The level of evidence for efficacy of conventional DMARDs is really low. The only high level evidence (i.e. a clinical trial does not show any benefit compared to placebo at a very low level of response (i.e ACR 30). Drugs such as methotrexate have been used for decades before bDMARDs effective in Still´s disease become available. The task force did not exclude that MTX may be of help for some patients or be a resource in some settings where IL-1 or IL-6 inhibitors cannot be used. The task force wanted to highlight that the ultimate goal is clinical inactive disease off medication and that this ambitious goal requires to use IL-1 or IL-6 inhibitors without loosing time with methotrexate or other potentially ineffective treatment, with the risk of missing the window of opportunity and, therefore endangering the long-term outcome of the patients.
The recently published paper by Yuan et al (1) convincingly show that NCF1 polymorphism is a major genetic cause of both diffuse cutaneous systemic sclerosis and lung fibrosis. The human association studies were confirmed in a single nucleotide polymorphism (SNP) knockin mouse. The description how the NCF1 polymorphism were discovered is however not correct. It is said that “We previously identified a hypofunctional variant (p.R90H) in neutrophil cytosolic factor 1 (NCF1), encoding a regulatory subunit of phagocyte NADPH oxidase 2 (NOX2), associated with robust risk of multiple autoimmune diseases including systemic lupus erythematosus (SLE), primary Sjögren’s syndrome (pSS) and rheumatoid arthritis (RA).” (2).
In fact the single nucleotide polymorphism (NCF1-339) leading to amino acid replacement of arginine to histidine at position 90 (R90H) was published by Olsson et al already 2012 (3). Importantly, this paper was built on positional cloning of NCF1 as the major underlying gene controlling autoimmune arthritis in rats (4). Based on this discovery, studies on copy number variation and sequencing of all functional exons of human NCF1 lead to identification of several SNPs leading to amino acid replacements(3). One of them was R90H, which lowered reactive oxygen species response in transfected COS cells. Based on this discovery both Olsson et al and Zhang et al independently found that the R90H variant was strongly associated with systemic lupus erythematosus (2, 5)...
The recently published paper by Yuan et al (1) convincingly show that NCF1 polymorphism is a major genetic cause of both diffuse cutaneous systemic sclerosis and lung fibrosis. The human association studies were confirmed in a single nucleotide polymorphism (SNP) knockin mouse. The description how the NCF1 polymorphism were discovered is however not correct. It is said that “We previously identified a hypofunctional variant (p.R90H) in neutrophil cytosolic factor 1 (NCF1), encoding a regulatory subunit of phagocyte NADPH oxidase 2 (NOX2), associated with robust risk of multiple autoimmune diseases including systemic lupus erythematosus (SLE), primary Sjögren’s syndrome (pSS) and rheumatoid arthritis (RA).” (2).
In fact the single nucleotide polymorphism (NCF1-339) leading to amino acid replacement of arginine to histidine at position 90 (R90H) was published by Olsson et al already 2012 (3). Importantly, this paper was built on positional cloning of NCF1 as the major underlying gene controlling autoimmune arthritis in rats (4). Based on this discovery, studies on copy number variation and sequencing of all functional exons of human NCF1 lead to identification of several SNPs leading to amino acid replacements(3). One of them was R90H, which lowered reactive oxygen species response in transfected COS cells. Based on this discovery both Olsson et al and Zhang et al independently found that the R90H variant was strongly associated with systemic lupus erythematosus (2, 5). Importantly the R90H variant is located in the same domain as the original T153M variant in rats and have similar effect on the NOX2 complex function and ROS response. In addition, the importance of R90H was later reproduced in humanised mice independently by several groups (6-9).
The discovery history is important as the NCF1 R90H variant is one of the few positionally cloned and functionally defined underlying genetic effects controlling complex disease. Importantly, the discovery was not based on genome wide association studies but on positional cloning using experimental animals and subsequently translated to humans.
1. Yuan X, Qin X, Takemoto K, Zhao J, Sanderson M, Xu X, et al. Human hypofunctional NCF1 variants promote pulmonary fibrosis in the bleomycin-induced mouse model and patients with systemic sclerosis via expansion of SPP1(+) monocytes-derived macrophages. Ann Rheum Dis. 2024.
2. Zhao J, Ma J, Deng Y, Kelly JA, Kim K, Bang SY, et al. A missense variant in NCF1 is associated with susceptibility to multiple autoimmune diseases. Nat Genet. 2017;49(3):433-7.
3. Olsson LM, Nerstedt A, Lindqvist AK, Johansson AC, Medstrand P, Olofsson P, et al. Copy number variation of the gene NCF1 is associated with Rheumatoid Arthritis. Antioxid Redox Signal. 2012;16(1):71-8.
4. Olofsson P, Holmberg J, Tordsson J, Lu S, Akerstrom B, Holmdahl R. Positional identification of Ncf1 as a gene that regulates arthritis severity in rats. Nat Genet. 2003;33(1):25-32.
5. Olsson LM, Johansson AC, Gullstrand B, Jonsen A, Saevarsdottir S, Ronnblom L, et al. A single nucleotide polymorphism in the NCF1 gene leading to reduced oxidative burst is associated with systemic lupus erythematosus. Ann Rheum Dis. 2017;76(9):1607-13.
6. Geng L, Zhao J, Deng Y, Molano I, Xu X, Xu L, et al. Human SLE variant NCF1-R90H promotes kidney damage and murine lupus through enhanced Tfh2 responses induced by defective efferocytosis of macrophages. Ann Rheum Dis. 2022;81(2):255-67.
7. Meng Y, Ma J, Yao C, Ye Z, Ding H, Liu C, et al. The NCF1 variant aggravates autoimmunity by facilitating the activation of plasmacytoid dendritic cells. J Clin Invest. 2022.
8. Li Y, Li Z, Nandakumar KS, Holmdahl R. Human NCF1(90H) Variant Promotes IL-23/IL-17-Dependent Mannan-Induced Psoriasis and Psoriatic Arthritis. Antioxidants (Basel). 2023;12(7).
9. Luo H, Urbonaviciute V, Saei AA, Lyu H, Gaetani M, Vegvari A, et al. NCF1-dependent production of ROS protects against lupus by regulating plasmacytoid dendritic cell development and functions. JCI Insight. 2023;8(7).
Dear Editor,
I thoroughly enjoyed reading the EULAR and PReS recommendations on the diagnosis and management of Still’s disease, authored by Fautrel et al., as a result of the joint efforts of these two communities (1). I congratulate the task force on their work on behalf of all physicians.
However, I would like to highlight some points that need further clarification and share my concerns.
1- As is well known, Still’s disease has various clinical courses: monocyclic, polycyclic, and chronic articular (2). The disease progression, outcomes, and treatment needs of these patients can differ. In addition to this classification, there are forms where systemic inflammation predominates, usually accompanied by macrophage activation syndrome, and forms characterized by chronic arthritis. Including these differences in the recommendations and shaping treatment suggestions accordingly would be more clinically beneficial.
2- In the proposed treatment algorithm and its explanation, it is recommended to initiate treatments targeting interleukin-1 or interleukin-6 regardless of the disease activity. The rationale given is that although there are small randomized controlled trials on therapies targeting interleukin-1 or interleukin-6, accumulated real-world data support the effectiveness of these agents. On the other hand, there is limited data regarding conventional DMARDs, and a randomized controlled trial in systemic JIA patients suggested that methotrexate w...
Dear Editor,
I thoroughly enjoyed reading the EULAR and PReS recommendations on the diagnosis and management of Still’s disease, authored by Fautrel et al., as a result of the joint efforts of these two communities (1). I congratulate the task force on their work on behalf of all physicians.
However, I would like to highlight some points that need further clarification and share my concerns.
1- As is well known, Still’s disease has various clinical courses: monocyclic, polycyclic, and chronic articular (2). The disease progression, outcomes, and treatment needs of these patients can differ. In addition to this classification, there are forms where systemic inflammation predominates, usually accompanied by macrophage activation syndrome, and forms characterized by chronic arthritis. Including these differences in the recommendations and shaping treatment suggestions accordingly would be more clinically beneficial.
2- In the proposed treatment algorithm and its explanation, it is recommended to initiate treatments targeting interleukin-1 or interleukin-6 regardless of the disease activity. The rationale given is that although there are small randomized controlled trials on therapies targeting interleukin-1 or interleukin-6, accumulated real-world data support the effectiveness of these agents. On the other hand, there is limited data regarding conventional DMARDs, and a randomized controlled trial in systemic JIA patients suggested that methotrexate was not superior to placebo. In this ranking, the long-standing use of conventional DMARDs, especially methotrexate, and the fact that clinicians who manage this patient group effectively and safely use these agents in clinical practice, have been overlooked, which may lead to various problems. One of the largest series on the use of conventional DMARDs in the treatment of Still’s disease was published by Kalyoncu et al., where 254 out of 306 patients (83%) achieved remission with corticosteroids and methotrexate ± other conventional DMARDs (3). Among 97 patients who received only corticosteroids and methotrexate, 85 (87.6%) achieved remission (3). In another recent study by Ruscitti et al., involving 171 Still’s disease patients registered in the AIDA Network Still Disease Registry, clinical remission was achieved in 38.6% of patients, regardless of whether they received a combination of any conventional or biological DMARDs (4). All these data show that conventional DMARDs, particularly methotrexate, cannot be easily excluded from the treatment process.
3- The authors mention that conventional DMARDs can be used in countries where treatments targeting interleukin-1 or interleukin-6 are not accessible. In countries where both options are available, this treatment hierarchy may lead to medicolegal problems. For instance, a patient diagnosed with Still’s disease who achieves remission with methotrexate might file a complaint with health authorities because interleukin-based therapies were not initiated.
REFERENCES
1. Fautrel B, Mitrovic S, De Matteis A, Bindoli S, Antón J, Belot A, et al. EULAR/PReS recommendations for the diagnosis and management of Still's disease, comprising systemic juvenile idiopathic arthritis and adult-onset Still's disease. Ann Rheum Dis. 2024.
2. Manger B, Rech J, Schett G. Use of methotrexate in adult-onset Still's disease. Clin Exp Rheumatol. 2010;28(5 Suppl 61):S168-71.
3. Kalyoncu U, Solmaz D, Emmungil H, Yazici A, Kasifoglu T, Kimyon G, et al. Response rate of initial conventional treatments, disease course, and related factors of patients with adult-onset Still's disease: Data from a large multicenter cohort. J Autoimmun. 2016;69:59-63.
4. Ruscitti P, Sota J, Vitale A, Lopalco G, Iannone F, Morrone M, et al. The administration of methotrexate in patients with Still's disease, "real-life" findings from AIDA Network Still Disease Registry. Semin Arthritis Rheum. 2023;62:152244.
We read with great interest the article by Marrugo et al. titled "Gout risk in adults with pre-diabetes initiating metformin" published in Annals of the Rheumatic Diseases[1]. The study provides valuable insights into the potential role of metformin in reducing the risk of gout among pre-diabetic patients. However, we would like to offer some constructive suggestions that we believe could enhance the robustness and applicability of the findings.
1. Stratified Analysis of Lifestyle Modifications
The study compares metformin users with non-users to evaluate the incidence of gout. While this comparison is informative, it does not fully account for the significant impact of lifestyle modifications, such as dietary changes, increased physical activity, weight control, and smoking cessation, which are well-documented strategies for preventing or delaying the onset of diabetes and gout.
We suggest a stratified analysis of the non-user cohort based on lifestyle changes. Specifically, dividing the non-users into those who have actively engaged in lifestyle modifications and those who have not could provide a more nuanced understanding of metformin’s effectiveness. This stratified approach would help isolate the effects of metformin from those of lifestyle interventions and offer clearer insights into the relative benefits of each strategy.
2. Clarification on Matching Ratio in Propensity Score Matching
The study employs...
We read with great interest the article by Marrugo et al. titled "Gout risk in adults with pre-diabetes initiating metformin" published in Annals of the Rheumatic Diseases[1]. The study provides valuable insights into the potential role of metformin in reducing the risk of gout among pre-diabetic patients. However, we would like to offer some constructive suggestions that we believe could enhance the robustness and applicability of the findings.
1. Stratified Analysis of Lifestyle Modifications
The study compares metformin users with non-users to evaluate the incidence of gout. While this comparison is informative, it does not fully account for the significant impact of lifestyle modifications, such as dietary changes, increased physical activity, weight control, and smoking cessation, which are well-documented strategies for preventing or delaying the onset of diabetes and gout.
We suggest a stratified analysis of the non-user cohort based on lifestyle changes. Specifically, dividing the non-users into those who have actively engaged in lifestyle modifications and those who have not could provide a more nuanced understanding of metformin’s effectiveness. This stratified approach would help isolate the effects of metformin from those of lifestyle interventions and offer clearer insights into the relative benefits of each strategy.
2. Clarification on Matching Ratio in Propensity Score Matching
The study employs a 1:n propensity score matching (PSM) method to balance baseline characteristics between metformin users and non-users. However, the rationale behind the choice of the matching ratio and the actual ratios used post-matching are not explicitly detailed. The selection of the matching ratio is critical as it influences the balance of covariates and the statistical power of the analysis.
Providing a detailed explanation of the matching ratio selection, including any sensitivity analyses performed to determine the optimal ratio, would strengthen the credibility of the PSM approach. Additionally, reporting the actual ratios achieved post-matching would offer transparency and allow readers to better assess the matching quality and the robustness of the study findings.
Incorporating these suggestions could provide a more comprehensive evaluation of metformin's role in reducing gout risk among pre-diabetic patients. A stratified analysis considering lifestyle modifications would offer a deeper understanding of the intervention effects, while a detailed explanation of the matching ratio would enhance the methodological rigor of the study.
We commend the authors for their significant contribution to this important field and hope these suggestions will be considered for future research.
We read with great interest the article by Yuan et al on “Human hypofunctional NCF1 variants promote pulmonary fibrosis in the bleomycin-induced mouse model and patients with systemic sclerosis via expansion of SPP1+ monocytes-derived macrophages” [1] , focusing on the assessment of the role of a systemic lupus erythematosus (SLE) causal hypofunctional variant, the neutrophil cytosolic factor 1
(NCF1)-p.Arg90His (p.R90H) substitution, in systemic sclerosis (SSc) [1] . In the framework of this article, authors conducted an elegant study using case–control cohorts as well as bleomycin-induced mouse models, both wild-type and knock-in.
Yuan et al nicely placed NCF1 - p. Arg90His polymorphism in a functional context, concluding that low NCF1 activity increases the risk for the development of diffuse cutaneous (dc) SSc and lung fibrosis, thus contributing to the severity of lung fibrosis in both BLM-treated mice and patients with SSc [1] . Notably, the amino acid substitution of arginine to histidine at position #90 of NCF1 protein that represents a subunit of NADPH oxidase, concerns a PX domain, which plays an important role in the membrane binding [2] and, in humans, it was found to lead to a reduced function of NADPH oxidase 2 . Of note, the p. Arg90His variant of NCF1 gene has been also associated, apart from SLE [3,4] , with rheumato...
We read with great interest the article by Yuan et al on “Human hypofunctional NCF1 variants promote pulmonary fibrosis in the bleomycin-induced mouse model and patients with systemic sclerosis via expansion of SPP1+ monocytes-derived macrophages” [1] , focusing on the assessment of the role of a systemic lupus erythematosus (SLE) causal hypofunctional variant, the neutrophil cytosolic factor 1
(NCF1)-p.Arg90His (p.R90H) substitution, in systemic sclerosis (SSc) [1] . In the framework of this article, authors conducted an elegant study using case–control cohorts as well as bleomycin-induced mouse models, both wild-type and knock-in.
Yuan et al nicely placed NCF1 - p. Arg90His polymorphism in a functional context, concluding that low NCF1 activity increases the risk for the development of diffuse cutaneous (dc) SSc and lung fibrosis, thus contributing to the severity of lung fibrosis in both BLM-treated mice and patients with SSc [1] . Notably, the amino acid substitution of arginine to histidine at position #90 of NCF1 protein that represents a subunit of NADPH oxidase, concerns a PX domain, which plays an important role in the membrane binding [2] and, in humans, it was found to lead to a reduced function of NADPH oxidase 2 . Of note, the p. Arg90His variant of NCF1 gene has been also associated, apart from SLE [3,4] , with rheumatoid arthritis (RA) and Sjögren’s syndrome (SS) in adult patients [5] as well as early-onset interferonopathy in pediatric patient [6] .
Our aim with this letter is to extend the information given from Yuan et al [1] by elucidating further the functional significance of the 90His variant from a structural biology viewpoint, considering its enrolment (in homozygous state) in multiple functions in SSc patients, including increased levels of various antibodies, increased incidence of lung fibrosis and elevated plasma osteopontin (OPN, SPP1), CCL2, ARG1, TIMP-1 and IL-6 [1] . Another reason pinpointing our interest for a multidisciplinary investigation of this variant refers to the extremely complexity of the genomic region of human NCF1 gene, due to presence of two pseudogenes, NCF1B and NCF1C, which are highly homologous to NCF1 [5] . To this end, we wish to add some pieces of additional information in an attempt to evaluate the structural significance of the Arg90His, by using a 3-dimensional (3-D) structural model of the p47phox PX domain of the NCF1 protein, which was developed previously by our group [7] . The highly conserved Arg90, located in a pocket of the p47phox PX domain, has been suggested to be involved in the recognition of the polar heads of phosphoinositides 7 . Our 3-D model demonstrated that the substitution of Arg90 to His eliminates the direct electrostatic interactions of the p47phox domain with the phosphate groups and also results in the weakening of the positive charge distribution on the molecular surface [8] . As a consequence, an affinity reduction to PtdIns(3,4)P2 appearsdue to the loss of interactions of specific phosphoinositide head group, thus affecting significantly the p47 phox translocation to the plasma membrane [8] .
In conclusion, although the structural biological information presented here is not associated directly with clinical applications, may help to further interpret the findings of Yuan et al 1 in the case of SSc from the structural-functional point of view, as also happened with data referred to the role of the 90His variant of NCF1 in SLE, thus emphasizing the significance of the NCF1 polymorphism under investigation.
Apparently, the potential role of other genetic polymorphisms and their functional consequences in future studies may contribute to an assessment of the possible confounding factors of these polymorphisms.
Maria I. Zervou1 and George N. Goulielmos1,2
1Section of Molecular Pathology and Human Genetics, Department of Internal Medicine, School of Medicine, University of Crete, Heraklion, Greece
2Department of Internal Medicine, University Hospital of Heraklion, Heraklion, Greece
Correspondence to Dr George N. Goulielmos, Section of Molecular Pathology and Human Genetics, Department of Internal Medicine, School of Medicine, University of Crete, Voutes, Heraklion 71003, Greece; goulielmos@med.uoc.gr
REFERENCES
[1] Yuan X, Qin X, Takemoto K, et al. Human hypofunctional NCF1 variants
promote pulmonary fibrosis in the bleomycin-induced mouse model and patients with
systemic sclerosis via expansion of SPP1+ monocytes-derived macrophages. Ann
Rheum Dis 2024;doi: 10.1136/ard-2024-226034.
[2] Zhong J, Olsson LM, Urbonaviciute V, et al. Association of Nox2 subunits
genetic variants with autoimmune diseases. Free Radic Biol Med 2018;125:72–80.
[3] Joob B, Wiwanitkit V. NCF1- 339 polymorphism and systemic lupus
erythematosus. Ann Rheum Dis 2021;80:e194.
[4] Linge P, Arve S, Olsson LM, et al. NCF1-339 polymorphism is associated with
altered formation of neutrophil extracellular traps, high serum interferon activity and
antiphospholipid syndrome in systemic lupus erythematosus. Ann Rheum Dis
2020;79:254–61.[
5] Yokoyama N, Kawasaki A, Matsushita T, et al. Association of NCF1
polymorphism with systemic lupus erythematosus and systemic sclerosis but not with
ANCA- associated vasculitis in a Japanese population. Sci Rep. 2019;9:16366.
[6] Schnappauf O, Heale L, Dissanayake D, et al. Homozygous variant p. Arg90His
in NCF1 is associated with early-onset Interferonopathy: a case report. Pediatr
Rheumatol Online J. 2021;19:54.
[7] Goulielmos GN, Zervou MI, Eliopoulos E. Comment on: homozygous variant p.
Arg90His in NCF1 is associated with early-onset interferonopathy: a case report.
Pediatr Rheumatol Online J. 2021;19:125.
[8] Goulielmos GN, Zervou MI, Eliopoulos E. Correspondence on ‘NCF1-339
polymorphism is associated with altered formation of neutrophil extracellular traps,
high serum interferon activity and antiphospholipid syndrome in systemic lupus
erythematosus’ by Linge et al. Ann Rheum Dis 2023;82:e231.
We have read with great interest the recent article by Chen et al. [1] on gout affecting the sternoclavicular joint (SCJ) [1]. It provides important insights into diagnosis and imaging of this rare condition. However, we noticed that while the authors mention that there were only three previously published cases [2-4] on SCJ involvement in gout, our case published in Rheumatology Advances in Practice [5] was notably absent from the discussion.
In our case, a 45-year-old male presented with acute onset swelling and severe pain in the left SCJ, initially suspected of malignancy but later confirmed as gout through histological analysis [5]. Noteworthy in this context is the normal serum uric acid level at presentation, a commonality with the case reported by Chen et al. [1]. This shows that gout can still be a possibility even when uric acid levels are normal, which is an important point for physicians to consider when diagnosing similar cases. The article [1] rightly points out the importance of considering gout in patients with unusual joint pain across various occupations. Our study [5] provides a similar perspective but from a slightly different angle, reinforcing the importance to acknowledge that such presentations can also appear in individuals with multiple metabolic risk factors, regardless of their uric acid history, which may be unknown.
We value the contributions by Chen et al. [1] and think that mentioning our findings [5] could lead to a fuller disc...
We have read with great interest the recent article by Chen et al. [1] on gout affecting the sternoclavicular joint (SCJ) [1]. It provides important insights into diagnosis and imaging of this rare condition. However, we noticed that while the authors mention that there were only three previously published cases [2-4] on SCJ involvement in gout, our case published in Rheumatology Advances in Practice [5] was notably absent from the discussion.
In our case, a 45-year-old male presented with acute onset swelling and severe pain in the left SCJ, initially suspected of malignancy but later confirmed as gout through histological analysis [5]. Noteworthy in this context is the normal serum uric acid level at presentation, a commonality with the case reported by Chen et al. [1]. This shows that gout can still be a possibility even when uric acid levels are normal, which is an important point for physicians to consider when diagnosing similar cases. The article [1] rightly points out the importance of considering gout in patients with unusual joint pain across various occupations. Our study [5] provides a similar perspective but from a slightly different angle, reinforcing the importance to acknowledge that such presentations can also appear in individuals with multiple metabolic risk factors, regardless of their uric acid history, which may be unknown.
We value the contributions by Chen et al. [1] and think that mentioning our findings [5] could lead to a fuller discussion on this topic.
References:
1. Chen S, Liu F, Chen J, Gu G, Yu H. Clinical image: tophus in the sternoclavicular joint. Ann Rheum Dis 2024;83:1225.
2. Fedeli AA, Vecchi M, Rodoni Cassis P. A patient with complex gout with an autoinflammatory syndrome and a sternoclavicular joint arthritis as presenting symptoms. Case Rep Rheumatol 2020;2020:5026490.
3. Sant GR, Dias E. Primary gout affecting the sternoclavicular joint. Br Med J 1976;1(6004):262.
4. Sachdev N, Smelt J, Avila Z, et al. Tophaceous gout in the sternoclavicular joint. J Surg Case Rep 2020;2020:rjaa398.
5. Smiyan S, Lepyavko A, Slaba U, et al. A rare clinical presentation of acute gouty arthritis. Rheumatol Adv Pract 2020;4:rkaa022.
We read the article by Dr. Minrui Liang et al. with great interest. This study, utilizing DEEP SEQ proteomics, identified and validated anti-PRMT5 antibodies as specific biomarkers for systemic sclerosis (SSc) and demonstrated their potential pathogenicity in immunised mice with recombinant protein PRMT5, thus contributing significantly to a more comprehensive understanding of the pathogenesis of SSc. However, we noted the absence of any discussion on the concordance between patients positive for anti-PRMT5 antibodies and those positive for classic SSc-related antibodies such as antitopoisomerase antibodies (ATAs), anticentromere antibodies (ACAs) and anti-RNA polymerase III antibodies (ARAs). Including such information would clarify the implications for clinical practice. Additionally, there is an inconsistency in the labeling of figures: Figure 2 is marked as "TOP1" and Figure 6 as "Topo Ⅰ," with the manuscript describing it as "Topo Ⅰ." This inconsistency may confuse readers within the same article. As the target antigen for anti-Scl-70 antibodies, the term "anti-Scl-70" might be more familiar than "Anti-Topo I" to physicians. Furthermore, although the article contains AUC curves, it does not provide the optimal cut-off value of the novel biomarker with sensitivity and specificity, which would have offered more direct and clear relevance for disease diagnosis.
I am writing to express my observations and constructive feedback on the recent study titled "Low uveitis rates in patients with axial spondyloarthritis treated with bimekizumab: pooled results from phase 2b/3 trials" published in your esteemed journal[1]. I commend the authors for their significant contribution to the field of rheumatology and the comprehensive analysis they have provided. However, I would like to highlight two aspects of the study design that, in my opinion, warrant further consideration.
1. Choice of Placebo Over Tumor Necrosis Factor Inhibitors
While the use of a placebo-controlled design is a standard and valuable approach in clinical trials, I believe that the current study would have greatly benefited from the inclusion of a comparator group treated with tumor necrosis factor inhibitors (TNFi). TNFi are currently recommended for patients with axial spondyloarthritis (axSpA) who have a history of recurrent acute anterior uveitis (AAU)[2]. The decision to use a placebo control, without comparing the efficacy and safety of bimekizumab directly against TNFi, limits the study’s ability to contextualize its findings within the existing therapeutic landscape. A direct comparison with TNFi would provide more robust evidence regarding the relative efficacy of bimekizumab, thereby offering clearer guidance for clinical practice.
2. Lack of Statistical Analysis in Table 1 and Table 2
The baseline characte...
I am writing to express my observations and constructive feedback on the recent study titled "Low uveitis rates in patients with axial spondyloarthritis treated with bimekizumab: pooled results from phase 2b/3 trials" published in your esteemed journal[1]. I commend the authors for their significant contribution to the field of rheumatology and the comprehensive analysis they have provided. However, I would like to highlight two aspects of the study design that, in my opinion, warrant further consideration.
1. Choice of Placebo Over Tumor Necrosis Factor Inhibitors
While the use of a placebo-controlled design is a standard and valuable approach in clinical trials, I believe that the current study would have greatly benefited from the inclusion of a comparator group treated with tumor necrosis factor inhibitors (TNFi). TNFi are currently recommended for patients with axial spondyloarthritis (axSpA) who have a history of recurrent acute anterior uveitis (AAU)[2]. The decision to use a placebo control, without comparing the efficacy and safety of bimekizumab directly against TNFi, limits the study’s ability to contextualize its findings within the existing therapeutic landscape. A direct comparison with TNFi would provide more robust evidence regarding the relative efficacy of bimekizumab, thereby offering clearer guidance for clinical practice.
2. Lack of Statistical Analysis in Table 1 and Table 2
The baseline characteristics and demographic data presented in Table 1 and Table 2 of the study are crucial for understanding the study population and ensuring the comparability of treatment groups. However, the absence of statistical analyses to compare these baseline characteristics between the groups is a notable omission. Conducting and reporting statistical tests, such as t-tests for continuous variables and chi-square tests for categorical variables, would allow for the assessment of any significant differences between the groups. This, in turn, would help in ensuring that the groups are well-matched and that any observed treatment effects are not confounded by baseline imbalances. The inclusion of these statistical analyses is essential for validating the internal validity of the study findings.
Conclusion
In conclusion, while the study provides valuable insights into the efficacy of bimekizumab in reducing uveitis rates among axSpA patients, addressing the aforementioned points would enhance the robustness and clinical applicability of the findings. I hope these suggestions are received in the constructive spirit intended and contribute to ongoing and future research efforts in this important area.
Thank you for considering my comments. I look forward to future publications that continue to advance our understanding and treatment of axSpA.
Yours sincerely,
Caifeng Li
Reference
1. Brown MA, Rudwaleit M, Van Gaalen FA, et al. Low uveitis rates in patients with axial spondyloarthritis treated with bimekizumab: pooled results from phase 2b/3 trials. Ann. Rheum. Dis. , ard-2024-225933 (2024).
2. Ramiro S, Nikiphorou E, Sepriano A, et al. ASAS-EULAR recommendations for the management of axial spondyloarthritis: 2022 update. Ann. Rheum. Dis. 82(1), 19–34 (2023).
The recent publication by Brunner et al. [1] on the long-term safety and efficacy of tofacitinib for juvenile idiopathic arthritis (JIA) provides critical insights into the management of this complex condition. Building on their findings, I would like to offer additional perspectives on the implications of these results and suggest areas for future research.
Firstly, the high incidence of infections observed in the study, particularly upper respiratory tract infections and nasopharyngitis, underscores the need for close monitoring of immunosuppression in pediatric patients. Future research should explore strategies to mitigate these risks, potentially through intermittent dosing schedules or the use of adjunctive therapies that enhance immune function without compromising the efficacy of tofacitinib. Additionally, concerning pediatric patients, it is imperative to assess the impact of long-term tofacitinib treatment on growth and development. Integrating comprehensive evaluations of growth metrics, bone density, and developmental milestones into future studies would ensure that the therapeutic benefits of tofacitinib do not adversely affect physiological development.
Second, we suggest the authors conduct subgroup analyses based on genetic, demographic, and disease severity indicators so that future research can identify which patients are most likely to benefit from tofacitinib, thereby refining patient selection criteria and enhancing tr...
The recent publication by Brunner et al. [1] on the long-term safety and efficacy of tofacitinib for juvenile idiopathic arthritis (JIA) provides critical insights into the management of this complex condition. Building on their findings, I would like to offer additional perspectives on the implications of these results and suggest areas for future research.
Firstly, the high incidence of infections observed in the study, particularly upper respiratory tract infections and nasopharyngitis, underscores the need for close monitoring of immunosuppression in pediatric patients. Future research should explore strategies to mitigate these risks, potentially through intermittent dosing schedules or the use of adjunctive therapies that enhance immune function without compromising the efficacy of tofacitinib. Additionally, concerning pediatric patients, it is imperative to assess the impact of long-term tofacitinib treatment on growth and development. Integrating comprehensive evaluations of growth metrics, bone density, and developmental milestones into future studies would ensure that the therapeutic benefits of tofacitinib do not adversely affect physiological development.
Second, we suggest the authors conduct subgroup analyses based on genetic, demographic, and disease severity indicators so that future research can identify which patients are most likely to benefit from tofacitinib, thereby refining patient selection criteria and enhancing treatment efficacy.
Another critical area for future research is the identification of biomarkers predictive of response to tofacitinib. Personalized medicine approaches, including pharmacogenomics, could help tailor treatments to individual patients, optimizing therapeutic outcomes and minimizing adverse effects. Exploring genetic, proteomic, and metabolomic profiles associated with favorable responses to tofacitinib could pave the way for more effective, individualized treatment regimens.
In conclusion, Brunner et al.’s study offers valuable insights into the use of tofacitinib for JIA. However, addressing the outlined considerations will be essential to fully elucidate the drug’s long-term safety, efficacy, and optimal use in clinical practice.
References
1. Brunner, H.I.; Akikusa, J.D.; Al-Abadi, E.; Bohnsack, J.F.; Boteanu, A.L.; Chedeville, G.; Cuttica, R.; De La Pena, W.; Jung, L.; Kasapcopur, O.; et al. Safety and Efficacy of Tofacitinib for the Treatment of Patients with Juvenile Idiopathic Arthritis: Preliminary Results of an Open-Label, Long-Term Extension Study. Ann Rheum Dis 2024, ard-2023-225094, doi:10.1136/ard-2023-225094.
We read with interest the recent metaanalysis by Burmester et al1 on the spectrum of adverse events that were recorded among the participants of global adalimumab clinical trials. However, the observed increased risk of Crohn’s disease (CD) patients to develop a skin squamous cell carcinoma (SCC) compared to base-line and to other adalimumab-treated patients is quite important to deserve an additional comment...
We read with interest the recent metaanalysis by Burmester et al1 on the spectrum of adverse events that were recorded among the participants of global adalimumab clinical trials. However, the observed increased risk of Crohn’s disease (CD) patients to develop a skin squamous cell carcinoma (SCC) compared to base-line and to other adalimumab-treated patients is quite important to deserve an additional comment.
In many studies SCC is registered along with basal cell carcinoma in non-melanoma skin cancer. However, the biological behaviour of these tumours is distinct and SCC can become extremely difficult to treat in certain patient subgroups, notably immunosuppressed patients.2 We suggest that the increased SCC rate among CD patients probably reflects the preferential use of azathioprine (AZA) for immune modulation in this group of patients compared to patients with all other diagnoses. Long term AZA is relatively well-tolerated in CD achieving sustained disease remission with an additional steroid-sparing effect.3 Thus recent treatment guidelines instigate AZA as an early treatment choice for CD patients.4 Moreover, among all other immunomodulatory strategies AZA is preferentially tested against biologicals in ongoing trials for patients with CD.5
However, AZA is a well established photocarcinogen too, as it increases the photosensitivity of the skin to ultraviolet A (UVA)6 through substitution of guanine for 6-thio-guanin in the DNA of patients under treatment. The accumulation of 6-thio-guanin moieties in the DNA of epidermal keratinocytes intensifies energy absorption at the DNA level with subsequent increased mutation and carcinogenesis rates.7,8 In transplanted patients the use of AZA has been associated with significant increase in the risk of skin malignancies,9,10 however the corresponding data concerning AZA-associated skin carcinogenesis in patients with inflammatory bowel diseases are not conclusive.11-13 Thus, in the light of the evidence of the recent adalimumab metaanalysis,1 the increased incidence of skin SCC among patients with CD becomes an important finding that merits further analysis.
The safety of biological therapies and their use is expanded as we learn to screen and be vigilant for acute infections. However, the next step will be to prevent long-term side-effects and from current experience with immunomodulation / immunosuppression regimes, non-melanoma skin cancer will be among the most perturbing ones.2,9,10 In this context the data of Burmester et al1 are also an important reminder that future studies should address explicitly the effect of the combination of biologicals and specific immunomodulatory drugs, like AZA, on skin carcinogenesis in order to ensure proper selection of combination regimens.
References
1. Burmester GR, Mease P, Dijkmans BAC, Gordon K, Lovell D, Panaccione R, et al. Adalimumab safety and mortality rates from global clinical trials of six immune-mediated inflammatory diseases. Ann Rheum Dis 2009. DOI:10.1136/ard.2008.102103.
2. Berg D, Otley CC. Skin cancer in organ transplant recipients: epidemiology, pathogenesis, and management. J Am Acad Dermatol 2002;47:1-17.
3. Prefontain E, Sutherland LR, MacDonald JK, Cepoiu M. Azathioprine or 6-mercapopurine for maintenance of remission in Crohn’s disease. Cochrane Database of Systematic Reviews 2009, Issue 1. Art. No.: CD000067. DOI: 10.1002/14651858.CD000067.pub2.
4. Lichtenstein GR, Abreu MT, Cohen R, Tremaine W. American Gastroenterological Association Institute technical review on corticosteroids, immunomoulators, and infliximab in inflammatory bowel disease. Gastroenterology 2006;130: 940-87.
5. Etchevers MJ, Aceituno M, Sans M. Are we giving azathioprine too late? The case of early immunomodulation in inflammatory bowel disease. World J Gastroenterol 2008;14:5512-8.
6. Perrett CM, Walker SL, O'Donovan P, Warwick J, Harwood CA, Karran P, et al. Azathioprine treatment photosensitizes human skin to ultraviolet A radiation. Br J Dermatol 2008;159: 198-204.
7. O'Donovan P, Perrett CM, Zhang X, Montaner B, Xu YZ, Harwood CA, et al. Azathioprine and UVA light generate mutagenic oxidative DNA damage. Science 2005;309:1871-4.
8. Zhang X, Jeffs G, Ren X, O’Donovan P, Montaner B, Perrett CM, et al. Novel DNA lesions generated by the interaction between therapeutic thiopurines and UVA light. DNA Repair 2007;6:344-54.
9. Ulrich C, Stockfleth E. Azathioprine, UV light, and skin cancer in organ transplant patients – do we have an answer? Nephrol Dial Transplant 2007;22:1027-9.
10. Harwood CA, Attard NR, O'Donovan P, Chambers P, Perrett CM, Proby CM, et al. PTCH mutations in basal cell carcinomas from azathioprine-treated organ transplant recipients. Br J Cancer 2008;21:1276-84.
11. Austin AS, Spiller RC. Inflammatory bowel disease, azathioprine and skin cancer: case report and literature review. Eur J Gastroenterol Hepatol 2001;13:193-4.
12. Fraser AG, Orchard TR, Robinson EM, Jewell DP. Long-term risk of malignancy after treatment of inflammatory bowel disease with azathioprine. Aliment Pharmacol Ther 2002;16:1225-32.
13. Maddox JS, Soltani K. Risk of nonmelanoma skin cancer with azathioprine use. Inflamm Bowel Dis 2008;14:1425-31.
The recently published paper by Yuan et al (1) convincingly show that NCF1 polymorphism is a major genetic cause of both diffuse cutaneous systemic sclerosis and lung fibrosis. The human association studies were confirmed in a single nucleotide polymorphism (SNP) knockin mouse. The description how the NCF1 polymorphism were discovered is however not correct. It is said that “We previously identified a hypofunctional variant (p.R90H) in neutrophil cytosolic factor 1 (NCF1), encoding a regulatory subunit of phagocyte NADPH oxidase 2 (NOX2), associated with robust risk of multiple autoimmune diseases including systemic lupus erythematosus (SLE), primary Sjögren’s syndrome (pSS) and rheumatoid arthritis (RA).” (2).
Show MoreIn fact the single nucleotide polymorphism (NCF1-339) leading to amino acid replacement of arginine to histidine at position 90 (R90H) was published by Olsson et al already 2012 (3). Importantly, this paper was built on positional cloning of NCF1 as the major underlying gene controlling autoimmune arthritis in rats (4). Based on this discovery, studies on copy number variation and sequencing of all functional exons of human NCF1 lead to identification of several SNPs leading to amino acid replacements(3). One of them was R90H, which lowered reactive oxygen species response in transfected COS cells. Based on this discovery both Olsson et al and Zhang et al independently found that the R90H variant was strongly associated with systemic lupus erythematosus (2, 5)...
Dear Editor,
Show MoreI thoroughly enjoyed reading the EULAR and PReS recommendations on the diagnosis and management of Still’s disease, authored by Fautrel et al., as a result of the joint efforts of these two communities (1). I congratulate the task force on their work on behalf of all physicians.
However, I would like to highlight some points that need further clarification and share my concerns.
1- As is well known, Still’s disease has various clinical courses: monocyclic, polycyclic, and chronic articular (2). The disease progression, outcomes, and treatment needs of these patients can differ. In addition to this classification, there are forms where systemic inflammation predominates, usually accompanied by macrophage activation syndrome, and forms characterized by chronic arthritis. Including these differences in the recommendations and shaping treatment suggestions accordingly would be more clinically beneficial.
2- In the proposed treatment algorithm and its explanation, it is recommended to initiate treatments targeting interleukin-1 or interleukin-6 regardless of the disease activity. The rationale given is that although there are small randomized controlled trials on therapies targeting interleukin-1 or interleukin-6, accumulated real-world data support the effectiveness of these agents. On the other hand, there is limited data regarding conventional DMARDs, and a randomized controlled trial in systemic JIA patients suggested that methotrexate w...
Dear Editor,
We read with great interest the article by Marrugo et al. titled "Gout risk in adults with pre-diabetes initiating metformin" published in Annals of the Rheumatic Diseases[1]. The study provides valuable insights into the potential role of metformin in reducing the risk of gout among pre-diabetic patients. However, we would like to offer some constructive suggestions that we believe could enhance the robustness and applicability of the findings.
1. Stratified Analysis of Lifestyle Modifications
The study compares metformin users with non-users to evaluate the incidence of gout. While this comparison is informative, it does not fully account for the significant impact of lifestyle modifications, such as dietary changes, increased physical activity, weight control, and smoking cessation, which are well-documented strategies for preventing or delaying the onset of diabetes and gout.
We suggest a stratified analysis of the non-user cohort based on lifestyle changes. Specifically, dividing the non-users into those who have actively engaged in lifestyle modifications and those who have not could provide a more nuanced understanding of metformin’s effectiveness. This stratified approach would help isolate the effects of metformin from those of lifestyle interventions and offer clearer insights into the relative benefits of each strategy.
2. Clarification on Matching Ratio in Propensity Score Matching
Show MoreThe study employs...
We read with great interest the article by Yuan et al on “Human hypofunctional NCF1 variants promote pulmonary fibrosis in the bleomycin-induced mouse model and patients with systemic sclerosis via expansion of SPP1+ monocytes-derived macrophages” [1] , focusing on the assessment of the role of a systemic lupus erythematosus (SLE) causal hypofunctional variant, the neutrophil cytosolic factor 1
Show More(NCF1)-p.Arg90His (p.R90H) substitution, in systemic sclerosis (SSc) [1] . In the framework of this article, authors conducted an elegant study using case–control cohorts as well as bleomycin-induced mouse models, both wild-type and knock-in.
Yuan et al nicely placed NCF1 - p. Arg90His polymorphism in a functional context, concluding that low NCF1 activity increases the risk for the development of diffuse cutaneous (dc) SSc and lung fibrosis, thus contributing to the severity of lung fibrosis in both BLM-treated mice and patients with SSc [1] . Notably, the amino acid substitution of arginine to histidine at position #90 of NCF1 protein that represents a subunit of NADPH oxidase, concerns a PX domain, which plays an important role in the membrane binding [2] and, in humans, it was found to lead to a reduced function of NADPH oxidase 2 . Of note, the p. Arg90His variant of NCF1 gene has been also associated, apart from SLE [3,4] , with rheumato...
We have read with great interest the recent article by Chen et al. [1] on gout affecting the sternoclavicular joint (SCJ) [1]. It provides important insights into diagnosis and imaging of this rare condition. However, we noticed that while the authors mention that there were only three previously published cases [2-4] on SCJ involvement in gout, our case published in Rheumatology Advances in Practice [5] was notably absent from the discussion.
In our case, a 45-year-old male presented with acute onset swelling and severe pain in the left SCJ, initially suspected of malignancy but later confirmed as gout through histological analysis [5]. Noteworthy in this context is the normal serum uric acid level at presentation, a commonality with the case reported by Chen et al. [1]. This shows that gout can still be a possibility even when uric acid levels are normal, which is an important point for physicians to consider when diagnosing similar cases. The article [1] rightly points out the importance of considering gout in patients with unusual joint pain across various occupations. Our study [5] provides a similar perspective but from a slightly different angle, reinforcing the importance to acknowledge that such presentations can also appear in individuals with multiple metabolic risk factors, regardless of their uric acid history, which may be unknown.
We value the contributions by Chen et al. [1] and think that mentioning our findings [5] could lead to a fuller disc...
Show MoreWe read the article by Dr. Minrui Liang et al. with great interest. This study, utilizing DEEP SEQ proteomics, identified and validated anti-PRMT5 antibodies as specific biomarkers for systemic sclerosis (SSc) and demonstrated their potential pathogenicity in immunised mice with recombinant protein PRMT5, thus contributing significantly to a more comprehensive understanding of the pathogenesis of SSc. However, we noted the absence of any discussion on the concordance between patients positive for anti-PRMT5 antibodies and those positive for classic SSc-related antibodies such as antitopoisomerase antibodies (ATAs), anticentromere antibodies (ACAs) and anti-RNA polymerase III antibodies (ARAs). Including such information would clarify the implications for clinical practice. Additionally, there is an inconsistency in the labeling of figures: Figure 2 is marked as "TOP1" and Figure 6 as "Topo Ⅰ," with the manuscript describing it as "Topo Ⅰ." This inconsistency may confuse readers within the same article. As the target antigen for anti-Scl-70 antibodies, the term "anti-Scl-70" might be more familiar than "Anti-Topo I" to physicians. Furthermore, although the article contains AUC curves, it does not provide the optimal cut-off value of the novel biomarker with sensitivity and specificity, which would have offered more direct and clear relevance for disease diagnosis.
Dear Editor,
I am writing to express my observations and constructive feedback on the recent study titled "Low uveitis rates in patients with axial spondyloarthritis treated with bimekizumab: pooled results from phase 2b/3 trials" published in your esteemed journal[1]. I commend the authors for their significant contribution to the field of rheumatology and the comprehensive analysis they have provided. However, I would like to highlight two aspects of the study design that, in my opinion, warrant further consideration.
1. Choice of Placebo Over Tumor Necrosis Factor Inhibitors
While the use of a placebo-controlled design is a standard and valuable approach in clinical trials, I believe that the current study would have greatly benefited from the inclusion of a comparator group treated with tumor necrosis factor inhibitors (TNFi). TNFi are currently recommended for patients with axial spondyloarthritis (axSpA) who have a history of recurrent acute anterior uveitis (AAU)[2]. The decision to use a placebo control, without comparing the efficacy and safety of bimekizumab directly against TNFi, limits the study’s ability to contextualize its findings within the existing therapeutic landscape. A direct comparison with TNFi would provide more robust evidence regarding the relative efficacy of bimekizumab, thereby offering clearer guidance for clinical practice.
2. Lack of Statistical Analysis in Table 1 and Table 2
Show MoreThe baseline characte...
Dear Editor,
The recent publication by Brunner et al. [1] on the long-term safety and efficacy of tofacitinib for juvenile idiopathic arthritis (JIA) provides critical insights into the management of this complex condition. Building on their findings, I would like to offer additional perspectives on the implications of these results and suggest areas for future research.
Firstly, the high incidence of infections observed in the study, particularly upper respiratory tract infections and nasopharyngitis, underscores the need for close monitoring of immunosuppression in pediatric patients. Future research should explore strategies to mitigate these risks, potentially through intermittent dosing schedules or the use of adjunctive therapies that enhance immune function without compromising the efficacy of tofacitinib. Additionally, concerning pediatric patients, it is imperative to assess the impact of long-term tofacitinib treatment on growth and development. Integrating comprehensive evaluations of growth metrics, bone density, and developmental milestones into future studies would ensure that the therapeutic benefits of tofacitinib do not adversely affect physiological development.
Second, we suggest the authors conduct subgroup analyses based on genetic, demographic, and disease severity indicators so that future research can identify which patients are most likely to benefit from tofacitinib, thereby refining patient selection criteria and enhancing tr...
Show MoreDear editor
We read with interest the recent metaanalysis by Burmester et al1 on the spectrum of adverse events that were recorded among the participants of global adalimumab clinical trials. However, the observed increased risk of Crohn’s disease (CD) patients to develop a skin squamous cell carcinoma (SCC) compared to base-line and to other adalimumab-treated patients is quite important to deserve an additional comment...
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