNA in such cases or, if not available, sorted CD3+ T lymphocytes with purity >95%.5,6 As a matter of fact, VAFs of DNA derived from nails in the Spanish study1 were significantly decreased (roughly 40% lower) as opposed to those found in PB or BM, likely suspicious of a contamination from blood cells. Finally, UBA1 VAF in DNA from CD3+ lymphocytes were virtually negative, thereby confirming the contamination hypothesis in line with previous literature contradicting UBA1 mosaicism. Therefore, we advise that confirmation of the findings from Mascaro et al in another non-hematopoietic source is warranted before drawing conclusions on VEXAS pathogenesis and UBA1 gene mosaicism.
References
1. Mascaro et al Annals of the Rheumatic Diseases, 2023
2. Grayson et al Blood 2021
3. Georgin-Lavialle S et al, Br J Dermatol, 2022
4. Beck et al, NEJM 2020
5 Homan et al Blood 2023
6. Roloff et al JCO Precision Oncology 2021
7. University of Chicago Hematopoietic Malignancies Cancer Risk Team, Blood 2016
We were intrigued by the recently published paper in the Annals of Rheumatic Diseases titled "HLA-B27, Axial Spondyloarthritis, and Survival" by Li et al.[1] This study explores the association between HLA-B27 carriage, axial spondyloarthritis (axSpA), and survival, offering valuable insights. By combining data from a 35-year follow-up study of Ankylosing Spondylitis (AS) and axSpA patients with the extensive UK Biobank dataset, the study significantly enhances our understanding of mortality patterns in AS/axSpA and the potential impact of HLA-B27 in the general population. We consider this study's implications important and look forward to critically examining its key findings and broader implications. However, there are some concerns that would better be clarified.
First and foremost, the observed gender-based differences in AS mortality are intriguing, with women generally exhibiting less severe sacroiliac joint damage.[2] However, an important consideration is the potential influence of HPV infection.[3] Surprisingly, the original study did not account for this factor, despite previous research linking HPV infection to autoimmune diseases, including AS, and suggesting a significantly elevated risk for AS development in HPV-infected individuals.[4] These findings underscore the complex interplay between infectious agents and autoimmune conditions. Additionally, prior research has indicated higher mortality in HPV-infected patients, emphasizing the...
We were intrigued by the recently published paper in the Annals of Rheumatic Diseases titled "HLA-B27, Axial Spondyloarthritis, and Survival" by Li et al.[1] This study explores the association between HLA-B27 carriage, axial spondyloarthritis (axSpA), and survival, offering valuable insights. By combining data from a 35-year follow-up study of Ankylosing Spondylitis (AS) and axSpA patients with the extensive UK Biobank dataset, the study significantly enhances our understanding of mortality patterns in AS/axSpA and the potential impact of HLA-B27 in the general population. We consider this study's implications important and look forward to critically examining its key findings and broader implications. However, there are some concerns that would better be clarified.
First and foremost, the observed gender-based differences in AS mortality are intriguing, with women generally exhibiting less severe sacroiliac joint damage.[2] However, an important consideration is the potential influence of HPV infection.[3] Surprisingly, the original study did not account for this factor, despite previous research linking HPV infection to autoimmune diseases, including AS, and suggesting a significantly elevated risk for AS development in HPV-infected individuals.[4] These findings underscore the complex interplay between infectious agents and autoimmune conditions. Additionally, prior research has indicated higher mortality in HPV-infected patients, emphasizing the need for a more in-depth investigation into the intricate relationship between infectious agents, autoimmune diseases, and mortality.
Second, understanding the factors contributing to high mortality in women with AS requires acknowledging the complex landscape of autoimmune diseases in this group. The study's female cohort likely included individuals with various autoimmune conditions, each impacting health and mortality differently. Additionally, the unique challenges related to reproductive health in women with AS, including the overlooked impact of pregnancy on disease outcomes, must be considered, given the higher prevalence of autoimmune diseases in women of childbearing age.[5] This highlights the importance of a holistic healthcare approach that accounts for the multifaceted aspects of women's health and the potential implications of pregnancy on both disease management and mortality in individuals with AS or other autoimmune conditions. While AS may indeed be linked to increased mortality, the confounding effect of coexisting autoimmune diseases should not be underestimated. The presence of multiple autoimmune conditions in the same study group complicates attributing mortality solely to AS or HLA-B27 status. To gain a more precise understanding of mortality patterns in AS, future studies may benefit from stratifying patients based on their autoimmune disease profiles and assessing mortality within more homogeneous subgroups.[6].
Third, the study appears to omit an examination of the impact of race, ethnicity, and social/lifestyle factors on mortality outcomes. These factors can affect disease susceptibility, severity, healthcare access, and social determinants of health, all of which shape mortality rates. Neglecting these variables can introduce bias and limit the study's generalizability.[7] Similarly, social and lifestyle factors, such as smoking, alcohol consumption, physical activity, diet, socioeconomic status, and more, can significantly impact health outcomes.[8] Future research on AS mortality should encompass the multifaceted influence of race, ethnicity, and social/lifestyle factors to gain a more comprehensive understanding of mortality contributors in this population.[9]
In conclusion, Li et al.'s paper offers a thought-provoking exploration of AS/axSpA mortality patterns and the role of HLA-B27 in survival. While its findings hold significant clinical and research implications, further investigation into nuanced mortality factors in AS/axSpA is warranted. As educators and researchers, we believe that ongoing research, with a focus on infectious agents, autoimmune comorbidities, reproductive health, and social determinants, will advance our understanding of these complexities and inform targeted patient care and public health interventions. We eagerly anticipate the field's continued evolution and its potential to improve the lives of those affected by AS/axSpA.
References:
1 Li Z, Khan MK, van der Linden SM, et al. HLA-B27, axial spondyloarthritis and survival. Ann Rheum Dis Published Online First: 7 September 2023. doi:10.1136/ard-2023-224434
2 Nam B, Jo S, Bang S-Y, et al. Clinical and genetic factors associated with radiographic damage in patients with ankylosing spondylitis. Ann Rheum Dis 2023;82:527–32.
3 Lichter K, Krause D, Xu J, et al. Adjuvant Human Papillomavirus Vaccine to Reduce Recurrent Cervical Dysplasia in Unvaccinated Women: A Systematic Review and Meta-analysis. Obstet Gynecol 2020;135:1070–83.
4 Wei C-Y, Lin J-Y, Wang Y-T, et al. Risk of ankylosing spondylitis following human papillomavirus infection: A nationwide, population-based, cohort study. J Autoimmun 2020;113:102482.
5 Meissner Y, Strangfeld A, Molto A, et al. Pregnancy and neonatal outcomes in women with axial spondyloarthritis: pooled data analysis from the European Network of Pregnancy Registries in Rheumatology (EuNeP). Ann Rheum Dis 2022;81:1524–33.
6 Singh AG, Chowdhary VR. Pregnancy-related issues in women with systemic lupus erythematosus. Int J Rheum Dis 2015;18:172–81.
7 GBD US Health Disparities Collaborators. Cause-specific mortality by county, race, and ethnicity in the USA, 2000-19: a systematic analysis of health disparities. Lancet 2023;402:1065–82.
8 Hosseini M, Rahimibarghani S, Ghorbanpour S, et al. The effects of supervision on the outcomes of exercise training in patients with ankylosing spondylitis: A single-blind randomized controlled trial. Int J Rheum Dis 2023;26:1120–8.
9 Inderjeeth CA, Boland E, Connor C, et al. Evaluation of an ankylosing spondylitis education and self-management program: Beneficial effects on ankylosing spondylitis specific outcomes. Int J Rheum Dis 2021;24:434–44.
To the Editor,
I am writing to address a recent article titled "Safety of colchicine and NSAID prophylaxis when initiating urate-lowering therapy for gout: propensity score-matched cohort studies in the UK Clinical Practice Research Datalink" (1). This study conducted two retrospective cohort studies to determine the risk of adverse events associated with colchicine or non-steroidal anti-inflammatory drug (NSAID) prophylaxis when initiating allopurinol for gout. The research presents valuable insights into the safety of these prophylactic measures, but it is essential to discuss both the limitations and strengths of this study.
The strengths of this study lie in its extensive sample size and its use of primary care consultation and prescription data linked to hospital records over a 20-year period. This approach provides a comprehensive and high-quality dataset, reflective of everyday clinical practice. The use of clinical diagnosis for gout, with a high positive predictive value, further reinforces the practical relevance of the study's findings. The researchers' recognition of limitations is commendable. It is essential to acknowledge that the observational design carries a risk of exposure status misclassification. Nevertheless, the study took measures to mitigate this risk through propensity score matching. Additionally, it should be noted that the study focused on adverse events severe enough to warrant consultation or hospitalization,...
To the Editor,
I am writing to address a recent article titled "Safety of colchicine and NSAID prophylaxis when initiating urate-lowering therapy for gout: propensity score-matched cohort studies in the UK Clinical Practice Research Datalink" (1). This study conducted two retrospective cohort studies to determine the risk of adverse events associated with colchicine or non-steroidal anti-inflammatory drug (NSAID) prophylaxis when initiating allopurinol for gout. The research presents valuable insights into the safety of these prophylactic measures, but it is essential to discuss both the limitations and strengths of this study.
The strengths of this study lie in its extensive sample size and its use of primary care consultation and prescription data linked to hospital records over a 20-year period. This approach provides a comprehensive and high-quality dataset, reflective of everyday clinical practice. The use of clinical diagnosis for gout, with a high positive predictive value, further reinforces the practical relevance of the study's findings. The researchers' recognition of limitations is commendable. It is essential to acknowledge that the observational design carries a risk of exposure status misclassification. Nevertheless, the study took measures to mitigate this risk through propensity score matching. Additionally, it should be noted that the study focused on adverse events severe enough to warrant consultation or hospitalization, potentially missing milder adverse events. Moreover, the inability to ascertain the use of over-the-counter NSAIDs or evaluate the effects of individual NSAIDs or colchicine dosing highlights areas for future research. Finally, the study's observational nature limits its ability to draw causal inferences.
The findings of this study provide valuable information to guide treatment decisions for people with gout and their clinicians. The increased occurrence of adverse events with prophylaxis when initiating allopurinol, particularly with colchicine, is noteworthy. While serious adverse events were rare, this study contributes to the ongoing discussion about the balance between the benefits and potential risks of prophylactic measures in gout treatment. Future research is warranted to determine which patients are at the greatest risk of adverse events and to explore the cardiovascular benefits of colchicine in gout patients.
In conclusion, the study serves as a valuable addition to the body of knowledge regarding gout treatment. Its limitations should be considered in interpreting the results, but the large dataset and real-world data sources make it a substantial contribution to the field. As further research is conducted, these findings will undoubtedly enhance the ability of patients and clinicians to make informed decisions about flare prophylaxis when initiating allopurinol, ultimately benefiting the well-being of individuals living with gout.
References
1. Roddy E, Bajpai R, Forrester H, et alSafety of colchicine and NSAID prophylaxis when initiating urate-lowering therapy for gout: propensity score-matched cohort studies in the UK Clinical Practice Research DatalinkAnnals of the Rheumatic Diseases Published Online First: 03 October 2023. doi: 10.1136/ard-2023-224154
We read with great interest the recent article by Roddy et al1 and commend their efforts to address a clinically relevant question using a large, generalizable database. However, we were surprised and concerned by their findings of notably increased absolute risks of serious adverse events with both colchicine and NSAID use, including neuropathy (4 excess cases/1000 person-years [PY]) and bone marrow suppression (10 excess cases/1000 PY) with colchicine and myocardial infarction (MI) with both colchicine (8 excess cases/1000 PY) and NSAIDs (6 excess cases/1000 PY). The corresponding HRs were 4.8, 3.3, 1.6, and 1.9, respectively. Together with the seriousness of these events, these data do not appear to support the authors’ conclusion that their findings provide reassurance for patients and clinicians. Conversely, if confirmed and true, these findings would raise safety concerns regarding the ACR/EULAR guideline recommendations, while being inconsistent with anecdotal clinical experience and recent randomized controlled trial (RCT) safety data.2,3 Indeed, the authors acknowledge that the higher MI risk with colchicine contradicts the RCT evidence4-6 demonstrating its cardiovascular benefit that resulted in FDA and EMA approval for MI prevention. All in all, we feel that additional analyses in the CPRD population and replications in different populations which consider the following would be critically important:
1. New user, active control design:...
We read with great interest the recent article by Roddy et al1 and commend their efforts to address a clinically relevant question using a large, generalizable database. However, we were surprised and concerned by their findings of notably increased absolute risks of serious adverse events with both colchicine and NSAID use, including neuropathy (4 excess cases/1000 person-years [PY]) and bone marrow suppression (10 excess cases/1000 PY) with colchicine and myocardial infarction (MI) with both colchicine (8 excess cases/1000 PY) and NSAIDs (6 excess cases/1000 PY). The corresponding HRs were 4.8, 3.3, 1.6, and 1.9, respectively. Together with the seriousness of these events, these data do not appear to support the authors’ conclusion that their findings provide reassurance for patients and clinicians. Conversely, if confirmed and true, these findings would raise safety concerns regarding the ACR/EULAR guideline recommendations, while being inconsistent with anecdotal clinical experience and recent randomized controlled trial (RCT) safety data.2,3 Indeed, the authors acknowledge that the higher MI risk with colchicine contradicts the RCT evidence4-6 demonstrating its cardiovascular benefit that resulted in FDA and EMA approval for MI prevention. All in all, we feel that additional analyses in the CPRD population and replications in different populations which consider the following would be critically important:
1. New user, active control design: A potential weakness of this study was that they compared active drug (colchicine or NSAID) with no drug. Despite their use of propensity score matching, this design is more susceptible to confounding, including confounding by indication. Furthermore, the covariates included in their propensity score model were relatively sparse and lacked key covariates such as rheumatology consultation, prior flare rates, and prior colchicine or NSAID use (before the preceding month). For example, comparing those who initiated colchicine vs. NSAIDs for gout flare prophylaxis would have better addressed this issue of potential confounding by indication, which can be otherwise intractable.
2. Follow-up duration: In this study, patients were followed up to 6 months or, in the case of the active drug groups, until the end of colchicine/NSAID treatment. As a result, the follow-up in both active drug groups was half that of unexposed groups (the mean follow-up duration = 3.1, 3.2, and 5.8 months in colchicine, NSAID, and no drug use group, respectively, based on the data from Tables 2 and 4). These large differences in follow-up carry major potential for selection bias associated with censoring, regardless of analytic adjustments. To this end, truncating follow-up properly and/or presenting an intention-to-treat analysis would help further evaluate the robustness of the findings.
3. Negative controls: Another way to ensure robustness of their findings would be to employ a negative control outcome. For example, one could examine certain NSAID-specific outcomes (expected to be null) in the colchicine group and vice versa. This is relevant as all study outcomes were positively associated, at least directionally. The study’s only overlapping outcome between colchicine and NSAID exposures was MI; both showed a positive association which was unexpected for colchicine as discussed above. As such, it appears critical to demonstrate that the analytic framework can validly discriminate null vs. genuine expected associations. If the analysis still finds an association with negative control outcomes, it may call into question the findings of the study at large.
In conclusion, while an important clinical question, further analyses and studies that consider the points above would be vital to validate the associations reported in this manuscript. We hope the study authors and others pursue these analyses to address these crucial clinical questions in gout care to be able to rigorously inform shared decision-making for patients.
1. Roddy E, Bajpai R, Forrester H, et al. Safety of colchicine and NSAID prophylaxis when initiating urate-lowering therapy for gout: propensity score-matched cohort studies in the UK Clinical Practice Research Datalink. Ann Rheum Dis 2023.
2. Mackenzie IS, Ford I, Nuki G, et al. Long-term cardiovascular safety of febuxostat compared with allopurinol in patients with gout (FAST): a multicentre, prospective, randomised, open-label, non-inferiority trial. Lancet 2020;396:1745-57.
3. O'Dell JR, Brophy MT, Pillinger MH, et al. Comparative Effectiveness of Allopurinol and Febuxostat in Gout Management. NEJM Evid 2022;1.
4. Nidorf SM, Eikelboom JW, Budgeon CA, Thompson PL. Low-dose colchicine for secondary prevention of cardiovascular disease. Journal of the American College of Cardiology 2013;61:404-10.
5. Tardif JC, Kouz S, Waters DD, et al. Efficacy and Safety of Low-Dose Colchicine after Myocardial Infarction. N Engl J Med 2019;381:2497-505.
6. Nidorf SM, Fiolet ATL, Mosterd A, et al. Colchicine in Patients with Chronic Coronary Disease. N Engl J Med 2020;383:1838-47.
This is a very interesting observational study on the cardiovascular risks of glucocorticoid therapy in RA. I particularly appreciate the balanced discussion, pointing to the problems of confounding by indication that were most likely not (completely) addressed by the analysis technique.
To further understand the findings I have a couple of requests:
1. Could the authors more clearly document how the exposure to GC developed over time? E.g., how many patients were on a mean dose of < 5mg/d, ≥ 5mg/d etc. for a set period of time? Were patterns of GC dosing visible? Previous studies (e.g. Michaud et al[1]) have documented that GC dosing can be dynamic with stops and starts over a period of time.
2. The primary analysis is based on a cut point of prednisolone 5 mg/d. Could the authors repeat the analysis where low dose is defined as ≤ 5mg/d, so including the 5 mg/d, to see whether the risk estimates (against intermediate dose defined as > 5 mg/d) change substantially? And perhaps even one where low dose is defined as ≤ 7.5 mg/d (in agreement with Buttgereit et al[2])? Such analyses would help inform clinicians, given that 5 and 7.5 mg/d dosing schedules are very frequently applied.
3. I have argued that current statistical analyses that adjust risk estimates for disease activity are suboptimal, because they obscure the fact that disease activity under treatment with GC is lower than it would be without treatment.[3] So, I would suggest that the r...
This is a very interesting observational study on the cardiovascular risks of glucocorticoid therapy in RA. I particularly appreciate the balanced discussion, pointing to the problems of confounding by indication that were most likely not (completely) addressed by the analysis technique.
To further understand the findings I have a couple of requests:
1. Could the authors more clearly document how the exposure to GC developed over time? E.g., how many patients were on a mean dose of < 5mg/d, ≥ 5mg/d etc. for a set period of time? Were patterns of GC dosing visible? Previous studies (e.g. Michaud et al[1]) have documented that GC dosing can be dynamic with stops and starts over a period of time.
2. The primary analysis is based on a cut point of prednisolone 5 mg/d. Could the authors repeat the analysis where low dose is defined as ≤ 5mg/d, so including the 5 mg/d, to see whether the risk estimates (against intermediate dose defined as > 5 mg/d) change substantially? And perhaps even one where low dose is defined as ≤ 7.5 mg/d (in agreement with Buttgereit et al[2])? Such analyses would help inform clinicians, given that 5 and 7.5 mg/d dosing schedules are very frequently applied.
3. I have argued that current statistical analyses that adjust risk estimates for disease activity are suboptimal, because they obscure the fact that disease activity under treatment with GC is lower than it would be without treatment.[3] So, I would suggest that the result of the disease activity measure (here, ESR or CRP) should be ‘corrected’ upwards before the adjustment procedure is applied. For DAS28 a correction of 0.6 could be applied for patients treated with doses around 5 mg. For other doses and disease activity measures the correction factor is not so clear, but simply applying a reasonable uniform correction in all GC treated patients would probably improve the model. Can the authors perform such an analysis?
1. Caplan L, Wolfe F, Russell AS, Michaud K. Corticosteroid use in rheumatoid arthritis: prevalence, predictors, correlates, and outcomes. J Rheumatol 2007;34:696-705.
2. Buttgereit F, Da Silva JA, Boers M, Burmester GR, Cutolo M, Jacobs J, et al. Standardised nomenclature for glucocorticoid dosages and glucocorticoid treatment regimens: current questions and tentative answers in rheumatology. Ann Rheum Dis 2002;61:718-22.
3. Boers M. Viewpoint: Glucocorticoids in the Treatment of Rheumatoid Arthritis: Points to (Re)consider. Rheumatology (Oxford) 2023.
The interesting paper by So et al.1 “Time and dose-dependent effect of systemic glucocorticoids on major adverse cardiovascular events in patients with rheumatoid arthritis” invites us to conduct an “artistic” dissection of glucocorticoids in our patients, remembering The Anatomy Lesson of Dr. Tulp by Rembrandt.
Rheumatoid arthritis (RA) is associated with CVD increased risk even before there is any clinical expression of RA, which continues to increase with the persistence and severity of the inflammatory process, making CVD the main cause of death particularly in seropositive patients.
The efficacy of glucocorticoids (GCs) is undeniable, including prevention or delay of structural changes, however, there is strong evidence that even “low doses” of GCs can increase the risk of CVD as well as other negative associations related to quality of life and survival. Additional to the risk of CVD associated to the systemic inflammatory nature of RA, 50% of the patients also have 1 or more other risk factors associated to major adverse cardiovascular events (MACE).1
The data presented emphasizes the potential presentation of MACE with GC-doses previously considered to be safe. Historically, the recommended therapeutic GC doses have been established based particularly on its efficacy, however, an increase of cardiovascular disease in 12 233 RA patients receiving more than 5 mg of prednisone per day has also been reported in this study, with reasonable follow up. 1...
The interesting paper by So et al.1 “Time and dose-dependent effect of systemic glucocorticoids on major adverse cardiovascular events in patients with rheumatoid arthritis” invites us to conduct an “artistic” dissection of glucocorticoids in our patients, remembering The Anatomy Lesson of Dr. Tulp by Rembrandt.
Rheumatoid arthritis (RA) is associated with CVD increased risk even before there is any clinical expression of RA, which continues to increase with the persistence and severity of the inflammatory process, making CVD the main cause of death particularly in seropositive patients.
The efficacy of glucocorticoids (GCs) is undeniable, including prevention or delay of structural changes, however, there is strong evidence that even “low doses” of GCs can increase the risk of CVD as well as other negative associations related to quality of life and survival. Additional to the risk of CVD associated to the systemic inflammatory nature of RA, 50% of the patients also have 1 or more other risk factors associated to major adverse cardiovascular events (MACE).1
The data presented emphasizes the potential presentation of MACE with GC-doses previously considered to be safe. Historically, the recommended therapeutic GC doses have been established based particularly on its efficacy, however, an increase of cardiovascular disease in 12 233 RA patients receiving more than 5 mg of prednisone per day has also been reported in this study, with reasonable follow up. 1
The ACR and EULAR guidelines continue to not clearly specify the time-length or dose of GCs, despite them being a therapeutic cornerstone.2,3 We recognize that GCs improve symptoms, although it is true that a few weeks may not be enough for optimal efficacy and modification of the natural course of RA. 4,5 Low-dose GC, defined as 5 mg of prednisone per day (pdn/d), modify the natural history of RA, unfortunately there are no studies comparing the difference on structural changes between <5 mg/d vs <10 mg/d,6 although similar efficacy achieved with <5 mg/d has been reported even after a decade of follow-up, without modifying adrenal function or suppressive response.7 Osteoporosis and infectious processes increase at doses greater than 5 mg/d of prednisone and the minimum reasonable safe length of time to avoid or restrict such effects is yet to be defined.8,9 Of transcendent interest is the fact that the requirements of low dose GCs are not limited to what we have called bridge-therapy and the adequate response is long-term maintained with very low doses of steroids. 10.11
The article by So et al, puts its finger on the sore point so as not to use more than 5 mg of pdn/d, because it monthly increases 7% of MACE. This important paper shows how the efficacy/safety index can be optimized with <5 mg pdn/day or equivalent, both to decrease CVD as a potential primary objective,1 and to prevent other comorbidities such as osteoporosis and infectious processes.8,9
We emphasize that these low doses can be left for long term to achieve the best response, and we must ask ourselves if the cardiovascular safety will be maintained over more years or decades.
Contrasting is the fact that despite the known accelerated atherosclerosis and increased MACE risk in RA patients, only a minority receive statins. Statins have demonstrated their immune-regulatory properties, showing efficacy in the activity of the disease and should be potentially prescribed in all of our patients, even without other CVD risk factors.
1. So H, Lam TO, Meng H, Lam SHM, Tam LS. Time and dose-dependent effect of systemic glucocorticoids on major adverse cardiovascular event in patients with rheumatoid arthritis: a population-based study. Ann Rheum Dis 2023;0: 1–7. doi:10.1136/ard-2023-224185
2. Fraenkel L, Bathon JM, England BR, et al. American college of rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken) 2021; 73: 924-39.
3. Smolen JS, Landewe RBM, Bergstra SA, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2022 update. Ann Rheum Dis 2022; 82: 3-18.
4. van Ouwerkerk L, Boers M, Emery P, de Jong PHP, Landewé RBM, Lems W et al. Individual patient data meta-analysis on continued use of glucocorticoids after their initiation as bridging therapy in patients with rheumatoid arthritis. Ann Rheum Dis 2023; 82: 468–475. doi:10.1136/ard-2022-223443
5. Doumen M, Pazmino S, Bertrand D, Westhovens R, Verschueren P. Glucocorticoids in rheumatoid arthritis: Balancing benefits and harm by leveraging the therapeutic window of opportunity. Joint Bone Spine 2023; 90: 105491. doi: 10.1016/j.jbspin.2022.105491.
6. Kirwan JR, Bijlsma JW, Boers M, Shea BJ. Effects of glucocorticoids on radiological progression in rheumatoid arthritis. Cochrane Database Syst Rev. 2007; 2007:CD006356. doi: 10.1002/14651858.CD006356.
7. Pincus T, Sokka T Castrejón I, Cutolo M. Decline of Mean Initial Prednisone Dosage From 10.3 to 3.6 mg/day to Treat Rheumatoid Arthritis Between 1980 and 2004 in One Clinical Setting, With Long-Term Effectiveness of Dosages Less Than 5 mg/day. Arthritis Care Res 2013; 65: 729-36. DOI 10.1002/acr.21899
8. Messina OD, Vidal LF, Wilman MV, Bultink IEM, Raterman HG, Lems W. Management of glucocorticoid-induced osteoporosis. Aging Clin Exp Res 2021; 33: 793-804. doi: 10.1007/s40520-021-01823-0.
9. George MD, Baker JF, Winthrop K, Hsu JY, Wu Q, Chen L, Xie F, Yun H, Curtis JR. Risk for serious infection with low-dose glucocorticoids in patients with rheumatoid arthritis : A cohort study. Ann Intern Med. 2020; 173: 870-8. doi: 10.7326/M20-1594.
10. Bergstra SA, Sepriano A, Kerschbaumer A, John Edwards C, van der Heijde D, Caporali R et al. Efficacy, duration of use and safety of glucocorticoids: a systematic literature review informing the 2022 update of the EULAR recommendations for the management of rheumatoid arthritis. Ann Rheum Dis.2022 Nov 21;ard-2022-223358. doi: 10.1136/ard-2022-223358.
11. Boers M, Hartman L, Opris-Belinski D, Bos R, Kok MR, Da Silva JAP et al. Low dose, add-on prednisolone in patients with rheumatoid arthritis aged 65+: the pragmatic randomised, double-blind placebo-controlled GLORIA trial. Ann Rheum Dis. 2022; 81: 925–936. doi: 10.1136/annrheumdis-2021-221957.
I wish to offer a comprehensive commentary on the article titled "Effect of Tapered versus Stable Treatment with Tumour Necrosis Factor Inhibitors on Disease Flares in Patients with Rheumatoid Arthritis in Remission: A Randomised, Open-Label, Non-Inferiority Trial"(1) authored by Lillegraven et al., published in Annals of the Rheumatic Diseases. This investigation is commendable for its rigorous scientific inquiry into the optimal management of patients with rheumatoid arthritis (RA) in prolonged remission, specifically addressing the contentious issue of tapering tumor necrosis factor inhibitors (TNFi) in this clinical context. I applaud the authors for their meticulous design, execution, and interpretation of the study's findings.
The authors' inquiry into the therapeutic approaches pertinent to patients with RA who have attained sustained remission is a timely and pertinent endeavor. Contemporary treatment paradigms have demonstrated that achieving remission necessitates the integration of TNFi therapy in patients exhibiting inadequate response or an inability to attain remission solely through methotrexate monotherapy. However, the broader clinical strategy concerning the tapering of TNFi in patients having achieved remission remains unresolved within the extant literature. The article under consideration offers a thoughtful exploration of this topic, effectively elucidating the consequences of tapering TNFi therapy to disc...
I wish to offer a comprehensive commentary on the article titled "Effect of Tapered versus Stable Treatment with Tumour Necrosis Factor Inhibitors on Disease Flares in Patients with Rheumatoid Arthritis in Remission: A Randomised, Open-Label, Non-Inferiority Trial"(1) authored by Lillegraven et al., published in Annals of the Rheumatic Diseases. This investigation is commendable for its rigorous scientific inquiry into the optimal management of patients with rheumatoid arthritis (RA) in prolonged remission, specifically addressing the contentious issue of tapering tumor necrosis factor inhibitors (TNFi) in this clinical context. I applaud the authors for their meticulous design, execution, and interpretation of the study's findings.
The authors' inquiry into the therapeutic approaches pertinent to patients with RA who have attained sustained remission is a timely and pertinent endeavor. Contemporary treatment paradigms have demonstrated that achieving remission necessitates the integration of TNFi therapy in patients exhibiting inadequate response or an inability to attain remission solely through methotrexate monotherapy. However, the broader clinical strategy concerning the tapering of TNFi in patients having achieved remission remains unresolved within the extant literature. The article under consideration offers a thoughtful exploration of this topic, effectively elucidating the consequences of tapering TNFi therapy to discontinuation.
The methodological stringency underpinning this study is noteworthy. Its randomized, open-label, non-inferiority design, executed across multiple rheumatology departments in Norway, bestows robustness upon the findings. The holistic assessment of patients through clinical and ultrasonographic examinations serves to enhance the reliability and granularity of the observed outcomes. Notwithstanding, the authors astutely acknowledge potential limitations such as the open-label nature of the trial and attendant biases stemming from patient expectations. This transparency is pivotal in contextualizing the findings within the broader landscape of rheumatological research.
Emanating from the study are cogent implications challenging the feasibility of tapering TNFi therapy to discontinuation in patients with RA in sustained remission. A notable disparity in disease flare rates between patients who underwent tapering and those subjected to stable therapy is delineated. This pronounced divergence corroborates the empirical notion that cessation of TNFi therapy is associated with an elevated risk of disease reactivation. Such findings, if corroborated across diverse cohorts, will invariably shape clinical practice by engendering a nuanced deliberation on therapeutic strategy among clinicians and their patients.
The article's thrust extends beyond the examination of clinical outcomes and merits consideration in light of existing literature. The authors astutely draw attention to the complex interplay between TNFi and other disease-modifying antirheumatic drugs (DMARDs) in the context of tapering strategies. This mechanistic insight underscores the multifaceted nature of therapeutic interventions and portends the necessity for tailored therapeutic approaches. Moreover, the article's discourse on the sustained remission outcomes among patients who experienced flares and subsequently regained remission following the reinstatement of full-dose treatment is germane to a holistic comprehension of therapeutic strategies in RA.
The scholarly discourse is further enriched through the discussion of methodological considerations and the juxtaposition of the study's outcomes against the broader literature. A lucid acknowledgment of the challenges posed by cross-study comparisons, consequent to disparate inclusion criteria and tapering protocols, evinces the authors' astute discernment. This salient insight underscores the need for standardized methodologies in future tapering studies. Additionally, the contemplation of the intricate interrelation between disease activity, TNFi administration, and radiographic joint damage, drawn from the extant literature, augments the study's depth and informs future research directions.
References
1. Siri L, Nina Paulshus S, Anna-Birgitte A, et al. Effect of tapered versus stable treatment with tumour necrosis factor inhibitors on disease flares in patients with rheumatoid arthritis in remission: a randomised, open label, non-inferiority trial. Annals of the Rheumatic Diseases. 2023:ard-2023-224476. doi: 10.1136/ard-2023-224476.
We read with interest Dr Pisetsky’s review of the role of autoantibodies in rheumatic diseases in which he states ‘neither the amount nor specificity of ACPAs appears to demarcate a transition from arthralgia to arthritis. Similarly, ACPA responses appear stable with remission and persist despite decreases in synovitis’ [1]. While we appreciate Dr. Pisetsky’s review is restricted to papers published in ARD, we do believe there is evidence to suggest the contrary view.
It is well established that the presence of circulating ACPA confers a greater risk of RA development and furthermore, that ACPA seropositive RA subjects have a more aggressive disease course with an increased risk of joint damage as detected by radiographic erosions [2]. The duration in which ACPA and rheumatoid factor (RF) are detectable before clinically apparent or classifiable RA develops varies greatly, and there is some evidence that this relates to age, with younger individuals having a shorter duration of seropositivity before development of RA when compared to older individuals [3]. It has been suggested that less than 50% of seropositive individuals will develop RA in a median follow-up time of 28 months, but this duration of follow up appears too short to accurately define the risk conferred by seropositivity [4].
ACPA titres may rise over time and higher titres are associated with development of clinically suspect arthralgia (CSA) before frank RA [5]. ACPA-positive individuals wi...
Show MoreWe have carefully reviewed the study by Mark D. Russell et al., titled "JAK Inhibitors and the Risk of Malignancy: A Meta-Analysis Across Disease Indications."[1].This meta-analysis, which compares JAK inhibitors with methotrexate, placebo, and TNF inhibitors (TNFi), suggests a heightened risk of tumors associated with JAK inhibitors. We commend the authors for their work and would like to offer several observations.
Show MoreFirstly, the study indicates a higher tumor risk with JAK inhibitors compared to
TNFi. However, considering methotrexate's known anti-tumor properties[2], and the
lack of significant difference in tumor risk between methotrexate and JAK inhibitors
observed in this study, it raises a question: Is the tumor risk associated with JAK
inhibitors comparable to that of methotrexate? Additionally, the study does not
compare the tumor risk between methotrexate and TNFi, which could have provided a
clearer perspective on the relative risk associated with JAK inhibitors.
Secondly, the study's scope in terms of types of tumors and risk factors[3], such
as smoking, BMI, and alcohol consumption, appears limited. Including more
comprehensive baseline information could enhance the study's persuasiveness. Thirdly, as meta-analyses typically involve subgroup analyses based on factors
like age, gender, and disease type to address heterogeneity, the absence of such
analyses in this st...
Dear editorial team,
Show MoreI recently had the opportunity to read the article titled "Disease activity drives transcriptomic heterogeneity in early untreated rheumatoid synovitis," and I wanted to express my appreciation for the insightful research you and your team have conducted in the field of rheumatoid arthritis (RA). Your study utilized RNASeq to analyze synovial tissue samples from patients with early, untreated RA, and I was particularly intrigued by your use of unbiased, data-driven approaches to identify clinically relevant subgroups. The application of principal components analysis (PCA) and unsupervised clustering to define patient clusters based on the expression of the most variable genes provided valuable insights into the disease's heterogeneity.
The identification of two patient clusters, PtC1 and PtC2, based on the expression of key genes associated with disease activity was a significant finding. The differentiation of these clusters in terms of disease activity and the probability of response to methotrexate therapy sheds light on the potential clinical implications of transcriptomic profiles. The observed upregulation of immune system genes in PtC1 and lipid metabolism genes in PtC2 provides important clues into the underlying pathophysiology of these subgroups. Additionally, I found your investigation of M2-like and M1-like macrophage ratios in relation to disease activity and synovial inflammation to be especially intriguing. The...
Mascaro and colleagues1 have nicely described a cohort of 30 Spanish cases of VEXAS syndrome from a group of 42 patients with adult-onset undiagnosed autoinflammatory disease. The authors showcase features of VEXAS in line with previous reports2,3 with regards to clinical characteristic and therapeutic responses. However, they also produce new evidence on the presence of UBA1 mosaicism, by detecting pathogenic variants in this gene in both hematopoietic and non-hematopoietic tissues. This piece of information questions the data of the original study by Beck et al4 whereby UBA1 variants were demonstrated to be somatic and largely restricted to the myeloid lineage. It must be noted that Mascaro et al replicated such findings in sorted peripheral blood (PB) populations showing the near absence (<1% of variant allele frequency -VAF) of the UBA1 variant in T and B lymphocytes, which instead was found at a mean VAF of 60.5% (14.6%-86.3%) in DNA samples extracted from whole PB or bone marrow (BM). The authors then used nails as a source of “an ectodermic tissue that may be easily and repetitively collected with no risk of blood contamination” and showed the presence of the respective UBA1 variants found in PB/BM samples at a mean VAF 24.2% (range 2.7%–73.7%). By this virtue, they conclude that such mosaicism may be due to the occurrence of UBA1 mutations during embryonic development, thereby questioning the ontogenesis of the disease so far accepted.4
Show MoreWe believe that som...
We were intrigued by the recently published paper in the Annals of Rheumatic Diseases titled "HLA-B27, Axial Spondyloarthritis, and Survival" by Li et al.[1] This study explores the association between HLA-B27 carriage, axial spondyloarthritis (axSpA), and survival, offering valuable insights. By combining data from a 35-year follow-up study of Ankylosing Spondylitis (AS) and axSpA patients with the extensive UK Biobank dataset, the study significantly enhances our understanding of mortality patterns in AS/axSpA and the potential impact of HLA-B27 in the general population. We consider this study's implications important and look forward to critically examining its key findings and broader implications. However, there are some concerns that would better be clarified.
First and foremost, the observed gender-based differences in AS mortality are intriguing, with women generally exhibiting less severe sacroiliac joint damage.[2] However, an important consideration is the potential influence of HPV infection.[3] Surprisingly, the original study did not account for this factor, despite previous research linking HPV infection to autoimmune diseases, including AS, and suggesting a significantly elevated risk for AS development in HPV-infected individuals.[4] These findings underscore the complex interplay between infectious agents and autoimmune conditions. Additionally, prior research has indicated higher mortality in HPV-infected patients, emphasizing the...
Show MoreTo the Editor,
Show MoreI am writing to address a recent article titled "Safety of colchicine and NSAID prophylaxis when initiating urate-lowering therapy for gout: propensity score-matched cohort studies in the UK Clinical Practice Research Datalink" (1). This study conducted two retrospective cohort studies to determine the risk of adverse events associated with colchicine or non-steroidal anti-inflammatory drug (NSAID) prophylaxis when initiating allopurinol for gout. The research presents valuable insights into the safety of these prophylactic measures, but it is essential to discuss both the limitations and strengths of this study.
The strengths of this study lie in its extensive sample size and its use of primary care consultation and prescription data linked to hospital records over a 20-year period. This approach provides a comprehensive and high-quality dataset, reflective of everyday clinical practice. The use of clinical diagnosis for gout, with a high positive predictive value, further reinforces the practical relevance of the study's findings. The researchers' recognition of limitations is commendable. It is essential to acknowledge that the observational design carries a risk of exposure status misclassification. Nevertheless, the study took measures to mitigate this risk through propensity score matching. Additionally, it should be noted that the study focused on adverse events severe enough to warrant consultation or hospitalization,...
Dear Editor,
We read with great interest the recent article by Roddy et al1 and commend their efforts to address a clinically relevant question using a large, generalizable database. However, we were surprised and concerned by their findings of notably increased absolute risks of serious adverse events with both colchicine and NSAID use, including neuropathy (4 excess cases/1000 person-years [PY]) and bone marrow suppression (10 excess cases/1000 PY) with colchicine and myocardial infarction (MI) with both colchicine (8 excess cases/1000 PY) and NSAIDs (6 excess cases/1000 PY). The corresponding HRs were 4.8, 3.3, 1.6, and 1.9, respectively. Together with the seriousness of these events, these data do not appear to support the authors’ conclusion that their findings provide reassurance for patients and clinicians. Conversely, if confirmed and true, these findings would raise safety concerns regarding the ACR/EULAR guideline recommendations, while being inconsistent with anecdotal clinical experience and recent randomized controlled trial (RCT) safety data.2,3 Indeed, the authors acknowledge that the higher MI risk with colchicine contradicts the RCT evidence4-6 demonstrating its cardiovascular benefit that resulted in FDA and EMA approval for MI prevention. All in all, we feel that additional analyses in the CPRD population and replications in different populations which consider the following would be critically important:
Show More1. New user, active control design:...
This is a very interesting observational study on the cardiovascular risks of glucocorticoid therapy in RA. I particularly appreciate the balanced discussion, pointing to the problems of confounding by indication that were most likely not (completely) addressed by the analysis technique.
Show MoreTo further understand the findings I have a couple of requests:
1. Could the authors more clearly document how the exposure to GC developed over time? E.g., how many patients were on a mean dose of < 5mg/d, ≥ 5mg/d etc. for a set period of time? Were patterns of GC dosing visible? Previous studies (e.g. Michaud et al[1]) have documented that GC dosing can be dynamic with stops and starts over a period of time.
2. The primary analysis is based on a cut point of prednisolone 5 mg/d. Could the authors repeat the analysis where low dose is defined as ≤ 5mg/d, so including the 5 mg/d, to see whether the risk estimates (against intermediate dose defined as > 5 mg/d) change substantially? And perhaps even one where low dose is defined as ≤ 7.5 mg/d (in agreement with Buttgereit et al[2])? Such analyses would help inform clinicians, given that 5 and 7.5 mg/d dosing schedules are very frequently applied.
3. I have argued that current statistical analyses that adjust risk estimates for disease activity are suboptimal, because they obscure the fact that disease activity under treatment with GC is lower than it would be without treatment.[3] So, I would suggest that the r...
The interesting paper by So et al.1 “Time and dose-dependent effect of systemic glucocorticoids on major adverse cardiovascular events in patients with rheumatoid arthritis” invites us to conduct an “artistic” dissection of glucocorticoids in our patients, remembering The Anatomy Lesson of Dr. Tulp by Rembrandt.
Show MoreRheumatoid arthritis (RA) is associated with CVD increased risk even before there is any clinical expression of RA, which continues to increase with the persistence and severity of the inflammatory process, making CVD the main cause of death particularly in seropositive patients.
The efficacy of glucocorticoids (GCs) is undeniable, including prevention or delay of structural changes, however, there is strong evidence that even “low doses” of GCs can increase the risk of CVD as well as other negative associations related to quality of life and survival. Additional to the risk of CVD associated to the systemic inflammatory nature of RA, 50% of the patients also have 1 or more other risk factors associated to major adverse cardiovascular events (MACE).1
The data presented emphasizes the potential presentation of MACE with GC-doses previously considered to be safe. Historically, the recommended therapeutic GC doses have been established based particularly on its efficacy, however, an increase of cardiovascular disease in 12 233 RA patients receiving more than 5 mg of prednisone per day has also been reported in this study, with reasonable follow up. 1...
Dear Editor,
I wish to offer a comprehensive commentary on the article titled "Effect of Tapered versus Stable Treatment with Tumour Necrosis Factor Inhibitors on Disease Flares in Patients with Rheumatoid Arthritis in Remission: A Randomised, Open-Label, Non-Inferiority Trial"(1) authored by Lillegraven et al., published in Annals of the Rheumatic Diseases. This investigation is commendable for its rigorous scientific inquiry into the optimal management of patients with rheumatoid arthritis (RA) in prolonged remission, specifically addressing the contentious issue of tapering tumor necrosis factor inhibitors (TNFi) in this clinical context. I applaud the authors for their meticulous design, execution, and interpretation of the study's findings.
Show MoreThe authors' inquiry into the therapeutic approaches pertinent to patients with RA who have attained sustained remission is a timely and pertinent endeavor. Contemporary treatment paradigms have demonstrated that achieving remission necessitates the integration of TNFi therapy in patients exhibiting inadequate response or an inability to attain remission solely through methotrexate monotherapy. However, the broader clinical strategy concerning the tapering of TNFi in patients having achieved remission remains unresolved within the extant literature. The article under consideration offers a thoughtful exploration of this topic, effectively elucidating the consequences of tapering TNFi therapy to disc...
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