Although, several novel autoantibodies in idiopathic inflammatory myopathies (IIM) have been described, a serological gap persists which poses a diagnostic challenge. In this context, we read with interest the article by Vulsteke et al. [1]. The untargeted protein immunoprecipitation combined with gel-free liquid chromatography-tandem mass spectrometry (IP-MS) identified a novel autoantibody to cytoplasmic cysteinyl-tRNA-synthetase (CARS1, anti-Ly). In addition, rare ASA, such as anti-OJ, anti-Zo and anti-KS, and common ASA could also be identified by IP-MS. Consequently, Vulsteke et al. [1] concluded that IP-MS is a promising method for discovery detection of autoantibodies, especially autoantibodies that target complex autoantigens.
We agree that IP-MS represents a powerful discovery tool for novel autoantibodies. However, the gained knowledge is most valuable for more conventional in-vitro diagnostic platforms. Although the IP-MS method holds promise, due to the lack of standardization it is unlikely that it will be applicable for IVD solutions soon. Established alternative methods include ELISA [2], line immunoassay (LIA) and a recently developed particle-based multi-analyte technology (PMAT) that has been evaluated for the detection of MSA [3-5].
Due to the antigen complexity, anti-OJ are among the most difficult MSA to detect [6, 7]. According to an international survey, despite concern about its accuracy, LIA is commonly used for the detection of MSA inc...
Although, several novel autoantibodies in idiopathic inflammatory myopathies (IIM) have been described, a serological gap persists which poses a diagnostic challenge. In this context, we read with interest the article by Vulsteke et al. [1]. The untargeted protein immunoprecipitation combined with gel-free liquid chromatography-tandem mass spectrometry (IP-MS) identified a novel autoantibody to cytoplasmic cysteinyl-tRNA-synthetase (CARS1, anti-Ly). In addition, rare ASA, such as anti-OJ, anti-Zo and anti-KS, and common ASA could also be identified by IP-MS. Consequently, Vulsteke et al. [1] concluded that IP-MS is a promising method for discovery detection of autoantibodies, especially autoantibodies that target complex autoantigens.
We agree that IP-MS represents a powerful discovery tool for novel autoantibodies. However, the gained knowledge is most valuable for more conventional in-vitro diagnostic platforms. Although the IP-MS method holds promise, due to the lack of standardization it is unlikely that it will be applicable for IVD solutions soon. Established alternative methods include ELISA [2], line immunoassay (LIA) and a recently developed particle-based multi-analyte technology (PMAT) that has been evaluated for the detection of MSA [3-5].
Due to the antigen complexity, anti-OJ are among the most difficult MSA to detect [6, 7]. According to an international survey, despite concern about its accuracy, LIA is commonly used for the detection of MSA including anti-OJ [8]. Recently, a summary of studies analyzing the performance of LIA for the detection of anti-OJ antibodies concluded poor performance for anti-OJ by LIA [9]. This lack of performance was also observed in a very recent study by Preger et al. [10] as well as by Vulsteke et al. [1] detecting anti-OJ antibodies via IP-MS in a patient that was negative by LIA.
When Mimori et al. developed an anti-ARS ELISA (mixture of Jo-1, EJ, PL-7, PL-12, KS), they originally included IARS but removed the antigen because it did not agree with IP [2]. Similarly, the original studies using the PMAT MSA assay excluded anti-OJ form the analysis due to the lack of a reliable assay configuration. The most recent PMAT study included OJ based on IARS and KARS (two components of the OJ complex) [9]. This and another recent study, concluded that IARS and KARS represent promising antigens for anti-OJ detection [6]. Comparison with IP indicated that anti-KARS might show higher correlation with IP vs. anti-IARS antibodies. Since the commercial LIA uses IARS [9], which was also successfully used in ELISA [6], it is most likely that the protein construct or the immobilization of the analyte in the LIA are responsible for the remarkable difference in performance. Another reason might be the origin of the protein used by Muro et al. which derived from a cell free system (other proteins of the OJ complex could be present in the cell—free derived antigen).
Interestingly, Vulsteke et al. [1] showed that two samples contain anti-OJ had similar peaks in IP-MS for all OJ components except for LARS (Spearman=0.32, 95% CI -0.37-0.78). High correlation between samples for components of macromolecular complexes is expected since the entire complex is immunoprecipitated. However, different reactivity patterns in IP are frequently observed for anti-OJ (not all bands show comparable reactivity between samples) [7], potentially mediated by antibodies that dissociate the complex and affect the amount of precipitated proteins. Whether those differences are indicative of different reactivity to the individual components of OJ, remains unclear. However, before drawing definitive conclusions from the data, it is important to generate and review data on reproducibility of the IP-MS method (e.g. intra-, and inter-assay variability). In conclusion, we congratulate the authors on the discovery of anti-Ly and on the gain knowledge on anti-OJ.
References
1. Vulsteke JB, Derua R, Dubucquoi S, Coutant F, Sanges S, Goncalves D, et al. Mass spectrometry-based identification of new anti-Ly and known antisynthetase autoantibodies. Ann Rheum Dis. 2022.
2. Nakashima R, Imura Y, Hosono Y, Seto M, Murakami A, Watanabe K, et al. The multicenter study of a new assay for simultaneous detection of multiple anti-aminoacyl-tRNA synthetases in myositis and interstitial pneumonia. PLoS One. 2014;9(1):e85062.
3. Richards M, Garcia-De La Torre I, Gonzalez-Bello YC, Vazquez-Del MM, Andrade-Ortega L, Medrano-Ramirez G, et al. Autoantibodies to Mi-2 alpha and Mi-2 beta in patients with idiopathic inflammatory myopathy. Rheumatology (Oxford). 2019.
4. Mahler M, Betteridge Z, Bentow C, Richards M, Seaman A, Chinoy H, et al. Comparison of Three Immunoassays for the Detection of Myositis Specific Antibodies. Front Immunol. 2019;10:848.
5. Cavazzana I, Richards M, Bentow C, Seaman A, Fredi M, Giudizi MG, et al. Evaluation of a novel particle-based assay for detection of autoantibodies in idiopathic inflammatory myopathies. J Immunol Methods. 2019:112661.
6. Muro Y, Yamano Y, Yoshida K, Oto Y, Nakajima K, Mitsuma T, et al. Immune recognition of lysyl-tRNA synthetase and isoleucyl-tRNA synthetase by anti-OJ antibody-positive sera. J Autoimmun. 2021;122:102680.
7. Vulsteke JB, Satoh M, Malyavantham K, Bossuyt X, De Langhe E, Mahler M. Anti-OJ autoantibodies: Rare or underdetected? Autoimmun Rev. 2019;18(7):658-64.
8. Tansley SL, Snowball J, Pauling JD, Lissina A, Kuwana M, Rider LG, et al. The promise, perceptions, and pitfalls of immunoassays for autoantibody testing in myositis. Arthritis Res Ther. 2020;22(1):117.
9. Fritzler MJ, Bentow C, Satoh M, McHugh N, Ghirardello A, Mahler M. Deciphering the Autoantibody Response to the OJ Antigenic Complex. Diagnostics (Basel). 2023;13(1).
10. Preger C, Notarnicola A, Hellström C, Wigren E, Fernandes-Cerqueira C, Kvarnström M, et al. Autoantigenic properties of the aminoacyl tRNA synthetase family in idiopathic inflammatory myopathies. J Autoimmun. 2022;134:102951.
We are submitting a correspondence in regards to the paper "Individual patient data meta-analysis on continued use of glucocorticoids after their initiation as bridging therapy in patients with rheumatoid arthritis" by Lotte van Ouwerkerk et al.1 published in Ann Rheum Dis. 2022 Dec 16. The study is an important contribution to the field as it aimed to investigate the effectiveness of glucocorticoids (GC) as a bridging therapy for rheumatoid arthritis (RA) patients. The study combined data from 7 clinical trial arms that included GC bridging schedule in the initial treatment of RA, to investigate whether patients with RA can discontinue GC after GC 'bridging' and to identify factors that may affect this. The study has several strengths, such as the use of individual patient data meta-analysis which allows for a more comprehensive and detailed analysis. Additionally, the study's aim to investigate the effectiveness of GC as a bridging therapy is admirable, as it addresses an important question in the field of RA treatment2 3. However, the study also has some limitations that must be taken into account when interpreting the results. Firstly, the sample size of 1653 patients may not be representative of the general population of RA patients. This could limit the generalizability of the study's findings and may not fully capture the diversity of RA patients. Additionally, the study's short-term follow-up period of 18 months may not be enough...
We are submitting a correspondence in regards to the paper "Individual patient data meta-analysis on continued use of glucocorticoids after their initiation as bridging therapy in patients with rheumatoid arthritis" by Lotte van Ouwerkerk et al.1 published in Ann Rheum Dis. 2022 Dec 16. The study is an important contribution to the field as it aimed to investigate the effectiveness of glucocorticoids (GC) as a bridging therapy for rheumatoid arthritis (RA) patients. The study combined data from 7 clinical trial arms that included GC bridging schedule in the initial treatment of RA, to investigate whether patients with RA can discontinue GC after GC 'bridging' and to identify factors that may affect this. The study has several strengths, such as the use of individual patient data meta-analysis which allows for a more comprehensive and detailed analysis. Additionally, the study's aim to investigate the effectiveness of GC as a bridging therapy is admirable, as it addresses an important question in the field of RA treatment2 3. However, the study also has some limitations that must be taken into account when interpreting the results. Firstly, the sample size of 1653 patients may not be representative of the general population of RA patients. This could limit the generalizability of the study's findings and may not fully capture the diversity of RA patients. Additionally, the study's short-term follow-up period of 18 months may not be enough time to understand the long-term effects of GC bridging therapy. Long-term follow-up is essential to understand the durability of treatment effects and potential side effects. Furthermore, the study's focus on the specific GC bridging schedule used in the clinical trials may not be generalizable to other GC bridging schedules used in clinical practice. This could limit the applicability of the study's findings to clinical practice. The study also found that oral GC bridging studies only, the probabilities of later and continuous GC use and the cumulative GC doses were higher compared to the combined analyses with also parenteral GC bridging studies included. This finding may be misleading as the oral GC bridging studies only were not randomized, which could have introduced bias. Randomization is important to ensure that the groups being compared are similar and to reduce the likelihood of bias4. In conclusion, while this study provides some insights into the use of GC as a bridging therapy in RA, its results must be viewed with caution given its limitations. Further research with larger sample sizes, longer follow-up periods, and randomized controlled trial are needed to fully understand the effects of GC bridging therapy on RA patients and to determine if patients can discontinue GC after GC 'bridging.'
REFERNECES
1 van Ouwerkerk L, Boers M, Emery P, et al. Individual patient data meta-analysis on continued use of glucocorticoids after their initiation as bridging therapy in patients with rheumatoid arthritis. Annals of the Rheumatic Diseases 2022
2 Fraenkel L, Bathon JM, England BR, et al. 2021 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis & Rheumatology 2021;73:1108-23.
3 Hua C, Buttgereit F, Combe B. Glucocorticoids in rheumatoid arthritis: current status and future studies. RMD open 2020;6:e000536.
4 Akobeng AK. Understanding randomised controlled trials. Archives of disease in childhood 2005;90:840-4.
I am writing a correspondence on the article "Influence of active versus placebo control on treatment responses in randomised controlled trials in rheumatoid arthritis" by Kerschbaumer et al 1. The authors' systematic approach to comparing the treatment effects of pharmaceutical compounds in rheumatoid arthritis clinical trials with placebo and active treatment controls is commendable. The results of the study, showing significantly higher responses in active comparator trials compared to placebo controlled trials, provide valuable insights into the influence of control groups in RCTs. However, I have a few critical points to raise regarding the study's methodology and conclusions. Firstly, the matching of active treatment arms to comparable regimens, populations, background therapy, and outcome reporting was based solely on the nature of the control group, which is not an ideal approach. This method of matching could have led to unequal comparison groups and biased results 2. In order to ensure that the comparison between active treatment and control groups is fair and accurate, a more comprehensive and systematic approach to matching should have been employed. Secondly, the conclusion that placebo controlled trials lead to smaller effect sizes of active compounds in RCTs compared with the same compound in head-to-head trials may be an overgeneralization. The authors did not consider other potential confounding factors that could explain the difference...
I am writing a correspondence on the article "Influence of active versus placebo control on treatment responses in randomised controlled trials in rheumatoid arthritis" by Kerschbaumer et al 1. The authors' systematic approach to comparing the treatment effects of pharmaceutical compounds in rheumatoid arthritis clinical trials with placebo and active treatment controls is commendable. The results of the study, showing significantly higher responses in active comparator trials compared to placebo controlled trials, provide valuable insights into the influence of control groups in RCTs. However, I have a few critical points to raise regarding the study's methodology and conclusions. Firstly, the matching of active treatment arms to comparable regimens, populations, background therapy, and outcome reporting was based solely on the nature of the control group, which is not an ideal approach. This method of matching could have led to unequal comparison groups and biased results 2. In order to ensure that the comparison between active treatment and control groups is fair and accurate, a more comprehensive and systematic approach to matching should have been employed. Secondly, the conclusion that placebo controlled trials lead to smaller effect sizes of active compounds in RCTs compared with the same compound in head-to-head trials may be an overgeneralization. The authors did not consider other potential confounding factors that could explain the difference in response rates. For example, factors such as the placebo effect, patient expectations, and the impact of patient-provider interaction could all contribute to the difference in response rates between the two types of trials. The authors also should have discussed the potential impact of study design, population, and background therapy that could have influenced the results. The study design may have limitations such as sample size, randomization, or blinding that can affect the results 2. Moreover, the study population, including patient characteristics and co-morbidities, can also impact the results and generalizability of the findings to other populations 3. In conclusion, while the study provides valuable insights into the influence of control groups in RCTs in rheumatoid arthritis, the limitations discussed above should be considered when interpreting the results and drawing conclusions.
REFERNECES
1 Kerschbaumer A, Stimakovits NM, Smolen JS, et al. Influence of active versus placebo control on treatment responses in randomised controlled trials in rheumatoid arthritis. Annals of the Rheumatic Diseases 2023
2 Sella F, Raz G, Cohen Kadosh R. When randomisation is not good enough: Matching groups in intervention studies. Psychonomic Bulletin & Review 2021;28:2085-93.
3 Chidambaram AG, Josephson M. Clinical research study designs: The essentials. Pediatric investigation 2019;3:245-52.
We have read with interest the results of the study conducted by Solomon and colleagues, showing that addition of tumor necrosis factor inhibitor (TNFi) versus sulfasalazine and hydroxychloroquine on methotrexate regimen among individuals with rheumatoid arthritis (RA) did not result in a significantly greater reduction in arterial inflammation, measured as an arterial target-to-background ratio (TBR) in the carotid arteries and aorta.1 A closer look at participants' baseline characteristics revealed that a significant proportion of recruited patients (45.2%) had concomitant arterial hypertension.1 Renin-angiotensin system (RAS) blockers have been shown to exert at some extent anti-inflammatory effects,2 partially explaining the relatively low TBR among patients with established atherosclerotic cardiovascular disease, treated with angiotensin converting enzyme inhibitors.3 Similarly, in subjects with a recent acute coronary syndrome, treatment with an angiotensin-II receptor blocker resulted in a significant reduction in TBR over a 6 month period of treatment.4 Therefore, we strongly believe that a subgroup analysis of the primary endpoint according to baseline use of RAS blockers would provide useful additional insights into the interesting research hypothesis formulated by Solomon and colleagues.
1. Solomon DH, Giles JT, Liao KP, et al. Reducing cardiovascular risk with immunomodulators: a randomised active comparator trial among patients with rheumatoid arth...
We have read with interest the results of the study conducted by Solomon and colleagues, showing that addition of tumor necrosis factor inhibitor (TNFi) versus sulfasalazine and hydroxychloroquine on methotrexate regimen among individuals with rheumatoid arthritis (RA) did not result in a significantly greater reduction in arterial inflammation, measured as an arterial target-to-background ratio (TBR) in the carotid arteries and aorta.1 A closer look at participants' baseline characteristics revealed that a significant proportion of recruited patients (45.2%) had concomitant arterial hypertension.1 Renin-angiotensin system (RAS) blockers have been shown to exert at some extent anti-inflammatory effects,2 partially explaining the relatively low TBR among patients with established atherosclerotic cardiovascular disease, treated with angiotensin converting enzyme inhibitors.3 Similarly, in subjects with a recent acute coronary syndrome, treatment with an angiotensin-II receptor blocker resulted in a significant reduction in TBR over a 6 month period of treatment.4 Therefore, we strongly believe that a subgroup analysis of the primary endpoint according to baseline use of RAS blockers would provide useful additional insights into the interesting research hypothesis formulated by Solomon and colleagues.
1. Solomon DH, Giles JT, Liao KP, et al. Reducing cardiovascular risk with immunomodulators: a randomised active comparator trial among patients with rheumatoid arthritis [published online ahead of print, 2022 Nov 30]. Ann Rheum Dis. 2022;ard-2022-223302. doi:10.1136/ard-2022-223302
2. Pang XF, Liu RM, Xia YF. Effects of inhibitors of the renin-angiotensin system on reducing blood pressure and expression of inflammatory factors in CHD patients: A network meta-analysis. J Cell Physiol. 2019;234(5):5988-5997. doi:10.1002/jcp.27147
3. Liu Y, Ghosh N, Dwivedi G, et al. Identification of inflamed aortic plaque in conventional fluorodeoxyglucose-positron emission tomography myocardial viability studies. Can J Cardiol. 2013;29(9):1069-1075. doi:10.1016/j.cjca.2013.02.005
4. Oh M, Lee CW, Ahn JM, et al. Comparison of fimasartan and amlodipine therapy on carotid atherosclerotic plaque inflammation. Clin Cardiol. 2019;42(2):241-246. doi:10.1002/clc.23133
We read with interest the publication by Tang and coauthors on occupational risks for rheumatoid arthritis (RA) (1), which builds on previous valuable observations from the Swedish EIRA cohort.
Their findings can be further strengthened when contextualized with other studies of occupation and RA from the U.S. and the U.K., in which higher prevalences of inhalational risk exposure are found. Results from U.S. population-based surveys, with a combined sample of nearly 5000 ever-employed males, showed that work in silica-exposing jobs exclusive of mining was associated with greater than three-fold odds of RA in both of the two regions studied (Appalachia and the Southwest Mountain States).(2,3) Because such non-mining silica exposure was common (28% and 18%, respectively), the population attributable fraction (PAF) within these groups was considerable: 27% (95% CI 23%, 30%) and 17% (95% CI 13%, 20%), respectively.
Results from a U.K. study show additional effects of inhalational exposures (with silica being the most common) on RA seropositivity, antibody titer, and age of onset. (4) A study of 726 men with RA from Cornwall demonstrated that inhalational exposures were strongly associated with having seropositive RA, with higher RF antibody titers and earlier age of onset compared to unexposed patients. In that study, 75% of subjects had inhalational exposures lasting more than one year, and the estimated PAF for being strongly RF positive RA was 24.2%.
We read with interest the publication by Tang and coauthors on occupational risks for rheumatoid arthritis (RA) (1), which builds on previous valuable observations from the Swedish EIRA cohort.
Their findings can be further strengthened when contextualized with other studies of occupation and RA from the U.S. and the U.K., in which higher prevalences of inhalational risk exposure are found. Results from U.S. population-based surveys, with a combined sample of nearly 5000 ever-employed males, showed that work in silica-exposing jobs exclusive of mining was associated with greater than three-fold odds of RA in both of the two regions studied (Appalachia and the Southwest Mountain States).(2,3) Because such non-mining silica exposure was common (28% and 18%, respectively), the population attributable fraction (PAF) within these groups was considerable: 27% (95% CI 23%, 30%) and 17% (95% CI 13%, 20%), respectively.
Results from a U.K. study show additional effects of inhalational exposures (with silica being the most common) on RA seropositivity, antibody titer, and age of onset. (4) A study of 726 men with RA from Cornwall demonstrated that inhalational exposures were strongly associated with having seropositive RA, with higher RF antibody titers and earlier age of onset compared to unexposed patients. In that study, 75% of subjects had inhalational exposures lasting more than one year, and the estimated PAF for being strongly RF positive RA was 24.2%.
Among exposures tested by Tang et. al., silica manifested one of the highest point estimates for increased odds of disease. The accompanying editorial emphasized that the increased occupational risk was limited to ACPA-positive disease. (5) Silica, however, stands out as an exception, where risk for both seropositive and seronegative disease was increased: ACPA-positive OR=2.18 (95% CI 1.63, 2.94); ACPA-negative OR=1.72 (95% CI 1.22, 2.44) [Supplemental Table 1]. Although a PAF estimate was not presented, other supplemental data allow its estimation. Based on silica exposures among 243/4033 (6%) and an odds ratio for RA of 1.97 (1.53, 2.53), the estimated PAF is 3% (95% CI 2%, 4%).
The lower PAF in the study by Tang et. al. should not be interpreted to mean that the risk associated with silica exposure is not relevant, but rather that the cohort studied (72% female and including persons with no past or present employment) has many participants with few or no exposures compared to ever-employed males, including those from the studies described above. (6) Crucially, inhalational exposure studies should be supported in countries with high exposure rates and poor working conditions, otherwise important risks will be missed or minimized. The finding of no increased RA risk for textile dust exposure in Sweden in this analysis, but an increased risk in Malaysia using the EIRA protocol, exemplifies this need (1,7). Marked differences in working practices and exposure prevalence in populations studied need to be contextualized. Without proper inhalational exposure protection for workers, globalized raw materials extraction and manufacturing will consequently globalize the risk for RA.
REFERENCES
(1) Tang B, Liu Q, Ilar A, et al. Occupational inhalable agents constitute major risk factors for rheumatoid arthritis, particularly in the context of genetic predisposition and smoking. Annals of the Rheumatic Diseases Published Online First: 06 December 2022. doi: 10.1136/ard-2022-223134
(2) Schmajuk G, Trupin L, Yelin EH, Blanc PD. Dusty trades and associated rheumatoid arthritis in a population-based study in the coal mining counties of Appalachia. Occup Environ Med. 2022 May;79(5):308-314. doi: 10.1136/oemed-2021-107899. Epub 2022 Jan 5. PMID: 34987082.
(3) Blanc PD, Trupin L, Yelin EH, Schmajuk G. Assessment of Risk of Rheumatoid Arthritis Among Underground Hard Rock and Other Mining Industry Workers in Colorado, New Mexico, and Utah. JAMA Netw Open. 2022 Oct 3;5(10):e2236738. doi: 10.1001/jamanetworkopen.2022.36738. PMID: 36251293; PMCID: PMC9577677.
(4) Murphy D, Bellis K, Hutchinson D. Vapour, gas, dust and fume occupational exposures in male patients with rheumatoid arthritis resident in Cornwall (UK) and their association with rheumatoid factor and anti-cyclic protein antibodies: a retrospective clinical study. BMJ Open 2018;8:e021754. doi:10.1136/bmjopen-2018-021754
(5) Kronzer VL, Sparks JA. Occupational inhalants, genetics and the respiratory mucosal paradigm for ACPA-positive rheumatoid arthritis. Annals of the Rheumatic Diseases Published Online First: 06 December 2022. doi: 10.1136/ard-2022-223286
(6) Murphy D, Hutchinson D. Is Male Rheumatoid Arthritis an Occupational Disease? A Review. Open Rheumatol J. 2017 Jul 27;11:88-105. doi: 10.2174/1874312901711010088. PMID: 28932330; PMCID: PMC5585464.
(7) Too CL, Muhamad NA, Ilar A, et al. Occupational exposure to textile dust increases the risk of rheumatoid arthritis: results from a Malaysian population-based case-control study. Ann Rheum Dis 2016;75:997–1002.
I read the paper by Curtis et al. with great interest [1]. A new analysis using this paper’s data has yielded important results that should be presented here.
The authors state that (1) in patients with rheumatoid arthritis (RA) aged ≥50 years with ≥1 additional cardiovascular risk factor, the risk of adjudicated malignancies excluding non-melanoma skin cancer (NMSC), lung cancer and NMSC was higher with tofacitinib versus tumor necrosis factor inhibitor (TNFi); (2) lung cancer was the most frequently reported malignancy in tofacitinib-treated patients; and (3) history of atherosclerotic cardiovascular disease (ASCVD) or increasing risk scores were associated with higher malignancy incidence rates (IRs) across treatment.
Atherosclerosis can be caused by various factors, such as smoking, high cholesterol, hypertension, hyperglycemia, diabetes, and genetic factors [2]. However, atherosclerosis can also develop due to infection [3]. These infections include Helicobacter pylori (H. pylori), pneumonia, periodontal disease, and viruses such as cytomegalovirus, human immunodeficiency virus (HIV), herpes simplex virus, Epstein-Barr virus (EBV), human papilloma viruses (HPV), hepatitis B virus (HBV), hepatitis C virus (HCV), and recently, severe acute respiratory syndrome coronavirus-2 [3, 4].
Some infections that cause atherosclerosis are thought to contribute to cancer in humans. The fractions of different types of cancer, and of all cancers worldwide and in dif...
I read the paper by Curtis et al. with great interest [1]. A new analysis using this paper’s data has yielded important results that should be presented here.
The authors state that (1) in patients with rheumatoid arthritis (RA) aged ≥50 years with ≥1 additional cardiovascular risk factor, the risk of adjudicated malignancies excluding non-melanoma skin cancer (NMSC), lung cancer and NMSC was higher with tofacitinib versus tumor necrosis factor inhibitor (TNFi); (2) lung cancer was the most frequently reported malignancy in tofacitinib-treated patients; and (3) history of atherosclerotic cardiovascular disease (ASCVD) or increasing risk scores were associated with higher malignancy incidence rates (IRs) across treatment.
Atherosclerosis can be caused by various factors, such as smoking, high cholesterol, hypertension, hyperglycemia, diabetes, and genetic factors [2]. However, atherosclerosis can also develop due to infection [3]. These infections include Helicobacter pylori (H. pylori), pneumonia, periodontal disease, and viruses such as cytomegalovirus, human immunodeficiency virus (HIV), herpes simplex virus, Epstein-Barr virus (EBV), human papilloma viruses (HPV), hepatitis B virus (HBV), hepatitis C virus (HCV), and recently, severe acute respiratory syndrome coronavirus-2 [3, 4].
Some infections that cause atherosclerosis are thought to contribute to cancer in humans. The fractions of different types of cancer, and of all cancers worldwide and in different regions, have been estimated using several methods, but primarily by reviewing evidence for the strength of associations and the prevalence of infection in different areas. The estimated total of infection-attributable cancer (IAC) in 2002 was 1.9 million cases, or 17.8% of the global cancer burden. The principal agents were H. pylori (5.5% of all cancers), HPV (5.2%), HBV and HCV (4.9%), EBV (1%), and HIV and human herpes virus 8 (0.9%) [5]. Helicobacter pylori–attributable gastric cancer, HBV/HCV-attributable hepatocellular cancer, HPV-attributable cervical, penile, anal, vulva, vaginal, oral cavity, and pharyngeal cancer, and EBV-attributable pharyngeal cancer and malignant lymphoma account for the majority of IACs [6]. Thus, many infections associated with ASCVD contribute to cancer.
I extracted IACs from Table 2 and Supplemental Table 3 of their paper (Table 1) and compared the ratio of IACs among all cancers (n = 186) between tofacitinib and TNFi. Vaginal and anal cancers were rare, and cervical cancer was observed only with tofacitinib. Fisher's exact test analysis using JMP software (version 14, SAS Institute Inc., Cary, NC, USA) indicated that tofacitinib (n = 27) was higher than TNFi (n = 3) (14.5% vs. 5.2%, p=0.045). Comparing tofacitinib 5 and 10 mg twice per day with TNFi, the IR of IAC tended to be higher with tofacitinib at each dose (15.1% vs 5.2%, p=0.0502) and (14.0% vs 5.2%, p=0.0715) by Fisher's exact test.
Of course, the extracted cancers were not confirmed to be related to infectious diseases. In addition, due to insufficient data, the hazard ratios of tofacitinib and TNFi could not be determined for the incidence of IACs. Thanks to these results, the relationship between tofacitinib and IAC will become clearer.
In the treatment of all RA patients, it is necessary to consider the potential for IACs, treatments for any infections, the effectiveness of treatment, and continued surveillance and monitoring of smoking history with or without tofacitinib. Until a causal relationship between tofacitinib and IACs is clarified, screening and surveillance for IACs are essential in the treatment of all RA patients aged ≥50 years with ≥1 additional cardiovascular risk factor.
Finally, I would like to give credit to the authors for their efforts in compiling data from many patients from multiple centers and sharing it in their paper.
REFERENCES
1 Curtis JR, Yamamoka K, Chen YH, et al. Malignancy risk with tofacitinib versus TNF inhibitors in rheumatoid arthritis: results from the open-label, randomised controlled ORAL Surveillance trial. Ann Rheum Dis. 2022 Dec 5:annrheumdis-2022-222543. doi: 10.1136/ard-2022-222543.
2 Goff DC Jr, Lloyd-Jones DM, Bennett G, et al. 2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;63:2935–59.
3 Szwed P, Gąsecka A, Zawadka M, et al. Infections as novel risk factors of atherosclerotic cardiovascular diseases: pathophysiological links and therapeutic implications. J Clin Med 2021;10:2539.
4 Dhakal BP, Sweitzer NK, Indik JH, et al. SARS-CoV-2 infection and cardiovascular disease: COVID-19 heart. Heart Lung Circ 2020;29:973–87.
5 Parkin DM. The global health burden of infection-associated cancers in the year 2002. Int J Cancer 2006;118:3030–44.
6 Inoue M, Sawada N, Matsuda T, et al. Attributable causes of cancer in Japan in 2005--systematic assessment to estimate current burden of cancer attributable to known preventable risk factors in Japan. Ann Oncol 2012;23:1362–69.
We read the article “2022 American College of Rheumatology/EULAR Classification Criteria for Giant Cell Arteritis" by Ponte et al. with great interest (1). There was a long-standing need for revision of classification criteria for giant cell arteritis (GCA) due to the insufficient sensitivity of the ACR 1990 criteria in recent studies (2). This could be explained by enrolment of patients with different clinical phenotypes to the cohorts depending on the improvement in the imaging methods in addition to clinician’s assessment over the years. Especially, implementation of cross-sectional imaging including FDG – PET improved the diagnosis of GCA and facilitated the recognition of disease patterns without cranial manifestations. Patients with isolated extra-cranial involvement were reported to have a diagnostic delay up to 5 months compared to classical GCA patients and late recognition of large vessel involvement could cause permanent organ damage (3). Thoracic aorta dilatation / aneurysm has been reported in 15% and large artery stenosis in 30% in patients with proven aortic inflammation (4). The ACR 1990 Criteria were not sufficient to identify this subgroup and patients who participate in clinical trials evaluating the efficacy of further treatment options. The new criteria were expected to fill this gap.
We implemented new criteria to our single reference center cohort with long-term follow-up consisted of 89 patients with a median follow-up time of 4 years T...
We read the article “2022 American College of Rheumatology/EULAR Classification Criteria for Giant Cell Arteritis" by Ponte et al. with great interest (1). There was a long-standing need for revision of classification criteria for giant cell arteritis (GCA) due to the insufficient sensitivity of the ACR 1990 criteria in recent studies (2). This could be explained by enrolment of patients with different clinical phenotypes to the cohorts depending on the improvement in the imaging methods in addition to clinician’s assessment over the years. Especially, implementation of cross-sectional imaging including FDG – PET improved the diagnosis of GCA and facilitated the recognition of disease patterns without cranial manifestations. Patients with isolated extra-cranial involvement were reported to have a diagnostic delay up to 5 months compared to classical GCA patients and late recognition of large vessel involvement could cause permanent organ damage (3). Thoracic aorta dilatation / aneurysm has been reported in 15% and large artery stenosis in 30% in patients with proven aortic inflammation (4). The ACR 1990 Criteria were not sufficient to identify this subgroup and patients who participate in clinical trials evaluating the efficacy of further treatment options. The new criteria were expected to fill this gap.
We implemented new criteria to our single reference center cohort with long-term follow-up consisted of 89 patients with a median follow-up time of 4 years The sensitivity of 75.3% ACR 1990 Criteria was 75.3% and the sensitivity of ACR 2022 Criteria was found to be 82% (5). Of the patients without apparent cranial manifestations in our cohort (n=19) only 20% and 35% met the 1990 and 2022 criteria, respectively. Since all our patients met at least one laboratory, biopsy or imaging criteria, this rate could be lower in cohorts which includes patients with normal laboratory values and/or negative imaging.
On the other hand, the presence of only subjective clinical criteria such as morning stiffness, headache and scalp tenderness, negative predictive value of new criteria may be lower than expected. In our cohort, 40 (45%) patients had ≥3 clinical criteria (only 8 of them had sudden vision loss) and met the classification criteria without the need for positive laboratory, biopsy, or imaging. Although specificity of the criteria with and without biopsy is around 95% in the study performed by experts of the disease in the present study, we suggest that mandatory requirement of a single objective criterion (e.g., high CRP, histopathology, imaging) in addition to clinical criteria except vision loss may improve specificity especially in less experienced centers.
1. Ponte C, Grayson PC, Robson JC, et al. 2022 American College of Rheumatology/EULAR classification criteria for giant cell arteritis. Annals of the Rheumatic Diseases. 2022;81,12:1647.
2. Seeliger B, Sznajd J, Robson JC, et al. Are the 1990 American College of Rheumatology vasculitis classification criteria still valid? Rheumatology (Oxford). 2017;56,7:1154-1161.
3. Tomelleri A, Campochiaro C, Sartorelli S, et al. Presenting features and outcomes of cranial-limited and large-vessel giant cell arteritis: a retrospective cohort study. Scand J Rheumatol. 2022;51,1:59-66.
4. de Boysson H, Liozon E, Espitia O, et al. Different patterns and specific outcomes of large-vessel involvements in giant cell arteritis. J Autoimmun. 2019;103:102283.
5. Ince B, Artan S, Yalcinkaya Y, et al. Long-term follow-up of 89 patients with giant cell arteritis: a retrospective observational study on disease characteristics, flares and organ damage. Rheumatol Int. 2021;41,2:439-448.
Title: Correspondence on “Recapture and retreatment rates with ixekizumab after withdrawal of therapy in patients with axial spondyloarthritis: results at week 104 from a randomised placebo-controlled withdrawal study”
To the Editor
I recently have read with great interest the research paper written by Dr. Landewé et al. entitled “Recapture and retreatment rates with ixekizumab after withdrawal of therapy in patients with axial spondyloarthritis: results at week 104 from a randomised placebo-controlled withdrawal study” published recently in Annals of the Rheumatic Diseases (1). In this study, patients with axial spondyloarthritis in remission who were on ixekizumab were randomised to either continue the treatment or withdraw to placebo. The study compared the rate of occurrence of flare between these two arms and assessed the efficacy of readministration of ixekizumab. This study provided strong evidence regarding treatment discontinuation with ixekizumab in patients with axial spondyloarthritis with a well-developed design and proper sample size; however, there are some points that should be more discussed in the article.
In the limitation, the authors have reported that they did not use Ankylosing Spondylitis Disease Activity Score (ASDAS) to define whether a patient had a flare or not; however, in the methods section of this article and their previously published article (2) and also in the protocol of COAST-Y (NCT03129100), this composite index, ASDA...
Title: Correspondence on “Recapture and retreatment rates with ixekizumab after withdrawal of therapy in patients with axial spondyloarthritis: results at week 104 from a randomised placebo-controlled withdrawal study”
To the Editor
I recently have read with great interest the research paper written by Dr. Landewé et al. entitled “Recapture and retreatment rates with ixekizumab after withdrawal of therapy in patients with axial spondyloarthritis: results at week 104 from a randomised placebo-controlled withdrawal study” published recently in Annals of the Rheumatic Diseases (1). In this study, patients with axial spondyloarthritis in remission who were on ixekizumab were randomised to either continue the treatment or withdraw to placebo. The study compared the rate of occurrence of flare between these two arms and assessed the efficacy of readministration of ixekizumab. This study provided strong evidence regarding treatment discontinuation with ixekizumab in patients with axial spondyloarthritis with a well-developed design and proper sample size; however, there are some points that should be more discussed in the article.
In the limitation, the authors have reported that they did not use Ankylosing Spondylitis Disease Activity Score (ASDAS) to define whether a patient had a flare or not; however, in the methods section of this article and their previously published article (2) and also in the protocol of COAST-Y (NCT03129100), this composite index, ASDAS, was mentioned to be considered and utilized for definition of flare. By the way, if this index was not used, the authors should discuss about the tool they used completely in the methods. Second, the authors mentioned that some of the patients had ASDAS of 2.1 at two consecutive visits but they did not have a flare. The article lacks information regarding the number of these patients and their clinical and laboratory features. Addition of this information to the work could increase its credibility and would remove any potential bias of selective reporting. Third, the method of active treatment discontinuation used in this study was not valid and ixekizumab was not tapered. Dr. Navarro-Compán and colleagues conducted a systematic review to assess the disease status of patients with axial spondyloarthritis following discontinuation or tapering strategies of tumor necrosis factor inhibitors (3). They suggested that the rate of flare would be higher in those with a discontinuation strategy. Therefore, for such studies like this study that the experience of a flare is the primary outcome, the method of withdrawal of the medication could be consequential, especially when this method was only applied to one arm of the study and could be considered as a source for confounding. The authors should at least justify the reason why they did not follow the recommendations of withdrawal.
Acknowledgement: None.
Conflict of Interest statement: Authors declare no conflict of interests.
Funding: None.
References
1. Landewé RBM, Poddubnyy D, Rahman P, Van den Bosch FE, Bolce R, Liu Leage S, et al. Recapture and retreatment rates with ixekizumab after withdrawal of therapy in patients with axial spondyloarthritis: results at week 104 from a randomised placebo-controlled withdrawal study. Annals of the Rheumatic Diseases. 2022:annrheumdis-2022-222731.
2. Landewé RBM, Gensler LS, Poddubnyy D, Rahman P, Hojnik M, Li X, et al. Continuing versus withdrawing ixekizumab treatment in patients with axial spondyloarthritis who achieved remission: efficacy and safety results from a placebo-controlled, randomised withdrawal study (COAST-Y). Annals of the Rheumatic Diseases. 2021;80(8):1022.
3. Navarro-Compán V, Plasencia-Rodríguez C, de Miguel E, Balsa A, Martín-Mola E, Seoane-Mato D, et al. Anti-TNF discontinuation and tapering strategies in patients with axial spondyloarthritis: a systematic literature review. Rheumatology. 2016;55(7):1188-94.
The recent Spondyloarthritis international Society-European Alliance of Associations for Rheumatology (ASAS-EULAR) recommendations provided a comprehensive update on the management of axial spondyloarthritis (axSpA). (1) The 15 recommendations were agreed upon with two relevant updates and two newly formulated. Recommendation 9 was updated based on systematic literature review from 2016 up to January 1st, 2022, to include targeted synthetic DMARDs (tsDMARDs, ie, Janus kinase inhibitors (JAKi)) for patients with persistently high disease activity despite conventional treatments, where current practice is to start therapy with biological DMARDs (bDMARDs), tumour necrosis factor inhibitors (TNFi) or interleukin-17 inhibitors (IL-17i). (1, 2) The new therapeutic option is appreciated by physicians and patients as previously bDMARDs were the only option in patients with persistently high disease activity despite conventional treatments and the current practice was to start with TNFi therapy. (3) At the time of formulation of the recommendation data from only four phase 2/3 randomized controlled trials (RCT) in radiographic axSpA were available (N = 779). (2) Since the recommendation was published upadacitinib was approved by European Medicines Agency (EMA) for non-radiographic axSpA based on the data from a phase 3 SELECT-AXIS 2 trial. (1, 4) Additionally due to the safety signals seen with tofacitinib in rheumatoid arthritis (RA), until additional data becomes available a note...
The recent Spondyloarthritis international Society-European Alliance of Associations for Rheumatology (ASAS-EULAR) recommendations provided a comprehensive update on the management of axial spondyloarthritis (axSpA). (1) The 15 recommendations were agreed upon with two relevant updates and two newly formulated. Recommendation 9 was updated based on systematic literature review from 2016 up to January 1st, 2022, to include targeted synthetic DMARDs (tsDMARDs, ie, Janus kinase inhibitors (JAKi)) for patients with persistently high disease activity despite conventional treatments, where current practice is to start therapy with biological DMARDs (bDMARDs), tumour necrosis factor inhibitors (TNFi) or interleukin-17 inhibitors (IL-17i). (1, 2) The new therapeutic option is appreciated by physicians and patients as previously bDMARDs were the only option in patients with persistently high disease activity despite conventional treatments and the current practice was to start with TNFi therapy. (3) At the time of formulation of the recommendation data from only four phase 2/3 randomized controlled trials (RCT) in radiographic axSpA were available (N = 779). (2) Since the recommendation was published upadacitinib was approved by European Medicines Agency (EMA) for non-radiographic axSpA based on the data from a phase 3 SELECT-AXIS 2 trial. (1, 4) Additionally due to the safety signals seen with tofacitinib in rheumatoid arthritis (RA), until additional data becomes available a note was added about consideration of risk factors for cardiovascular/thromboembolic events and malignancies when intending to prescribe a JAKi especially for patients age over 65 years. (5)
Additional data on JAKi has been made available to EMA. Based on the results from tofacitinib clinical trial and preliminary findings from an observational study (B023) involving baricitinib suggesting increased risk of major adverse cardiovascular events (MACE) and venous thromboembolism (VTE) in patients with RA compared with those treated with TNFi, EMA’s human medicines committee (CHMP) has endorsed the measures to minimize the risk of serious side effects with JAKi used to treat several chronic inflammatory disorders in November 2022. CHMP recommends JAKi should be used in the patients aged 65 years or above, those at increased risk of major cardiovascular problems (such as heart attack or stroke), those who smoke or have done so for a long time in the past and those at increased risk of cancer only if no suitable treatment alternatives are available. (6) It is important to note that advice was from an expert group of rheumatologists, dermatologists, gastroenterologists and patient representatives was included. However, the aforementioned safety signals have not been described in patients with axSpA to date.
The benefit of evidence based international recommendations is the potential to improve patient outcomes and health equity. Although most clinical practice guidelines become outdates after 3 years, recommendations for disease management in an area of high research interest and result availability are very likely going to be missing some important information at the time of publication. (7) Therefore, clinicians must consult numerous and/or differing guidelines/recommendations, hence choice of therapy becomes a work of art. As we await the final decision of the European Commission in January 2023 the question remains: should the use of JAKi in axSpA be restricted only for use if no alternative suitable treatment is available.
References:
1. Ramiro S, Nikiphorou E, Sepriano A, et al. ASAS-EULAR recommendations for the management of axial spondyloarthritis: 2022 update. Ann Rheum Dis 2023;82(1):19-34. doi:10.1136/ard-2022-223296
2. Ortolan A, Webers C, Sepriano A, et al. Efficacy and safety of non-pharmacological and non-biological interventions: a systematic literature review informing the 2022 update of the ASAS/EULAR recommendations for the management of axial spondyloarthritis Ann Rheum Dis 2023;82(1):142-152. doi:10.1136/ard-2022-223297
3. van der Heijde D, Ramiro S, Landewé R, et al. 2016 update of the ASAS-EULAR management recommendations for axial spondyloarthritis. Ann Rheum Dis 2017;76(6):978-991. doi:10.1136/annrheumdis-2016-210770
4. Deodhar A, Van den Bosch F, Poddubnyy D, et al. Upadacitinib for the treatment of active non-radiographic axial spondyloarthritis (SELECT-AXIS 2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2022;400(10349):369-379. doi:10.1016/S0140-6736(22)01212-0
5. Ytterberg SR, Bhatt DL, Mikuls TR, et al. Cardiovascular and cancer risk with tofacitinib in rheumatoid arthritis. N Engl J Med 2022;386(4):316–26. doi:10.1136/ard-2022-223297
6. EMA confirms measures to minimise risk of serious side effects with Janus kinase inhibitors for chronic inflammatory disorders [online]. https://www.ema.europa.eu/en/medicines/human/referrals/janus-kinase-inhi... (accessed 28 December 2022)
7. Guerra-Farfan E, Garcia-Sanchez Y, Jornet-Gibert M, Nuñez JH, Balaguer-Castro M, Madden K. Clinical practice guidelines: The good, the bad, and the ugly. Injury. 2022;S0020-1383(22)00077-8. doi:10.1016/j.injury.2022.01.047
To the Editor
I recently have read with great interest the article written by Dr. Feist et al. entitled “Olokizumab, a monoclonal antibody against interleukin-6, in combination with methotrexate in patients with rheumatoid arthritis inadequately controlled by tumour necrosis factor inhibitor therapy: efficacy and safety results of a randomised controlled phase III study” published in Annals of the Rheumatic Diseases (1). In this randomized double-blinded clinical study, the effect of a monoclonal antibody against a proinflammatory cytokine, interleukin-6, was compared to placebo. The study showed beneficial effects of Olokizumab in patients with rheumatoid arthritis on their clinical manifestations and their self-reported outcomes. This study provides strong evidence regarding the use of this monoclonal antibody for treatment of adult patients with moderate to severe active rheumatoid arthritis not responding to tumor necrosis factor inhibitors; however, there are several issues that worth mentioning.
In this study, adult patients with active disease status who received methotrexate for at least 12 weeks prior to the initial screening of the study were enrolled. Based on the inclusion criteria of the study, the eligible participants were those individuals with moderate to severe rheumatoid arthritis who had not an adequate response to methotrexate alone and therefore, they were in need for disease-modifying antirheumatic drugs and they should had received and f...
To the Editor
I recently have read with great interest the article written by Dr. Feist et al. entitled “Olokizumab, a monoclonal antibody against interleukin-6, in combination with methotrexate in patients with rheumatoid arthritis inadequately controlled by tumour necrosis factor inhibitor therapy: efficacy and safety results of a randomised controlled phase III study” published in Annals of the Rheumatic Diseases (1). In this randomized double-blinded clinical study, the effect of a monoclonal antibody against a proinflammatory cytokine, interleukin-6, was compared to placebo. The study showed beneficial effects of Olokizumab in patients with rheumatoid arthritis on their clinical manifestations and their self-reported outcomes. This study provides strong evidence regarding the use of this monoclonal antibody for treatment of adult patients with moderate to severe active rheumatoid arthritis not responding to tumor necrosis factor inhibitors; however, there are several issues that worth mentioning.
In this study, adult patients with active disease status who received methotrexate for at least 12 weeks prior to the initial screening of the study were enrolled. Based on the inclusion criteria of the study, the eligible participants were those individuals with moderate to severe rheumatoid arthritis who had not an adequate response to methotrexate alone and therefore, they were in need for disease-modifying antirheumatic drugs and they should had received and failed a course of minimum-12-week of treatment with at least one anti-tumor necrosis factor agent. Therefore, treatment with methotrexate and placebo would not suffice for the patients in the placebo group and it could raise ethical concerns. By the way, even if the authors were obligated to include an arm treated with only methotrexate as the placebo arm, it would have been better if there was no prespecified exact time for rescue medication with sulfasalazine, hydroxychloroquine, or both. Besides, consideration a non-inferior arm even with other interleukin-6 inhibitors in the study could help for a better comparison of the efficacy and safety of Olokizumab in patients with rheumatoid arthritis. Although, the endpoints considered in this study for evaluation of the response to treatments are appropriate, lack of an objective tool such as imaging of joints could be regarded as a limitation of the work. Besides, in the protocol of the work with trial registration number of NCT02760433, 165 study locations were mentioned that have been selected for enrollment of the participants; in the published report of the study, however, it was mentioned that in 123 centers, the study was conducted. This discrepancy in number of the locations was not discussed neither in the main text of the article nor in the supplementary material.
Authors’ contributions: Both authors contributed in all processes of the preparation of this paper.
Acknowledgement: None.
Conflict of Interest statement: Authors declare no conflict of interests.
Funding: None.
References
1. Feist E, Fatenejad S, Grishin S, Korneva E, Luggen ME, Nasonov E, et al. Olokizumab, a monoclonal antibody against interleukin-6, in combination with methotrexate in patients with rheumatoid arthritis inadequately controlled by tumour necrosis factor inhibitor therapy: efficacy and safety results of a randomised controlled phase III study. Annals of the Rheumatic Diseases. 2022;81(12):1661.
Although, several novel autoantibodies in idiopathic inflammatory myopathies (IIM) have been described, a serological gap persists which poses a diagnostic challenge. In this context, we read with interest the article by Vulsteke et al. [1]. The untargeted protein immunoprecipitation combined with gel-free liquid chromatography-tandem mass spectrometry (IP-MS) identified a novel autoantibody to cytoplasmic cysteinyl-tRNA-synthetase (CARS1, anti-Ly). In addition, rare ASA, such as anti-OJ, anti-Zo and anti-KS, and common ASA could also be identified by IP-MS. Consequently, Vulsteke et al. [1] concluded that IP-MS is a promising method for discovery detection of autoantibodies, especially autoantibodies that target complex autoantigens.
Show MoreWe agree that IP-MS represents a powerful discovery tool for novel autoantibodies. However, the gained knowledge is most valuable for more conventional in-vitro diagnostic platforms. Although the IP-MS method holds promise, due to the lack of standardization it is unlikely that it will be applicable for IVD solutions soon. Established alternative methods include ELISA [2], line immunoassay (LIA) and a recently developed particle-based multi-analyte technology (PMAT) that has been evaluated for the detection of MSA [3-5].
Due to the antigen complexity, anti-OJ are among the most difficult MSA to detect [6, 7]. According to an international survey, despite concern about its accuracy, LIA is commonly used for the detection of MSA inc...
We are submitting a correspondence in regards to the paper "Individual patient data meta-analysis on continued use of glucocorticoids after their initiation as bridging therapy in patients with rheumatoid arthritis" by Lotte van Ouwerkerk et al.1 published in Ann Rheum Dis. 2022 Dec 16. The study is an important contribution to the field as it aimed to investigate the effectiveness of glucocorticoids (GC) as a bridging therapy for rheumatoid arthritis (RA) patients. The study combined data from 7 clinical trial arms that included GC bridging schedule in the initial treatment of RA, to investigate whether patients with RA can discontinue GC after GC 'bridging' and to identify factors that may affect this. The study has several strengths, such as the use of individual patient data meta-analysis which allows for a more comprehensive and detailed analysis. Additionally, the study's aim to investigate the effectiveness of GC as a bridging therapy is admirable, as it addresses an important question in the field of RA treatment2 3. However, the study also has some limitations that must be taken into account when interpreting the results. Firstly, the sample size of 1653 patients may not be representative of the general population of RA patients. This could limit the generalizability of the study's findings and may not fully capture the diversity of RA patients. Additionally, the study's short-term follow-up period of 18 months may not be enough...
Show MoreI am writing a correspondence on the article "Influence of active versus placebo control on treatment responses in randomised controlled trials in rheumatoid arthritis" by Kerschbaumer et al 1. The authors' systematic approach to comparing the treatment effects of pharmaceutical compounds in rheumatoid arthritis clinical trials with placebo and active treatment controls is commendable. The results of the study, showing significantly higher responses in active comparator trials compared to placebo controlled trials, provide valuable insights into the influence of control groups in RCTs. However, I have a few critical points to raise regarding the study's methodology and conclusions. Firstly, the matching of active treatment arms to comparable regimens, populations, background therapy, and outcome reporting was based solely on the nature of the control group, which is not an ideal approach. This method of matching could have led to unequal comparison groups and biased results 2. In order to ensure that the comparison between active treatment and control groups is fair and accurate, a more comprehensive and systematic approach to matching should have been employed. Secondly, the conclusion that placebo controlled trials lead to smaller effect sizes of active compounds in RCTs compared with the same compound in head-to-head trials may be an overgeneralization. The authors did not consider other potential confounding factors that could explain the difference...
Show MoreWe have read with interest the results of the study conducted by Solomon and colleagues, showing that addition of tumor necrosis factor inhibitor (TNFi) versus sulfasalazine and hydroxychloroquine on methotrexate regimen among individuals with rheumatoid arthritis (RA) did not result in a significantly greater reduction in arterial inflammation, measured as an arterial target-to-background ratio (TBR) in the carotid arteries and aorta.1 A closer look at participants' baseline characteristics revealed that a significant proportion of recruited patients (45.2%) had concomitant arterial hypertension.1 Renin-angiotensin system (RAS) blockers have been shown to exert at some extent anti-inflammatory effects,2 partially explaining the relatively low TBR among patients with established atherosclerotic cardiovascular disease, treated with angiotensin converting enzyme inhibitors.3 Similarly, in subjects with a recent acute coronary syndrome, treatment with an angiotensin-II receptor blocker resulted in a significant reduction in TBR over a 6 month period of treatment.4 Therefore, we strongly believe that a subgroup analysis of the primary endpoint according to baseline use of RAS blockers would provide useful additional insights into the interesting research hypothesis formulated by Solomon and colleagues.
1. Solomon DH, Giles JT, Liao KP, et al. Reducing cardiovascular risk with immunomodulators: a randomised active comparator trial among patients with rheumatoid arth...
Show MoreWe read with interest the publication by Tang and coauthors on occupational risks for rheumatoid arthritis (RA) (1), which builds on previous valuable observations from the Swedish EIRA cohort.
Their findings can be further strengthened when contextualized with other studies of occupation and RA from the U.S. and the U.K., in which higher prevalences of inhalational risk exposure are found. Results from U.S. population-based surveys, with a combined sample of nearly 5000 ever-employed males, showed that work in silica-exposing jobs exclusive of mining was associated with greater than three-fold odds of RA in both of the two regions studied (Appalachia and the Southwest Mountain States).(2,3) Because such non-mining silica exposure was common (28% and 18%, respectively), the population attributable fraction (PAF) within these groups was considerable: 27% (95% CI 23%, 30%) and 17% (95% CI 13%, 20%), respectively.
Results from a U.K. study show additional effects of inhalational exposures (with silica being the most common) on RA seropositivity, antibody titer, and age of onset. (4) A study of 726 men with RA from Cornwall demonstrated that inhalational exposures were strongly associated with having seropositive RA, with higher RF antibody titers and earlier age of onset compared to unexposed patients. In that study, 75% of subjects had inhalational exposures lasting more than one year, and the estimated PAF for being strongly RF positive RA was 24.2%.
...Show MoreI read the paper by Curtis et al. with great interest [1]. A new analysis using this paper’s data has yielded important results that should be presented here.
Show MoreThe authors state that (1) in patients with rheumatoid arthritis (RA) aged ≥50 years with ≥1 additional cardiovascular risk factor, the risk of adjudicated malignancies excluding non-melanoma skin cancer (NMSC), lung cancer and NMSC was higher with tofacitinib versus tumor necrosis factor inhibitor (TNFi); (2) lung cancer was the most frequently reported malignancy in tofacitinib-treated patients; and (3) history of atherosclerotic cardiovascular disease (ASCVD) or increasing risk scores were associated with higher malignancy incidence rates (IRs) across treatment.
Atherosclerosis can be caused by various factors, such as smoking, high cholesterol, hypertension, hyperglycemia, diabetes, and genetic factors [2]. However, atherosclerosis can also develop due to infection [3]. These infections include Helicobacter pylori (H. pylori), pneumonia, periodontal disease, and viruses such as cytomegalovirus, human immunodeficiency virus (HIV), herpes simplex virus, Epstein-Barr virus (EBV), human papilloma viruses (HPV), hepatitis B virus (HBV), hepatitis C virus (HCV), and recently, severe acute respiratory syndrome coronavirus-2 [3, 4].
Some infections that cause atherosclerosis are thought to contribute to cancer in humans. The fractions of different types of cancer, and of all cancers worldwide and in dif...
We read the article “2022 American College of Rheumatology/EULAR Classification Criteria for Giant Cell Arteritis" by Ponte et al. with great interest (1). There was a long-standing need for revision of classification criteria for giant cell arteritis (GCA) due to the insufficient sensitivity of the ACR 1990 criteria in recent studies (2). This could be explained by enrolment of patients with different clinical phenotypes to the cohorts depending on the improvement in the imaging methods in addition to clinician’s assessment over the years. Especially, implementation of cross-sectional imaging including FDG – PET improved the diagnosis of GCA and facilitated the recognition of disease patterns without cranial manifestations. Patients with isolated extra-cranial involvement were reported to have a diagnostic delay up to 5 months compared to classical GCA patients and late recognition of large vessel involvement could cause permanent organ damage (3). Thoracic aorta dilatation / aneurysm has been reported in 15% and large artery stenosis in 30% in patients with proven aortic inflammation (4). The ACR 1990 Criteria were not sufficient to identify this subgroup and patients who participate in clinical trials evaluating the efficacy of further treatment options. The new criteria were expected to fill this gap.
We implemented new criteria to our single reference center cohort with long-term follow-up consisted of 89 patients with a median follow-up time of 4 years T...
Show MoreTitle: Correspondence on “Recapture and retreatment rates with ixekizumab after withdrawal of therapy in patients with axial spondyloarthritis: results at week 104 from a randomised placebo-controlled withdrawal study”
Show MoreTo the Editor
I recently have read with great interest the research paper written by Dr. Landewé et al. entitled “Recapture and retreatment rates with ixekizumab after withdrawal of therapy in patients with axial spondyloarthritis: results at week 104 from a randomised placebo-controlled withdrawal study” published recently in Annals of the Rheumatic Diseases (1). In this study, patients with axial spondyloarthritis in remission who were on ixekizumab were randomised to either continue the treatment or withdraw to placebo. The study compared the rate of occurrence of flare between these two arms and assessed the efficacy of readministration of ixekizumab. This study provided strong evidence regarding treatment discontinuation with ixekizumab in patients with axial spondyloarthritis with a well-developed design and proper sample size; however, there are some points that should be more discussed in the article.
In the limitation, the authors have reported that they did not use Ankylosing Spondylitis Disease Activity Score (ASDAS) to define whether a patient had a flare or not; however, in the methods section of this article and their previously published article (2) and also in the protocol of COAST-Y (NCT03129100), this composite index, ASDA...
The recent Spondyloarthritis international Society-European Alliance of Associations for Rheumatology (ASAS-EULAR) recommendations provided a comprehensive update on the management of axial spondyloarthritis (axSpA). (1) The 15 recommendations were agreed upon with two relevant updates and two newly formulated. Recommendation 9 was updated based on systematic literature review from 2016 up to January 1st, 2022, to include targeted synthetic DMARDs (tsDMARDs, ie, Janus kinase inhibitors (JAKi)) for patients with persistently high disease activity despite conventional treatments, where current practice is to start therapy with biological DMARDs (bDMARDs), tumour necrosis factor inhibitors (TNFi) or interleukin-17 inhibitors (IL-17i). (1, 2) The new therapeutic option is appreciated by physicians and patients as previously bDMARDs were the only option in patients with persistently high disease activity despite conventional treatments and the current practice was to start with TNFi therapy. (3) At the time of formulation of the recommendation data from only four phase 2/3 randomized controlled trials (RCT) in radiographic axSpA were available (N = 779). (2) Since the recommendation was published upadacitinib was approved by European Medicines Agency (EMA) for non-radiographic axSpA based on the data from a phase 3 SELECT-AXIS 2 trial. (1, 4) Additionally due to the safety signals seen with tofacitinib in rheumatoid arthritis (RA), until additional data becomes available a note...
Show MoreTo the Editor
Show MoreI recently have read with great interest the article written by Dr. Feist et al. entitled “Olokizumab, a monoclonal antibody against interleukin-6, in combination with methotrexate in patients with rheumatoid arthritis inadequately controlled by tumour necrosis factor inhibitor therapy: efficacy and safety results of a randomised controlled phase III study” published in Annals of the Rheumatic Diseases (1). In this randomized double-blinded clinical study, the effect of a monoclonal antibody against a proinflammatory cytokine, interleukin-6, was compared to placebo. The study showed beneficial effects of Olokizumab in patients with rheumatoid arthritis on their clinical manifestations and their self-reported outcomes. This study provides strong evidence regarding the use of this monoclonal antibody for treatment of adult patients with moderate to severe active rheumatoid arthritis not responding to tumor necrosis factor inhibitors; however, there are several issues that worth mentioning.
In this study, adult patients with active disease status who received methotrexate for at least 12 weeks prior to the initial screening of the study were enrolled. Based on the inclusion criteria of the study, the eligible participants were those individuals with moderate to severe rheumatoid arthritis who had not an adequate response to methotrexate alone and therefore, they were in need for disease-modifying antirheumatic drugs and they should had received and f...
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