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.
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.
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
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.
With great interest, we read the study by Proft et al. 1In this prospective multicenter study, the authors applied a dermatologist-centered screening tool followed by a structured rheumatologic examination, including MRI of the sacroiliac joints and spine, for the early identification of psoriatic arthritis with axial involvement (axPsA). We endorse the authors for completing an important clinical study, the results of which could have important implications for the early identification of axPsA in patients with psoriasis. However, there are some aspects that need to be focused on and discussed.
First, there is some controversy regarding the definition of axPsA. Some studies have emphasized the importance of imaging, and the presence of sacroiliac arthritis with grade 3 unilaterally or grade 2 and above bilaterally, or spinal syndesmophyte(s) according to CASPAR criteria is defined as axPsA.2 It has also been suggested that axPsA requires meeting the modified New York criteria of AS criteria or applying the Assessment of SpondyloArthritis International Society (ASAS) classification criteria for axial spondyloarthritis (axSpA), which require the presence of inflammatory back pain (IBP) in the patient. However, back pain is not always present in patients with axPsA. The use of chronic back pain as the primary screening condition is debatable. One study showed that up to 44% to 55% of patients with axPsA had only imaging involvement (including sacroiliac joints or spine...
With great interest, we read the study by Proft et al. 1In this prospective multicenter study, the authors applied a dermatologist-centered screening tool followed by a structured rheumatologic examination, including MRI of the sacroiliac joints and spine, for the early identification of psoriatic arthritis with axial involvement (axPsA). We endorse the authors for completing an important clinical study, the results of which could have important implications for the early identification of axPsA in patients with psoriasis. However, there are some aspects that need to be focused on and discussed.
First, there is some controversy regarding the definition of axPsA. Some studies have emphasized the importance of imaging, and the presence of sacroiliac arthritis with grade 3 unilaterally or grade 2 and above bilaterally, or spinal syndesmophyte(s) according to CASPAR criteria is defined as axPsA.2 It has also been suggested that axPsA requires meeting the modified New York criteria of AS criteria or applying the Assessment of SpondyloArthritis International Society (ASAS) classification criteria for axial spondyloarthritis (axSpA), which require the presence of inflammatory back pain (IBP) in the patient. However, back pain is not always present in patients with axPsA. The use of chronic back pain as the primary screening condition is debatable. One study showed that up to 44% to 55% of patients with axPsA had only imaging involvement (including sacroiliac joints or spine) with no symptoms of axial involvement such as back pain. 3In addition, in this study, the authors included the onset of back pain before the age of 45 as one of the screening conditions. This may have missed some patients, as one study showed that the mean (SD) age of axPsA patients with past or current back pain was 44.29 (11.3) years. 4In conclusion, we suggest that the inclusion of back pain as the primary screening condition may reduce inclusion of patients with axPsA.
Second, the authors included spinal MRI in the evaluation of axPsA, which is important for the recognition of axPsA. However, they found only 5 patients out of the 100 enrolled subjects who showed only spine involvement on MRI. This is close to the results of the previous study,in which axial involvement can be seen in approximately 7-20% of psoriasis. 5 Clearly, this number is relatively small, and the high cost of spinal MRI makes its use significantly more financially burdensome to screen psoriasis populations. The need for spine MRI to detect this population is controversial.
Third, the patient's psoriasis type may require attention during the initial screening or even a categorical screening based on the different psoriasis types. The likelihood of axial involvement may differ for different types of psoriasis. As a type of psoriasis with pustules, Palmoplantar pustulosis (PPP) has always been a concern. One of our previous cohort studies found that the percentage of axial involvement caused by PPP was about 40.9%（137/335）, while that caused by psoriasis of the common type was only 7.46%(25/335).6 This suggests that there may be a difference in the axial involvement of different psoriasis subtypes and that classification at the screening stage could reveal additional features that could be helpful for further studies.
Finally, the authors found elevated CRP and increased HLA-B27 positivity in axPsA, which are important for our detection of axPsA. In summary, our recommended referral strategy is for patients with axial features, including symptoms in the neck, low back, or sacroiliac region. This group of patients with elevated CRP, positive HLA-B27, and pustular psoriasis may need more attention.
REFERENCES
1. Proft F, Lüders S, Hunter T, et al. Early identification of axial psoriatic arthritis among patients with psoriasis: a prospective multicentre study. Annals of the rheumatic diseases 2022;81(11):1534-40.
2. Jadon DR, Sengupta R, Nightingale A, et al. Axial Disease in Psoriatic Arthritis study: defining the clinical and radiographic phenotype of psoriatic spondyloarthritis. Annals of the rheumatic diseases 2017;76(4):701-07.
3. Chandran V, Barrett J, Schentag CT, et al. Axial psoriatic arthritis: update on a longterm prospective study. The Journal of rheumatology 2009;36(12):2744-50.
4. Yap KS, Ye JY, Li S, et al. Back pain in psoriatic arthritis: defining prevalence, characteristics and performance of inflammatory back pain criteria in psoriatic arthritis. Annals of the rheumatic diseases 2018;77(11):1573-77.
5. Poddubnyy D, Jadon DR, Van den Bosch F, et al. Axial involvement in psoriatic arthritis: An update for rheumatologists. Seminars in arthritis and rheumatism 2021;51(4):880-87.
6. Cao Y, Li C, Xu W, et al. Spinal and sacroiliac involvement in SAPHO syndrome: A single center study of a cohort of 354 patients. Seminars in arthritis and rheumatism 2019;48(6):990-96.
Correspondence to Dr.Chen Li, Department of Rheumatology, Fangshan Hospital, Beijing University of Chinese Medicine, Beijing, China, casio1981@163.com
Contributors All other authors (XJS, QT, XJH,SFW, and CL) provided their input by contributing to the conceptualisation. SXJ and CL contributed to the editing of the manuscript. XJS, QT, SJH and SFW contributed equally.
Funding This research was funded by the National Natural Science Foundation of China (grant numbers 82074246).
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved inthe design, or conduct, or reporting, or dissemination plans of this research.
Patient consent for publication Not required.
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.
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.
With great interest, we have read the article by Timothy et al. exclusively examined the prevalence and differences associated with isolated axial PsA (axPsA) and isolated axial AS with psoriasis.1 To some extent, we agree with the authors that isolated axPsA and isolated axial AS with psoriasis may be two distinct clinical phenotypes. However, we would like to raise a few important issues that need to be addressed.
First, the definition of patients with axPsA needs to be discussed. Patients with PsA may have only isolated syndesmophytes without sacroiliitis, one study showed that up to a third of all patients with axPsA have spondylitis without sacroiliitis. 2 In this study, patients with axPsA were identified only by the presence of sacroiliitis on radiographs, which was defined as the presence of sacroiliitis ( grade 2 bilateral or grade 3 unilateral) on sacroiliac joint radiographs, according to the 1984 AS modified New York criteria. However, some patients with axPsA could present with spondylitis alone but without sacroiliitis, who were not included in the study. Therefore, the overall spectrum of axPsA in this study may be underestimated.
Second, AS patients with psoriasis must be defined with caution. In terms of clinical features, axPsA differs from AS in several ways, most notably in the radiographic patterns of the disease. axPsA shows radiographic features such as asymmetric sacroiliitis, nonmarginal (which includes “chunky” and “comma”), asymmet...
With great interest, we have read the article by Timothy et al. exclusively examined the prevalence and differences associated with isolated axial PsA (axPsA) and isolated axial AS with psoriasis.1 To some extent, we agree with the authors that isolated axPsA and isolated axial AS with psoriasis may be two distinct clinical phenotypes. However, we would like to raise a few important issues that need to be addressed.
First, the definition of patients with axPsA needs to be discussed. Patients with PsA may have only isolated syndesmophytes without sacroiliitis, one study showed that up to a third of all patients with axPsA have spondylitis without sacroiliitis. 2 In this study, patients with axPsA were identified only by the presence of sacroiliitis on radiographs, which was defined as the presence of sacroiliitis ( grade 2 bilateral or grade 3 unilateral) on sacroiliac joint radiographs, according to the 1984 AS modified New York criteria. However, some patients with axPsA could present with spondylitis alone but without sacroiliitis, who were not included in the study. Therefore, the overall spectrum of axPsA in this study may be underestimated.
Second, AS patients with psoriasis must be defined with caution. In terms of clinical features, axPsA differs from AS in several ways, most notably in the radiographic patterns of the disease. axPsA shows radiographic features such as asymmetric sacroiliitis, nonmarginal (which includes “chunky” and “comma”), asymmetric and irregular syndesmophytes, and paravertebral ossification. Discovertebral lesions such as Romanus lesion and vertebral squaring are less common in axPsA than in AS. The radiographic presentation of syndesmophytes in AS is symmetrical, regular and from margin to margin. These unique features can be helpful in differentiating axPsA from axial AS. 3 In this article, for the patients with AS and psoriasis, “the presence of psoriasis was defined as at least one documented occurrence of psoriasis from initial consultation to most recent follow-up, or any previous history of psoriasis as diagnosed by a rheumatologist or dermatologist”. Actually, in a number of patients with PsA, musculoskeletal manifestations may present prior to the onset of psoriasis or associated skin or nail lesions. Previous studies reported that approximately 10–15% of patients develop arthritis prior to psoriasis.4 AS patients with psoriasis should therefore be defined by specific manifestations rather than delayed onset of psoriasis. According to the authors described, those PsA patients who developed the skin disease after the onset of spondylitis could be mis-defined as AS patients with psoriasis. Additionally, AS patients were enrolled in this study from July 2003 to November 2019, however, the CASPAR criteria were developed in 2006 and then widely used for PsA classification. Based on the CASPAR criteria, the AS patients with a previous history of physician-diagnosed psoriasis should be re-classified as axPsA patients. Taken together, we reasonably speculate that some true axPsA patients in Timothy’s study might be mis-classified as “AS patients with psoriasis”.
REFERENCES
1. Kwok TSH, Sutton M, Pereira D, et al. Isolated axial disease in psoriatic arthritis and ankylosing spondylitis with psoriasis. Ann Rheum Dis. 2022; annrheumdis-2022-222537
2. Jadon DR, Sengupta R, Nightingale A, et al. Axial Disease in Psoriatic Arthritis study: defining the clinical and radiographic phenotype of psoriatic spondyloarthritis. Ann Rheum Dis. 2017;76(4):701-707
3. Feld J, Chandran V, Haroon N, Inman R, Gladman D. Axial disease in psoriatic arthritis and ankylosing spondylitis: a critical comparison. Nat Rev Rheumatol. 2018;14(6):363-371
4. Coates LC, Helliwell PS. Psoriatic arthritis: state of the art review. Clin Med (Lond). 2017;17(1):65-70
Correspondence to Dr Sheng-Ming Dai, Department of Rheumatology & Immunology, Shanghai Sixth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China, shengmingdai@163.com
Contributors All other authors (QT, HZ and SMD) provided their input by contributing to the conceptualisation. QT and SMD contributed to the editing of the manuscript. QT and HZ contributed equally.
Funding The authors have 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.
Patient consent for publication Not required.
Cheng et al. recently reported the changes in fecal microbiota and peripheral blood metabolites in patients with rheumatoid arthritis (RA) across four stages of the disease. In addition, they performed 16S rRNA sequencing and identified bacteria in synovial fluid of RA. and successfully isolated and identified many microbes in synovial fluid samples of RA patients at the stage 4 (RAS4). Moreover, substances shaped like bacteria in rod-like or spherical forms were also observed under scanning electron microscopy.1 This is the first time that bacteria were successfully isolated from the synovial fluid of RA and this finding deserves attention.
First, it is always an interesting question whether bacteria are actually present in the synovial fluid of RA. Up to date, several studies have reported the presence of microbial DNA in joint effusion of RA by 16S rRNA gene sequencing technology (Table 1). However, there is no direct evidence on isolation of bacteria from RA synovial fluid. The synovial fluid is usually sterile, and RA is a kind of chronic non-infectious arthritis induced by autoimmune disorder.2 It was indeed reported that bacteria were found in the synovial fluid of RA, however, this was mainly because of multiple arthroscopic washouts and joint injections. Unfortunately, the history information of repeated arthroscopy or arthrocentesis was missing in RAS4 of which bacteria were isolated from synovial fluid in this article. Thus, it is uncertain if these isolat...
Cheng et al. recently reported the changes in fecal microbiota and peripheral blood metabolites in patients with rheumatoid arthritis (RA) across four stages of the disease. In addition, they performed 16S rRNA sequencing and identified bacteria in synovial fluid of RA. and successfully isolated and identified many microbes in synovial fluid samples of RA patients at the stage 4 (RAS4). Moreover, substances shaped like bacteria in rod-like or spherical forms were also observed under scanning electron microscopy.1 This is the first time that bacteria were successfully isolated from the synovial fluid of RA and this finding deserves attention.
First, it is always an interesting question whether bacteria are actually present in the synovial fluid of RA. Up to date, several studies have reported the presence of microbial DNA in joint effusion of RA by 16S rRNA gene sequencing technology (Table 1). However, there is no direct evidence on isolation of bacteria from RA synovial fluid. The synovial fluid is usually sterile, and RA is a kind of chronic non-infectious arthritis induced by autoimmune disorder.2 It was indeed reported that bacteria were found in the synovial fluid of RA, however, this was mainly because of multiple arthroscopic washouts and joint injections. Unfortunately, the history information of repeated arthroscopy or arthrocentesis was missing in RAS4 of which bacteria were isolated from synovial fluid in this article. Thus, it is uncertain if these isolated bacteria are result of endogenous gut-derived microbiome or exogenous infection.
Second, if the isolated bacteria were indeed present in synovial fluid from RA without exogenous infection, the role of bacteria in joints is still worthy to inquire. In addition to initiating infection, according to the results of Cheng et al., it is unclear whether low-virulent bacteria in the synovial fluid are possessed of antigen activity to induce autoantibodies formation and participate in the pathological process of RA. Then whether these bacteria are through the way to transfer, which Cheng et al.'s elaboration, "microbes and microbial metabolites would then be transferred to the joints via blood ". In the current researches on gut-joint axis, the mainstream view is that gut microbiota contributed to the development of RA joints through microbial-derived metabolites and secreted compounds.3 Cheng et al.'s view is different from this. If gut microbiome is transferred through the blood circulation, gut microbiota is more likely to be enriched in visceral organs with rich blood supply, such as liver and kidney,4 5 causing bloodstream infections. It was also unclear if the RA patients involved in the study had related symptoms of accumulation of bacteria in organs or if the gut microbiota was affected by specific chemokines and directed to the joints.
Third, it is worthy to discuss how the presence of bacteria in the synovial fluid of RA affects our therapeutic choices. At present, biological agents such as TNF-α, IL-6 inhibitors have achieved excellent efficacy in the treatment of RA in clinical practice.6 But long-term usage can increase the risk of infection in RA.7 According to the findings of Cheng et al., bacteria are present in the synovial fluid of RAS4, and long-term use of biological agents may lead to increased bacteria and joint infection. In the future, doctors should be more cautious when using related biological agents in RAS4. For patients with advanced RA, topical or systemic antibiotic therapy could be considered to control microbial invasion into joint.
In conclusion, isolation of bacteria from RA synovial fluid is a novel finding. Further investigation of the effect of bacteria in synovial fluid on RA synovial fluid, which will definitely expand our understanding of the gut-joint axis, RA pathogenesis and clinical management.
References
1. Cheng M, Zhao Y, Cui Y, et al. Stage-specific roles of microbial dysbiosis and metabolic disorders in rheumatoid arthritis. Annals of the rheumatic diseases 2022 doi: 10.1136/ard-2022-222871 [published Online First: 2022/08/20]
2. Smolen JS, Aletaha D, McInnes IB. Rheumatoid arthritis. Lancet (London, England) 2016;388(10055):2023-38. doi: 10.1016/s0140-6736(16)30173-8 [published Online First: 2016/10/30]
3. Zaiss MM, Joyce Wu HJ, Mauro D, et al. The gut-joint axis in rheumatoid arthritis. Nature reviews Rheumatology 2021;17(4):224-37. doi: 10.1038/s41584-021-00585-3 [published Online First: 2021/03/07]
4. Chung DR. Hypervirulent Klebsiella pneumoniae: Liver Abscess Isolates versus Intestinal Flora. Journal of Korean medical science 2020;35(2):e28. doi: 10.3346/jkms.2020.35.e28 [published Online First: 2020/01/11]
5. Shah NB, Nigwekar SU, Kalim S, et al. The Gut and Blood Microbiome in IgA Nephropathy and Healthy Controls. Kidney360 2021;2(8):1261-74. doi: 10.34067/kid.0000132021 [published Online First: 2022/04/05]
6. Fraenkel L, Bathon JM, England BR, et al. 2021 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis & rheumatology (Hoboken, NJ) 2021;73(7):1108-23. doi: 10.1002/art.41752 [published Online First: 2021/06/09]
7. Chiu YM, Chen DY. Infection risk in patients undergoing treatment for inflammatory arthritis: non-biologics versus biologics. Expert review of clinical immunology 2020;16(2):207-28. doi: 10.1080/1744666x.2019.1705785 [published Online First: 2019/12/20]
The question of whether the use of biologic disease-modifying antirheumatic drugs (bDMARDs) can prevent psoriatic arthritis (PsA) in psoriasis (PsO) patients may be confusing. Some observational studies reported that biologic therapies were associated with a decreased risk of PsA1-2, but other studies did not3-5.
We read with great interest the recent article published in Annals of the Rheumatic Diseases by Gisondiet and colleagues regarding the impact of biologic therapy on development of PsA1. This study is very interesting and important; however, we would like to share with the authors our perplexities about the conclusions drawn from this report.
First and foremost, Gisondiet et al identified that treatment with bDMARDs was significantly associated with a lower risk of incident PsA in moderate-to-severe PsO (aHR 0.27, 95%CI 0.11 to 0.66) compared with nb-UVB phototherapy. However, we noted that this association was reversed if HRs were calculated using propensity score matching (PSM) data (aHR 2.07, 95%CI 0.87 to 4.93, Supplementary Table 2), and the explanation provided by the authors may be related to the limited sample size after PSM. In fact, these well-known risk factors, including age, scalp psoriasis, nail psoriasis, psoriasis duration, and family history of PsA, showed larger effect values after PSM even with smaller sample sizes. Thus, we reckon that, rather than a smaller sample size, this discrepancy is more likely the consequence of the pre-matc...
The question of whether the use of biologic disease-modifying antirheumatic drugs (bDMARDs) can prevent psoriatic arthritis (PsA) in psoriasis (PsO) patients may be confusing. Some observational studies reported that biologic therapies were associated with a decreased risk of PsA1-2, but other studies did not3-5.
We read with great interest the recent article published in Annals of the Rheumatic Diseases by Gisondiet and colleagues regarding the impact of biologic therapy on development of PsA1. This study is very interesting and important; however, we would like to share with the authors our perplexities about the conclusions drawn from this report.
First and foremost, Gisondiet et al identified that treatment with bDMARDs was significantly associated with a lower risk of incident PsA in moderate-to-severe PsO (aHR 0.27, 95%CI 0.11 to 0.66) compared with nb-UVB phototherapy. However, we noted that this association was reversed if HRs were calculated using propensity score matching (PSM) data (aHR 2.07, 95%CI 0.87 to 4.93, Supplementary Table 2), and the explanation provided by the authors may be related to the limited sample size after PSM. In fact, these well-known risk factors, including age, scalp psoriasis, nail psoriasis, psoriasis duration, and family history of PsA, showed larger effect values after PSM even with smaller sample sizes. Thus, we reckon that, rather than a smaller sample size, this discrepancy is more likely the consequence of the pre-matched data not being fully adjusted for key confounder of the baseline Psoriasis Area and Severity Index (PASI). As shown in Table 1, baseline PASI was adjusted as a confounder in the form of dichotomous variables (cut-off of 10) in multivariate model 1 and model 2. However, based on baseline characteristics (Supplementary Table 1), the majority of baseline PASIs in the bDMARDS group were higher than 10 (Mean±SD, 15.24±0.37). Thus, it is more logical and reasonable to adjust baseline PASI as a continuous variable.
Second, even though the authors tried to adjust for several baseline variables, some significant risk factors, such as BMI and socioeconomic status, should be considered as potential confounders. Studies have identified obesity as a known risk factor for developing PsA6-8. Besides, obesity is linked to a high disease activity and a poor response to biological treatments7-8. Similarly, in addition to its association with PsA incidence and psoriasis severity9-10, socioeconomic status factors including economic income and education directly influenced the treatment choice in this study.
Third, several numerical discrepancies appear in Supplementary Table 1. The duration of psoriasis after PSM was 54.06±0.02 and 54.06±0.02 in the two groups, respectively? How can the duration of psoriasis be older than age?
Finally, there is an inaccurate description in the results of univariate Cox regression analysis. Here, the description of baseline PASI≥10 was significantly associated with a higher risk of incident PsA. can the effect value HR 0.47 (95%CI 0.27 to 0.82) be related to the higher risk of PsA (Table 1)?
In summary, the limited evidence available does not fully address the issue of biologic treatment of PsO to prevent PsA. Retrospective observational studies involve significant methodological limitations and biases that may skew the relationship between treatment and arthritis development3,7. Randomized controlled trials (RCTs) seem to be the gold standard for establishing causality. However, it is hardly feasible because it would recruit two groups of patients with moderate to severe psoriasis and long-term comparison of treatment outcomes against no treatment. Therefore, the question of "treating the skin to intercept PsA" will remain a fascinating challenge for years.
References
1.Gisondi P, Bellinato F, Targher G, Idolazzi L, Girolomoni G. Biological disease-modifying antirheumatic drugs may mitigate the risk of psoriatic arthritis in patients with chronic plaque psoriasis. Ann Rheum Dis 2022;81(1):68-73.
2.Acosta Felquer ML, LoGiudice L, Galimberti ML, et al. Treating the skin with biologics in patients with psoriasis decreases the incidence of psoriatic arthritis. Ann Rheum Dis 2022;81(1):74-79.
3.Meer E, Merola JF, Fitzsimmons R, et al. Does biologic therapy impact the development of PsA among patients with psoriasis? Ann Rheum Dis 2022;81(1):80-86.
4.Napolitano M, Balato N, Caso F, et al. Paradoxical onset of psoriatic arthritis during treatment with biologic agents for plaque psoriasis: a combined dermatology and rheumatology clinical study. Clin Exp Rheumatol 2017;35:137–40
5.Cuchacovich R, Espinoza CG, Virk Z, et al. Biologic therapy (TNF- alpha antagonists)-induced psoriasis: a cytokine imbalance between TNF- alpha and IFN- alpha? J ClinRheumatol 2008;14:353–6.
6.Armstrong AW, Harskamp CT, Armstrong EJ. The association between psoriasis and obesity: a systematic review and meta-analysis of observational studies. Nutr Diabetes 2012; 2:e54.
7.Scher JU, Ogdie A, Merola JF, Ritchlin C. Preventing psoriatic arthritis: focusing on patients with psoriasis at increased risk of transition. Nat Rev Rheumatol 2019;15:153–66.
8.Green A, Shaddick G, Charlton R, et al. Modifiable risk factors and the development of psoriatic arthritis in people with psoriasis. Br J Dermatol 2020;182(3):714-720.
9.Hawro T, Zalewska A, Hawro M, et al. Impact of psoriasis severity on family income and quality of life. J Eur Acad Dermatol Venereol 2015;29(3):438-443.
10.De Vlam K, Steinfeld S, Toukap AN, et al. The burden of psoriatic arthritis in the biologics era: data from the Belgian Epidemiological Psoriatic Arthritis Study. Rheumatology 2021;60(12):5677-5685.
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%.
...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...
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 MoreCorrespondence
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...
With great interest, we read the study by Proft et al. 1In this prospective multicenter study, the authors applied a dermatologist-centered screening tool followed by a structured rheumatologic examination, including MRI of the sacroiliac joints and spine, for the early identification of psoriatic arthritis with axial involvement (axPsA). We endorse the authors for completing an important clinical study, the results of which could have important implications for the early identification of axPsA in patients with psoriasis. However, there are some aspects that need to be focused on and discussed.
Show MoreFirst, there is some controversy regarding the definition of axPsA. Some studies have emphasized the importance of imaging, and the presence of sacroiliac arthritis with grade 3 unilaterally or grade 2 and above bilaterally, or spinal syndesmophyte(s) according to CASPAR criteria is defined as axPsA.2 It has also been suggested that axPsA requires meeting the modified New York criteria of AS criteria or applying the Assessment of SpondyloArthritis International Society (ASAS) classification criteria for axial spondyloarthritis (axSpA), which require the presence of inflammatory back pain (IBP) in the patient. However, back pain is not always present in patients with axPsA. The use of chronic back pain as the primary screening condition is debatable. One study showed that up to 44% to 55% of patients with axPsA had only imaging involvement (including sacroiliac joints or spine...
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...
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”
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...
With great interest, we have read the article by Timothy et al. exclusively examined the prevalence and differences associated with isolated axial PsA (axPsA) and isolated axial AS with psoriasis.1 To some extent, we agree with the authors that isolated axPsA and isolated axial AS with psoriasis may be two distinct clinical phenotypes. However, we would like to raise a few important issues that need to be addressed.
Show MoreFirst, the definition of patients with axPsA needs to be discussed. Patients with PsA may have only isolated syndesmophytes without sacroiliitis, one study showed that up to a third of all patients with axPsA have spondylitis without sacroiliitis. 2 In this study, patients with axPsA were identified only by the presence of sacroiliitis on radiographs, which was defined as the presence of sacroiliitis ( grade 2 bilateral or grade 3 unilateral) on sacroiliac joint radiographs, according to the 1984 AS modified New York criteria. However, some patients with axPsA could present with spondylitis alone but without sacroiliitis, who were not included in the study. Therefore, the overall spectrum of axPsA in this study may be underestimated.
Second, AS patients with psoriasis must be defined with caution. In terms of clinical features, axPsA differs from AS in several ways, most notably in the radiographic patterns of the disease. axPsA shows radiographic features such as asymmetric sacroiliitis, nonmarginal (which includes “chunky” and “comma”), asymmet...
Cheng et al. recently reported the changes in fecal microbiota and peripheral blood metabolites in patients with rheumatoid arthritis (RA) across four stages of the disease. In addition, they performed 16S rRNA sequencing and identified bacteria in synovial fluid of RA. and successfully isolated and identified many microbes in synovial fluid samples of RA patients at the stage 4 (RAS4). Moreover, substances shaped like bacteria in rod-like or spherical forms were also observed under scanning electron microscopy.1 This is the first time that bacteria were successfully isolated from the synovial fluid of RA and this finding deserves attention.
Show MoreFirst, it is always an interesting question whether bacteria are actually present in the synovial fluid of RA. Up to date, several studies have reported the presence of microbial DNA in joint effusion of RA by 16S rRNA gene sequencing technology (Table 1). However, there is no direct evidence on isolation of bacteria from RA synovial fluid. The synovial fluid is usually sterile, and RA is a kind of chronic non-infectious arthritis induced by autoimmune disorder.2 It was indeed reported that bacteria were found in the synovial fluid of RA, however, this was mainly because of multiple arthroscopic washouts and joint injections. Unfortunately, the history information of repeated arthroscopy or arthrocentesis was missing in RAS4 of which bacteria were isolated from synovial fluid in this article. Thus, it is uncertain if these isolat...
The question of whether the use of biologic disease-modifying antirheumatic drugs (bDMARDs) can prevent psoriatic arthritis (PsA) in psoriasis (PsO) patients may be confusing. Some observational studies reported that biologic therapies were associated with a decreased risk of PsA1-2, but other studies did not3-5.
Show MoreWe read with great interest the recent article published in Annals of the Rheumatic Diseases by Gisondiet and colleagues regarding the impact of biologic therapy on development of PsA1. This study is very interesting and important; however, we would like to share with the authors our perplexities about the conclusions drawn from this report.
First and foremost, Gisondiet et al identified that treatment with bDMARDs was significantly associated with a lower risk of incident PsA in moderate-to-severe PsO (aHR 0.27, 95%CI 0.11 to 0.66) compared with nb-UVB phototherapy. However, we noted that this association was reversed if HRs were calculated using propensity score matching (PSM) data (aHR 2.07, 95%CI 0.87 to 4.93, Supplementary Table 2), and the explanation provided by the authors may be related to the limited sample size after PSM. In fact, these well-known risk factors, including age, scalp psoriasis, nail psoriasis, psoriasis duration, and family history of PsA, showed larger effect values after PSM even with smaller sample sizes. Thus, we reckon that, rather than a smaller sample size, this discrepancy is more likely the consequence of the pre-matc...
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