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.
Dear Editor,
We read with great interest the paper by Gwinnutt et al. on the recommendations regarding lifestyle behaviors and work participation to prevent progression of rheumatic and musculoskeletal diseases [1]. First, we applaud to the efforts of the EULAR task force to increase awareness around such important topic. Second, we congratulate with the authors for the attempt at harmonizing the recommendations on lifestyle and rheumatic musculoskeletal diseases (RMD) across European countries. We also acknowledge that trying to synthetize the available evidence regarding the impact of lifestyle on RMD is not an easy job. The task force focused on 6 main exposures (exercise, diet, weight, alcohol, smoking and work participation), which were probably chosen based on the relative World Health Organization (WHO) factsheets. However, we think that environmental air pollution, an important factor linked to RMD risk and aggravation [2–6], should have been at least mentioned in the manuscript. The WHO recently identified air pollution as: “one of the greatest environmental risk to health” [7]. According to the WHO report, 99% of the world population is living in places where the air quality guidelines are not met. Albeit 91% of premature deaths and disability related to air pollution affects the population living in low- and middle-income countries, European countries are impacted as well [8]. In addition, there is accumulating evidence that exposure to pollutants can be e...
Dear Editor,
We read with great interest the paper by Gwinnutt et al. on the recommendations regarding lifestyle behaviors and work participation to prevent progression of rheumatic and musculoskeletal diseases [1]. First, we applaud to the efforts of the EULAR task force to increase awareness around such important topic. Second, we congratulate with the authors for the attempt at harmonizing the recommendations on lifestyle and rheumatic musculoskeletal diseases (RMD) across European countries. We also acknowledge that trying to synthetize the available evidence regarding the impact of lifestyle on RMD is not an easy job. The task force focused on 6 main exposures (exercise, diet, weight, alcohol, smoking and work participation), which were probably chosen based on the relative World Health Organization (WHO) factsheets. However, we think that environmental air pollution, an important factor linked to RMD risk and aggravation [2–6], should have been at least mentioned in the manuscript. The WHO recently identified air pollution as: “one of the greatest environmental risk to health” [7]. According to the WHO report, 99% of the world population is living in places where the air quality guidelines are not met. Albeit 91% of premature deaths and disability related to air pollution affects the population living in low- and middle-income countries, European countries are impacted as well [8]. In addition, there is accumulating evidence that exposure to pollutants can be effectively reduced by simple environment and lifestyle related strategies [9]. Nevertheless, the evidence is still scarce as regards intervention in RMD. For these reasons, we think that future recommendations for the lifestyle modifications in RMD should at least acknowledge the air pollution problem in the research agenda.
References
1 Gwinnutt JM, Wieczorek M, Balanescu A, et al. 2021 EULAR recommendations regarding lifestyle behaviours and work participation to prevent progression of rheumatic and musculoskeletal diseases. Annals of the Rheumatic Diseases Published Online First: 7 March 2022. doi:10.1136/annrheumdis-2021-222020
2 Adami G, Viapiana O, Rossini M, et al. Association between environmental air pollution and rheumatoid arthritis flares. Rheumatology (Oxford) Published Online First: 20 January 2021. doi:10.1093/rheumatology/keab049
3 Adami G, Rossini M, Viapiana O, et al. Environmental Air Pollution Is a Predictor of Poor Response to Biological Drugs in Chronic Inflammatory Arthritides. ACR Open Rheumatol 2021;3:451–6. doi:10.1002/acr2.11270
4 Bellinato F, Adami G, Vaienti S, et al. Association Between Short-term Exposure to Environmental Air Pollution and Psoriasis Flare. JAMA Dermatol Published Online First: 16 February 2022. doi:10.1001/jamadermatol.2021.6019
5 Adami G, Pontalti M, Cattani G, et al. Association between long-term exposure to air pollution and immune-mediated diseases: a population-based cohort study. RMD Open;In Press-Accepted. doi:10.1136/rmdopen-2021-002055
6 Adami G, Cattani G, Rossini M, et al. Association between exposure to fine particulate matter and osteoporosis: a population-based cohort study. Osteoporos Int Published Online First: 15 July 2021. doi:10.1007/s00198-021-06060-9
7 Ambient (outdoor) air pollution. https://www.who.int/news-room/fact-sheets/detail/ambient-(outdoor)-air-quality-and-health (accessed 11 Mar 2022).
8 Khomenko S, Cirach M, Pereira-Barboza E, et al. Premature mortality due to air pollution in European cities: a health impact assessment. The Lancet Planetary Health 2021;5:e121–34. doi:10.1016/S2542-5196(20)30272-2
9 Bennett DH, Moran RE, Krakowiak P, et al. Reductions in particulate matter concentrations resulting from air filtration: A randomized sham-controlled crossover study. Indoor Air 2022;32:e12982. doi:10.1111/ina.12982
On October 28th, the European Medicine Agency extended to the entire class of Janus Kinase inhibitors (JAKi) the recommendation to use a JAKi only if no suitable therapeutic alternatives are available in patients older than 65 years, those at increased risk of MACE, and those who smoke or have smoked extensively in the past [1].
The ORAL surveillance would have shown that patients with active rheumatoid arthritis (RA) aged ≥50 years and with at least one additional cardiovascular (CV) risk factor (current smoker, hypertension, low high-density lipoprotein cholesterol, diabetes mellitus, family history of premature coronary heart disease, extra-articular rheumatoid arthritis, or history of coronary artery disease) had an increased risk of major adverse cardiovascular events (MACE) with tofacitinib versus tumour necrosis factor inhibitors (TNFi) [2]. In the ORAL Surveillance not all risk factors were well balanced between the tofacitinib and TNFi arms, i.e, unstable angina was more prevalent in patients taking tofacitinib 5 mg than in those on TNFi (17/1438 vs 7/1444, respectively; Chi-square=4.174, p=0.04), as reported in the Table S2 of the main study [2]. This bias presumably influenced the higher rate of MACE observed in the tofacitinib group. Therefore, we were not surprised that the post-hoc analysis published by Charles-Schoemann et al showed that the difference between tofacitinib and TNFi in the risk of MACE was primarily seen in patients with a history of...
On October 28th, the European Medicine Agency extended to the entire class of Janus Kinase inhibitors (JAKi) the recommendation to use a JAKi only if no suitable therapeutic alternatives are available in patients older than 65 years, those at increased risk of MACE, and those who smoke or have smoked extensively in the past [1].
The ORAL surveillance would have shown that patients with active rheumatoid arthritis (RA) aged ≥50 years and with at least one additional cardiovascular (CV) risk factor (current smoker, hypertension, low high-density lipoprotein cholesterol, diabetes mellitus, family history of premature coronary heart disease, extra-articular rheumatoid arthritis, or history of coronary artery disease) had an increased risk of major adverse cardiovascular events (MACE) with tofacitinib versus tumour necrosis factor inhibitors (TNFi) [2]. In the ORAL Surveillance not all risk factors were well balanced between the tofacitinib and TNFi arms, i.e, unstable angina was more prevalent in patients taking tofacitinib 5 mg than in those on TNFi (17/1438 vs 7/1444, respectively; Chi-square=4.174, p=0.04), as reported in the Table S2 of the main study [2]. This bias presumably influenced the higher rate of MACE observed in the tofacitinib group. Therefore, we were not surprised that the post-hoc analysis published by Charles-Schoemann et al showed that the difference between tofacitinib and TNFi in the risk of MACE was primarily seen in patients with a history of atherosclerotic cardiovascular disease (ASCVD), representing nearly 15% of the enrolled population [3]. Moreover, the post-hoc analysis clarifies that, despite the small number of events in the population at lower risk, there was no difference among treatment arms in patients with a high, intermediate, or low 10-year risk of CV events [3], rather highlighting the greater clinical relevance of a history of coronary artery disease (CAD), defined as myocardial infarction and unstable angina. Overall, the distribution of CV risk factors in patients enrolled in the ORAL Surveillance was significantly different in North American patients compared to those from other geographic areas, the former being significantly older, more frequently males, smokers, overweight/obese, with a higher prevalence of diabetes, hypertension, dyslipidemia (table S4 of the main study [2]): a significantly more pronounced CV risk profile in North Americans may account for their higher incidence rates of MACE [2]. Other populations, underrepresented in the study, may have a different risk profile that should be considered when prescribing tofacitinib [4].
The results of the post hoc analysis pointed out that the history of MI or unstable angina acquires the highest relevance in the therapeutic choice of a Janus Kinase inhibitors (JAKi) [3].
Thus, the results of the ORAL Surveillance study should be contextualized since they represent a breakthrough in the worldwide use of JAKi, a valuable treatment option for many patients with RA and other autoimmune and inflammatory diseases.
The ongoing update of the 2019 EULAR recommendations for RA management [5], no longer putting biologic-DMARDs and JAKi on the same level, will suggest considering the latter only after considering pertinent risk factors (age over 65 years, current or past smoking history, other CV risk factors as well as risk factors for malignancies and thromboembolic events).
This emphasizes the importance of assessing the overall CV risk rather than each individual risk factor in the treatment strategy of RA patients, and according to EULAR recommendations for CV risk management in patients with inflammatory arthritis [6], rheumatologists should be confident with CV risk stratification in their clinical practice.
References
1. https://www.ema.europa.eu/en/news/ema-recommends-measures-minimise-risk-...
2. Ytterberg SR, Bhatt DL, Mikuls TR, et al. ORAL Surveillance Investigators. Cardiovascular and Cancer Risk with Tofacitinib in Rheumatoid Arthritis. N Engl J Med 2022; 386: 316-26.
3. Charles-Schoeman C, Buch MH, Dougados M, et al. Risk of major adverse cardiovascular events with tofacitinib versus tumour necrosis factor inhibitors in patients with rheumatoid arthritis with or without a history of atherosclerotic cardiovascular disease: a post hoc analysis from ORAL Surveillance. Ann Rheum Dis 2022 Sep 22:annrheumdis-2022-222259.
4. Cacciapaglia F, Spinelli FR, Piga M, et al. Estimated 10-year cardiovascular risk in a large Italian cohort of rheumatoid arthritis patients: Data from the Cardiovascular Obesity and Rheumatic DISease (CORDIS) Study Group. Eur J Intern Med 2022;96:60-5.
5. Smolen JS, Landewé RBM, Bergstra SA, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2022 update. Ann Rheum Dis. 2022 Nov 10:ard-2022-223356.
6. Agca R, Heslinga SC, Rollefstad S, et al. EULAR recommendations for cardiovascular disease risk management in patients with rheumatoid arthritis and other forms of inflammatory joint disorders: 2015/2016 update. Ann Rheum Dis 2017;76:17–28.
Correspondence on “Tocilizumab in patients with new onset polymyalgia rheumatica (PMR-SPARE): a phase 2/3 randomised controlled trial”
Satoshi Takanashi, M.D., Ph.D.
Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
Correspondence: Satoshi Takanashi, M.D., Ph.D.
Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
TEL: +81-3-5363-3786
FAX: +81-3-5379-5037
Email: satoshi-takanashi@hotmail.co.jp
ORCID: 0000-0002-3607-2140
I read the paper by Michael Bonelli et al in your journal with great interest [1]. They showed the effectiveness and safety of tocilizumab for polymyalgia rheumatica (PMR) by conducting the first double-blind, randomised, placebo-controlled study (PMR-SPARE trial). Because majority of patients with PMR are elderly, there is an urgent need to establish a treatment strategy to reduce the adverse events of glucocorticoids. While clinical trials on PMR are limited, this study was well-designed and provided valuable results. Here, I would like to comment to clarify the further usefulness of this study and development of PMR management in the future focusing on the necessity for novel a criteria of remission and relapse, biomarkers reflecting disease activity under the IL-6 b...
Correspondence on “Tocilizumab in patients with new onset polymyalgia rheumatica (PMR-SPARE): a phase 2/3 randomised controlled trial”
Satoshi Takanashi, M.D., Ph.D.
Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
Correspondence: Satoshi Takanashi, M.D., Ph.D.
Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
TEL: +81-3-5363-3786
FAX: +81-3-5379-5037
Email: satoshi-takanashi@hotmail.co.jp
ORCID: 0000-0002-3607-2140
I read the paper by Michael Bonelli et al in your journal with great interest [1]. They showed the effectiveness and safety of tocilizumab for polymyalgia rheumatica (PMR) by conducting the first double-blind, randomised, placebo-controlled study (PMR-SPARE trial). Because majority of patients with PMR are elderly, there is an urgent need to establish a treatment strategy to reduce the adverse events of glucocorticoids. While clinical trials on PMR are limited, this study was well-designed and provided valuable results. Here, I would like to comment to clarify the further usefulness of this study and development of PMR management in the future focusing on the necessity for novel a criteria of remission and relapse, biomarkers reflecting disease activity under the IL-6 blockade, and the optimal strategy for tapering glucocorticoids and biological targeted therapy in the era of ageing society.
First, PMR-SPARE trial showed the difficulty in defining remission and relapse of PMR. Because the nature of PMR that occurs in elderly and its clinical manifestations which are difficult to distinguish from orthopedic-derived musculoskeletal symptoms, the accurate assessment of disease activity is challenging, especially in the situations where inflammation markers are unavailable or uninterpretable. In addition, widespread of IL-6 inhibitors which strongly suppress serum inflammation markers has caused confusion in the assessment of disease activity of PMR and other rheumatic diseases [2-5]. Although there is a validated disease activity score of PMR, named PMR-AS [6], I believe that defining remission and relapse guided by imaging findings such as ultrasound without inflammation markers could be one solution. Similar problem is also seen in other rheumatic diseases such as giant cell arteritis, and disease activity evaluation by using positron emission tomography has been developed and its validity has been verified [5, 7, 8]. Establishment of disease activity score of PMR that includes ultrasound findings without inflammation marker may be necessary in the era of biological targeted therapy.
Second, PMR-SPARE trial demonstrated the possibility for the drug-free remission in some patients with PMR. Considering the results of this trial and clinical practice, the responsiveness to treatment of PMR differ individually. Some of the cases can achieve remission with glucocorticoid monotherapy, otherwise there are also refractory cases that require glucocorticoid sparing agent such as tocilizumab. In addition, from the viewpoint of health economic or cost-effectiveness, tocilizumab may be not necessary for all patients with PMR, indicating precision medicine is desired by predicting treatment response. Furthermore, regarding the strategy for tapering glucocorticoid, I hope that multiple strategies will be compared and the optimal protocol will be found like COBRA study in rheumatoid arthritis [9].
Third, I think tocilizumab is a good steroid-sparing agent for PMR, however, serum useful biomarker including C-reactive protein become uninterpretable. It wound be desirable to develop novel serum biomarkers that independently work from the IL-6 cascade, as also researched in giant cell arteritis [10]
This study is noteworthy in establishing the treatment strategy for PMR and I am looking forward to obtaining the additional reports of long term efficacy and safety data in the future. In the ageing society, I wish that further research will progress on the best use of glucocorticoids and targeted drugs, that must lead to the extension of the healthy life expectancy in patients with PMR.
Reference
1. Bonelli M, Radner H, Kerschbaumer A,et al. Tocilizumab in patients with new onset polymyalgia rheumatica (PMR-SPARE): a phase 2/3 randomised controlled trial. Ann Rheum Dis. 2022;81(6):838-844.
2. Devauchelle-Pensec V, Saraux L, Berthelot JM, et al. Assessing polymyalgia rheumatica activity when C-reactive protein is unavailable or uninterpretable. Rheumatology (Oxford). 2018;57(4):666-670.
3. Schoels M, Alasti F, Smolen JS, et al. Evaluation of newly proposed remission cut-points for disease activity score in 28 joints (DAS28) in rheumatoid arthritis patients upon IL-6 pathway inhibition. Arthritis Res Ther. 2017;19(1):155.
4. Takanashi S, Kaneko Y, Takeuchi T. CDAI and DAS28 in the management of rheumatoid arthritis in clinical practice. Ann Rheum Dis. 2020;79(5):671-674.
5. Quinn KA, Dashora H, Novakovich E, et al. Use of 18F-fluorodeoxyglucose positron emission tomography to monitor tocilizumab effect on vascular inflammation in giant cell arteritis. Rheumatology (Oxford). 2021;60(9):4384-4389.
6. Leeb BF, Bird HA. A disease activity score for polymyalgia rheumatica. Ann Rheum Dis. 2004;63(10):1279-83.
7. Quinn KA, Ahlman MA, Malayeri AA, et al. Comparison of magnetic resonance angiography and 18F-fluorodeoxyglucose positron emission tomography in large-vessel vasculitis. Ann Rheum Dis. 2018;77(8):1165-1171.
8. Grayson PC, Alehashemi S, Bagheri AA, et al. 18 F-Fluorodeoxyglucose-Positron Emission Tomography As an Imaging Biomarker in a Prospective, Longitudinal Cohort of Patients With Large Vessel Vasculitis. Arthritis Rheumatol. 2018;70(3):439-449.
9. Verschueren P, De Cock D, Corluy L, et al. Methotrexate in combination with other DMARDs is not superior to methotrexate alone for remission induction with moderate-to-high-dose glucocorticoid bridging in early rheumatoid arthritis after 16 weeks of treatment: the CareRA trial. Ann Rheum Dis. 2015;74(1):27-34.
10. Prieto-González S, Terrades-García N, Corbera-Bellalta M, et al. Serum osteopontin: a biomarker of disease activity and predictor of relapsing course in patients with giant cell arteritis. Potential clinical usefulness in tocilizumab-treated patients. RMD Open. 2017;3(2):e000570.
Contributors: ST designed the study and wrote manuscript.
Funding: The author has not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient and public involvement: Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
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...
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...
Dear Editor,
Show MoreWe read with great interest the paper by Gwinnutt et al. on the recommendations regarding lifestyle behaviors and work participation to prevent progression of rheumatic and musculoskeletal diseases [1]. First, we applaud to the efforts of the EULAR task force to increase awareness around such important topic. Second, we congratulate with the authors for the attempt at harmonizing the recommendations on lifestyle and rheumatic musculoskeletal diseases (RMD) across European countries. We also acknowledge that trying to synthetize the available evidence regarding the impact of lifestyle on RMD is not an easy job. The task force focused on 6 main exposures (exercise, diet, weight, alcohol, smoking and work participation), which were probably chosen based on the relative World Health Organization (WHO) factsheets. However, we think that environmental air pollution, an important factor linked to RMD risk and aggravation [2–6], should have been at least mentioned in the manuscript. The WHO recently identified air pollution as: “one of the greatest environmental risk to health” [7]. According to the WHO report, 99% of the world population is living in places where the air quality guidelines are not met. Albeit 91% of premature deaths and disability related to air pollution affects the population living in low- and middle-income countries, European countries are impacted as well [8]. In addition, there is accumulating evidence that exposure to pollutants can be e...
On October 28th, the European Medicine Agency extended to the entire class of Janus Kinase inhibitors (JAKi) the recommendation to use a JAKi only if no suitable therapeutic alternatives are available in patients older than 65 years, those at increased risk of MACE, and those who smoke or have smoked extensively in the past [1].
Show MoreThe ORAL surveillance would have shown that patients with active rheumatoid arthritis (RA) aged ≥50 years and with at least one additional cardiovascular (CV) risk factor (current smoker, hypertension, low high-density lipoprotein cholesterol, diabetes mellitus, family history of premature coronary heart disease, extra-articular rheumatoid arthritis, or history of coronary artery disease) had an increased risk of major adverse cardiovascular events (MACE) with tofacitinib versus tumour necrosis factor inhibitors (TNFi) [2]. In the ORAL Surveillance not all risk factors were well balanced between the tofacitinib and TNFi arms, i.e, unstable angina was more prevalent in patients taking tofacitinib 5 mg than in those on TNFi (17/1438 vs 7/1444, respectively; Chi-square=4.174, p=0.04), as reported in the Table S2 of the main study [2]. This bias presumably influenced the higher rate of MACE observed in the tofacitinib group. Therefore, we were not surprised that the post-hoc analysis published by Charles-Schoemann et al showed that the difference between tofacitinib and TNFi in the risk of MACE was primarily seen in patients with a history of...
Correspondence
Correspondence on “Tocilizumab in patients with new onset polymyalgia rheumatica (PMR-SPARE): a phase 2/3 randomised controlled trial”
Satoshi Takanashi, M.D., Ph.D.
Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
Correspondence: Satoshi Takanashi, M.D., Ph.D.
Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
TEL: +81-3-5363-3786
FAX: +81-3-5379-5037
Email: satoshi-takanashi@hotmail.co.jp
ORCID: 0000-0002-3607-2140
Show MoreI read the paper by Michael Bonelli et al in your journal with great interest [1]. They showed the effectiveness and safety of tocilizumab for polymyalgia rheumatica (PMR) by conducting the first double-blind, randomised, placebo-controlled study (PMR-SPARE trial). Because majority of patients with PMR are elderly, there is an urgent need to establish a treatment strategy to reduce the adverse events of glucocorticoids. While clinical trials on PMR are limited, this study was well-designed and provided valuable results. Here, I would like to comment to clarify the further usefulness of this study and development of PMR management in the future focusing on the necessity for novel a criteria of remission and relapse, biomarkers reflecting disease activity under the IL-6 b...
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