Cardiac arrhythmias associated with S1RPMs: a pharmacovigilance study based on real-world data

Cardiac arrhythmias associated with S1RPMs: a pharmacovigilance study based on real-world data | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Cardiac arrhythmias associated with S1RPMs: a pharmacovigilance study based on real-world data siqi wang, linli xie, pan ma This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7912836/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Sphingosine-1-phosphate receptor modulators (S1PRMs) are an effective class of disease-modifying therapies (DMTs) for the treatment of multiple sclerosis (MS). But its clinical application is limited due to its adverse reactions. Methods In this study we mined cardiac arrhythmias adverse event signals of S1PRMs based on the Food and Drug Administration Adverse Event Reporting System (FAERS) from the first quarter of 2004 to the first quarter of 2024, using the Reported Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confdence Propagation Neural Network (BCPNN) and Multi-item Gamma Poisson Shrinker (MGPS) methods to provide a reference for the safe clinical use of the drug. Results We identified 2,059 arrhythmia-related adverse events associated with S1PRMs, including 1,860 cases for fingolimod, 153 for siponimod, 38 for ozanimod, and 8 for ponesimod. Patients aged 18–65 and female patients were at a higher risk. High risk signals in the report include heart rate decreased, cardiac flutter, extrasystoles. Conclusion Mining the adverse reaction signal study of S1PRMs based on the FAERS database provides some support for the clinical monitoring and risk identification of this drug. S1PRMs Cardiac arrhythmias FAERS Signal detection Drug safety Figures Figure 1 Figure 2 Introduction Multiple sclerosis (MS) is an immune-mediated inflammatory demyelinating disease of central nervous system (CNS), characterized by dissemination in time and dissemination in space 1 – 3 . The etiology of MS is unknown, but Epstein-Barr virus infection, low serum vitamin D levels, insufficient sun exposure, smoking, and adolescent obesity may be risk factors for MS. Multiple sclerosis is prevalent in patients between the ages of 20 and 40 years, and is more common in women 4 . According to the latest MS Atlas, a joint project of the International Multiple Sclerosis Federation and WHO, 2.8 million people worldwide suffered from MS. Since 2013, there has been an increase of 500,000 new cases of MS global. The prevalence and incidence of MS has been steadily increasing worldwide, including in the Middle East and North Africa (MENA) region, over the past few decades 4 . The prevalence of MS varies according to geographic regions, with the highest incidence rates (111–300 cases per 100,000 population) reported in the WHO European Region and the Americas 5 . There is no definitive cure for MS, but a number of disease-modifying therapies (DMTs) that primarily target the inflammatory milieu have been designed to reduce the rate of relapses and the accumulation of disability in patients with MS 6 . Sphingosine-1-phosphate receptor modulators (S1PRMs), a class of disease-modifying therapies (DMTs), are structurally similar to Sphingosine 1-phosphate (S1P). S1P is a biologically active soluble hemolytic phospholipid signaling molecule. Under normal homeostatic conditions, erythrocytes and endothelial cells are thought to be the major sources of S1P in plasma, whereas mast cells and platelets lead to a localized increase in S1P under noninflammatory and prethrombotic conditions 7 – 9 . Sphingosine-1-phosphate receptors (S1PRs) are expressed throughout the body and mediate a wide range of biological functions. However, due to the widespread expression of S1PRs on cardiomyocytes and vascular endothelial cells, all drugs related to them will have some cardiovascular effects 9 – 11 . Fingolimod, the first approved S1PRMs, non-selectively targets S1PR1, S1PR3, S1PR4 and S1PR5. Some arrhythmic adverse events (AEs) of fingolimod, such as atrioventricular block and sinus bradycardia, have been reported. In early clinical trials of fingolimod, it was found that patients experienced a transient decrease in mean measured heart rate 4–5 h after the first dose of the drug 12 , 13 . Since studies have shown that this cardiovascular effect may be mediated by transient agonism of S1PR1 or S1PR3, second-generation S1PRMs with low affinity for S1PR3 have been widely developed. However, similar cardiovascular AEs were observed in MS patients receiving siponimod, ozanimod, and other second-generation drugs that reduce S1PR3 binding 14 . Currently, for proved S1PRMs, 6 hours of continuous cardiac monitoring after the first dose is recommended to somewhat minimize these side effects 15 . However, to date, there was few studies with data from the real world have elucidated the risk of arrhythmic adverse events in MS patients treated with S1PRMs. The FDA Adverse Drug Event Reporting System (FAERS), established in 2012, is one of the largest pharmacovigilance databases in the world, harboring a large number of drug-related AEs to monitor the safety of drugs once they reach the market. Therefore, this study utilized the FAERS database of S1PRMs-related arrhythmia adverse reactions using proportional imbalance method to provide a comprehensive and systematic study. Methods Data sources and procedures This study is a retrospective, observational pharmacovigilance study using data from the FAERS database. The reports of S1PRMs-related adverse reactions submitted from the forth quarter of 2010 when the first approved S1PRM listed to the first quarter of 2024 were extracted from the FAERS database. FAERS was queried by using the generic names “fingolimod” “siponimod” ozanimod” and “ponesimod” with primary suspect, after removing duplicate reports (with the same ISR number), the reports were analyzed. Two researchers used SMQ-narrow and PTs to classify S1PRMs-related cardiac arrhythmias and extracted patient and drug information from reports. Data analysis Statistical analysis is based on the proportional imbalance method, we used the Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi Item Gamma Poisson Shrinker (MGPS) algorithm to study the association between drugs and a specific AE. The equations and criteria for these four algorithms are given in Table 1 . Table 1 ROR, PRR, BCPNN, and EBGM methods, formulas, and criterias Algorithms Calculation formula Criteria ROR (1) a ≥ 3 (2) 95%CI > 1 PRR n = a + b + c + d (1) (2) PRR ≥ 2 (3) BCPNN (1) a ≥ 3 (2) IC-2SD > 0 EBGM EBGM= \(\:\frac{a\left(a+b+c+d\right)}{\left(a+b\right)\left(a+c\right)}\) \(\:95\text{\%}\text{C}\text{I}={\text{e}}^{\text{l}\text{n}\left(\text{E}\text{B}\text{G}\text{M}\right)\pm\:1.96\sqrt{(\frac{1}{\text{a}}+\frac{1}{\text{b}}+\frac{1}{\text{c}}+\frac{1}{\text{d}})}}\) EBGM05>2 Statistical analysis All data were analysed using IBM® SPSS® statistical software. p-value less than 0.05 was considered statistically significant. Results and Discussion Descriptive analysis We extracted all reported cases from the FAERS database, after deduplication and screening totaling 2059 cases of S1PRMs-related cardiac arrhythmias were reported, 1860 of Fingolimod, 153 of Siponimod, 38 of Ozanimod, 8 of Ponesimod. In this study, the reported data were analysed, and the demographic characteristics of the AEs associated are shown in Table 2 . Among the adverse events reported, the proportion of women was slightly higher than that of men. In terms of age distribution, although the proportion of patients with unknown age reached 30.69%, the highest proportion of AEs was in the age group of 18–65 years (64.50%). The median age of the four drugs was 45, 56, 43, 60. The country with the most reports is the United States (45.12%), followed by the United Kingdom(20.12%), Germany (6.31%), Canada(2.78%), etc. The number of cases peaked in 2018 with fingolimod. A total of 282 serious adverse events were mainly reported by fingolimod, including 5 deaths, 257 hospitalization-initial or prolonged, and 18 life-threatening. Table 2 Clinical characteristics of reports with S1PRMs-related cardiac arrhythmias from the FAERS database Reports characteristics Fingolimod Siponimod Ozanimod Ponesimod N 1860 153 38 8 Age 65 35 19 1 - Missing 584 33 10 5 Gender Female 1302 103 25 3 Male 440 44 8 2 Missing 118 6 5 3 Country of the reporter United States 655 121 38 6 United Kingdom 30 14 - - Germany 96 9 - 1 Canada 62 12 - 0 Reported years 2010–2015 493 - - - 2016–2020 1067 49 - - 2020–2024 300 104 38 8 Outcomes Death 5 1 - - Hospitalization-Initial or Prolonged 257 7 - - Life-Threatening 18 1 - - Disability 2 - - - Other - - Standardized signal detection Table 3 shows the signal intensity of S1PRMs-associated AEs classified by SMQ. Based on our statistical analysis, a total of 22 Standardised MedDRA Queries (SMQ) were affected by adverse events related to fingolimod, 14 by Siponimod, 10 by Ozanimod and 8 by Ponesimod, respectively. Two of the SMQs involved in all four drugs are haematopoietic leukopenia and tachyarrhythmia, term nonspecific. In this study, adverse reactions related to arrhythmias are highlighted ( Table 4 ). Based on our statistical analysis, fingolimod was most strongly associated with the occurrence of adverse arrhythmias, which may be related to its poor selectivity for S1PR receptors. Fingolimod non-selectively targets S1PR1, S1PR3, S1PR4 and S1PR5, and is widely expressed in cardiomyocytes and vascular endothelial cells. Table 3 ROR of S1PRMs-associated SMQ SMQ Fingolimod Siponimod Ozanimod Ponesimod skin premalignant disorders 3.70(3.58) 2.98(2.57) - - optic nerve disorders 3.27(3.17) - - - gastrointestinal premalignant disorders - - 2.62(2.43) - gastrointestinal ulceration - - 2.01(1.91) - haematopoietic leukopenia 2.56(2.53) 2.39(2.38) 1.46(1.30) 1.00(0.21) skin tumours of unspecified malignancy 2.28(1.81) 2.27(2.04) - - conditions associated with central nervous system haemorrhages and cerebrovascular accidents 2.48(2.37) 1.93(1.55) - - optic nerve disorders - 2.17(1.79) 1.44(0.88) - reproductive premalignant disorders 2.38(1.81) - - - disorders of sinus node function 2.39(2.23) - - - retinal disorders 2.20(2.13) 1.72(1.49) - - immune-mediated/autoimmune disorders 1.89(1.86) 1.67(1.58) 2.01(1.91) - breast tumours of unspecified malignancy 1.68(1.03) - - - skin malignant tumours 1.94(1.85) - - 1.39(0.27) liver related investigations signs and symptoms 1.73(1.68) - - - vestibular disorders 1.75(1.65) 1.45(1.13) - - conduction defects 1.75(1.66) 1.09(0.77) - - tachyarrhythmia terms nonspecific 1.43(1.21) 1.45(0.86) 1.69(1.09) 1.28(0.16) hypertension - 1.59(1.46) 1.04(0.85) - noninfectious meningitis 1.43(1.21) - - - ocular motility disorders 1.43(1.26) - - - uterine and fallopian tube malignant tumours 1.23(1.02) - - - depression (excl suicide and self injury) 1.17(1.12) - - - noninfectious encephalitis 1.02(0.69) - - - liver neoplasms benign (incl cysts and polyps) 0.98(0.53) 1.11(0.94) - - gastrointestinal nonspecific inflammation - - 0.96(0.57) 1.57(0.79) cOVID-19 - 2.35(2.21) 1.61(1.42) 1.57(0.79) interstitial lung disease - - - 1.03(0.10) Table 4 Comparison of the Constituent Ratio of Caused arrhythmias by S1PRMs Case number ROR (95%CI) PRR (χ 2 ) IC(IC 025 ) EBGM(EBGM 05 ) Fingolimod 350 4.11(3.70,4.57) 4.05(800.69) 2.00(1.87) 4.03(3.93) Siponimod 16 3.18(1.95,5.20) 3.18(21.72) 1.45(0.86) 3.17(2.68) Ozanimod 15 3.97(2.39,6.60) 3.96(3.27) 1.69(1.09) 3.96(3.45) Ponesimod 5 6.40(2.64,15.53) 6.29(17.32) 1.62(0.59) 6.29(5.40) PT level signal detection Figure 1 shows the PTs for each S1PRMs. Fingolimod involves 30 PTs, with higher signal values primarily including electrocardiogram PR shortened (ROR = 30.54, 95% CI = 20.45, 45.62), heart rate decreased (ROR = 21.39, 95% CI = 20.47, 22.34), atrioventricular block first degree (ROR = 21.30, 95% CI = 18.97, 23.93), atrioventricular block second degree (ROR = 18.85, 95% CI = 16.16, 21.98), electrocardiogram PR prolongation (ROR = 13.04, 95% = 9.06, 18.79), and sinus arrhythmia (ROR = 10.76, 95% CI = 8.18, 14.17). Siponimod was associated with 7 PTs including atrioventricular block first degree (ROR = 24.23, 95% = 18.04, 32.55), heart rate decreased (ROR = 20.77, 95% = 18.41, 20.77), cardiac flutter (ROR = 7.65, 95% = 4.87, 12.02), extrasystoles (ROR = 4.68, 95% = 2.72, 8.07). Ozanimod demonstrated 4 PTs involved cardiac flutter (ROR = 9.38, 95% = 5.44, 16.17), heart rate decreased (ROR = 7.35, 95% = 5.65, 9.57), heart rate abnormal (ROR = 3.59, 95% = 1.35, 9.58), and palpitations (ROR = 2.36, 95% = 1.82,3.05). Ponesimod has 4 PTs heart rate decreased (ROR = 8.85, 95% = 2.83, 27.67), arrhythmia (ROR = 7.99, 95% = 2.979, 21.48), palpitations(ROR = 3.62, 95% = 1.34, 9.72), and loss of consciousness (ROR = 3.24 (1.21,8.72). Notably, all four S1PRMs exhibited significant heart rate decreased (Fig. 2 ), consistent with the results of previous RCT (Randomized Controlled Trial) experiments. Based on these findings, clinical guidelines emphasize stringent electrocardiographic monitoring protocols during treatment initiation, including baseline ECG evaluation (focusing on PR interval and QTc duration), continuous cardiac monitoring ≥ 6 hours after initial dosing, and contraindication in patients with baseline heart rate < 55 bpm or history of atrioventricular block. Univariate logistic regression analysis To investigate the effects of age and gender on the adverse reaction of arrhythmia, a univariate logistic regression analysis was performed (Table 5 ). The analysis results showed that gender had no significant effect on the adverse reaction of arrhythmia caused by the four drugs. Except for ponesimod, the use of S1PRMs was more likely to cause arrhythmia adverse reactions with increasing age. This may be related to the fact that elderly individuals often have cardiovascular underlying diseases such as hypertension and coronary heart disease, as well as the situation of multiple drug combinations. Therefore, when administering medications to elderly patients, it is necessary to fully understand the patients' medical history, and active electrocardiogram monitoring of heart rate is required after drug administration. Table 5 logistic regression analysis Fingolimod Siponimod Ozanimod Ponesimod OR(CI%) P OR(CI%) P OR(CI%) P OR(CI%) P Age 1.26 (1.21,1.31) ๤0.001 1.17 (1.11,1.24) ๤0.001 1.26 (1.21,1.31) ๤0.001 1.09 (0.99,1.21) 0.077 Gender 0.50 (0.24,1.04) 0.064 1.28 (0.36,4.53) 0.704 0.50 (0.24,1.04) 0.064 0.91 (0.08.9.80) 0.939 Discussion Since fingolimod was approved by the U.S. Food and Drug Administration in 2010 as the first sphingosine-1-phosphate receptor modulator for the treatment of relapsed multiple sclerosis, the development of such novel therapeutic compounds has become a pharmacological target of great concern in clinical trial 16 , 17 . However, S1PR is expressed in a variety of body tissues to regulate multiple physiological and pathological cellular responses involving innate and adaptive immunity, cardiovascular and neurological functions. Due to their widespread expression in cardiomyocytes and vascular endothelial cells, drugs associated with S1PRMs can all produce certain cardiovascular effects. To alleviate this adverse reaction, selective second-generation S1PRMs were subsequently developed 11 . Nevertheless, similar cardiovascular adverse events were also observed in multiple sclerosis patients treated with siponimod, ozanimod and other second-generation drugs that reduce the binding of S1PR3. Most of the previous studies have focused on the exploration of the mechanism of adverse reactions. So there is a lack of adverse reaction studies from the real-world data. In this study, we identified 2,059 arrhythmia-related adverse events associated with S1PRMs, including 1,860 cases for fingolimod, 153 for siponimod, 38 for ozanimod, and 8 for ponesimod. The proportion of reports from women is higher, and the proportion of patients aged 18–65 is even greater. This may be related to the fact that the prevalence of multiple sclerosis varies by gender, with epidemiological studies finding a total ratio of 3:1 for women to men. In addition, the study described a high proportion of AEs in the United States (45.12%), United Kingdom (20.12%), Germany (6.31%), which may be related to the fact that is currently mainly listed in Western countries. Based on our statistical analysis, a total of 22 SMQs were affected by adverse events related to fingolimod, 14 to Siponimod , 10 and 8 to Ozanimod, Ponesimod, respectively . Two of the SMQs involved in all four drugs are haematopoietic leukopenia and tachyarrhythmia terms nonspecific. In this study, we investigated the adverse effects associated with arrhythmias caused by S1PRs in detail. The results showed that fingolimod has the strongest association with arrhythmia, while there was no significant difference in the association strength between selective second-generation S1PRMs and arrhythmia. The PTs with the highest signal value for fingolimod were bradycardia and first- and second-degree AV block. This is consistent with the adverse reactions observed in clinical trials 18 . After the first administration of fingolimod, the heart rate usually shows a brief decrease, with the lowest point typically occurring 4 to 5 hours after administration. The pooled data analysis of the phase III trial of fingolimod showed that only 0.6% of the patients had symptomatic bradycardia. The incidence of first-degree atrioventricular block was 4.7%, while the incidence of second-degree atrioventricular block (Mobitz type I) was lower, at 0.2% 19 . Five months after the marketing of fingolimod, a death case was reported. The deceased patient was 48 years old 20 . The autopsy results showed that ventricular arrhythmia was the main cause of death. Therefore, for those taking fingolimod for the first time, their vital signs and electrocardiograms should be closely observed. Studies have found that bradycardia occurs in 4.4% of users of siponimod. It is usually asymptomatic and resolves spontaneously within 24 hours without the need for intervention. The five-day dose escalation method can be adopted for the use of siponimod to alleviate the reducing effect of siponimod on heart rate in the initial stage of use. If the patient has no history of heart disease, there is no need for monitoring in a medical institution during treatment 9 , 21 . Ozanimod and ponesimod are relatively safe. The overall incidence of serious adverse events was low. No clinically significant cardiac conduction abnormalities were reported, but it could still cause a decrease in heart rate. To mitigate the impact on heart rate during the first administration, the same dose-escalation regimen could be used 22 , 23 . Furthermore, this study explored the impact of age and gender on adverse reactions to arrhythmia. The results of the univariate logistic regression analysis showed that gender did not significantly affect the adverse reactions of arrhythmia caused by the four drugs. Except for ponosimod, the risk of arrhythmia increased with age when using S1PRMs, possibly due to the presence of cardiovascular conditions such as hypertension and coronary heart disease, as well as the use of multiple medications. This suggests that clinicians should conduct a comprehensive assessment of potential risk factors before prescribing these drugs and closely monitor the patient's heart rate and blood pressure during treatment. Conclusion In summary, this study systematically analyzed the arrhythmia-related adverse event signals after the use of S1PRMs based on real-world data from FAERS. Through comprehensive studies, arrhythmia-related adverse reactions have been found to occur mainly in women and patients around 45 years of age. Fingolimod involves a relatively large number of PTs, and the new generation of S1PRMs has a shorter time to market than fingolimod, so it is necessary to conduct research through multi-dimensional real-world databases to further reveal its arrhythmia adverse events associated with multiple sclerosis. Declarations Acknowledgements This study was performed using the FAERS source that was provided by the FDA. The information, results, or interpretation of the current study do not represent any opinion of the FDA. Author contributions Pan Ma conceived the study; Siqi Wang collected the report; Xie Linli and Siqi Wang wrote the manuscript and edited the manuscript. All authors have approved publishment of the manuscript. Funding The work was supported by Chongqing Clinical Pharmacy Key Specialties Construction Project (425Z2M2). Data Availability Statement All information was obtained via the public FDA Adverse Event Reporting System database. DOI: 10.6084/m9.figshare.29900117 Declarations Conflict of interest The authors declare no conficts of interest. Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. References Marcus, R. (2022). What Is Multiple Sclerosis? Jama 328 (20), 2078. Oh, J., Vidal-Jordana, A., & Montalban, X. (2018). Multiple sclerosis: clinical aspects. Current opinion in neurology , 31 (6), 752–759. Koch-Henriksen, N., & Magyari, M. (2021). Apparent changes in the epidemiology and severity of multiple sclerosis. Nature reviews Neurology , 17 (11), 676–688. Yamout, B., Al-Jumah, M., Sahraian, M. A., Almalik, Y., Khaburi, J. A., Shalaby, N., Aljarallah, S., Bohlega, S., Dahdaleh, M., Almahdawi, A., Khoury, S. J., Koussa, S., Slassi, E., Daoudi, S., Aref, H., Mrabet, S., Zeineddine, M., Zakaria, M., Inshasi, J., Gouider, R., & Alroughani, R. (2024). 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Cohen, J. A., Arnold, D. L., Comi, G., Bar-Or, A., Gujrathi, S., Hartung, J. P., Cravets, M., Olson, A., Frohna, P. A., & Selmaj, K. W. (2016). Safety and efficacy of the selective sphingosine 1-phosphate receptor modulator ozanimod in relapsing multiple sclerosis (RADIANCE): a randomised, placebo-controlled, phase 2 trial. The Lancet Neurology , 15 (4), 373–381. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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14:48:54","extension":"xml","order_by":31,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":102514,"visible":true,"origin":"","legend":"","description":"","filename":"545ea1a6cddd4f95b9e06b39563b7bee1structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-7912836/v1/8975a1bf1e6debbb96a518ee.xml"},{"id":95845282,"identity":"9a2557ca-81e1-4f8f-9715-975c73142409","added_by":"auto","created_at":"2025-11-13 14:48:55","extension":"html","order_by":32,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":107705,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7912836/v1/c1e5776767ca6f7bc9c81192.html"},{"id":95845252,"identity":"2e4b6aad-e2b5-4971-8951-7abe20d6c4ab","added_by":"auto","created_at":"2025-11-13 14:48:54","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":186903,"visible":true,"origin":"","legend":"\u003cp\u003ePT level analysis of S1PRMs-associated arrhythmia (A. Fingolimod B. Siponimod C. Ozanimod D. Ponesimod)\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7912836/v1/cb5a877066edca7945129f78.png"},{"id":95845248,"identity":"8e25e9c4-ef0e-48ea-9a94-eaa8e2d29c35","added_by":"auto","created_at":"2025-11-13 14:48:54","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":75571,"visible":true,"origin":"","legend":"\u003cp\u003eHeatmap of S1PRMs-associated arrhythmia\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7912836/v1/599a5bb5c389f41401ae5534.png"},{"id":102298125,"identity":"6b519b21-0712-45ed-ab5c-554eb5e9491c","added_by":"auto","created_at":"2026-02-10 10:30:56","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1072745,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7912836/v1/e016f24b-40b4-4e9a-9076-8aa4126ee460.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Cardiac arrhythmias associated with S1RPMs: a pharmacovigilance study based on real-world data","fulltext":[{"header":"Introduction","content":"\u003cp\u003eMultiple sclerosis (MS) is an immune-mediated inflammatory demyelinating disease of central nervous system (CNS), characterized by dissemination in time and dissemination in space\u003csup\u003e\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. The etiology of MS is unknown, but Epstein-Barr virus infection, low serum vitamin D levels, insufficient sun exposure, smoking, and adolescent obesity may be risk factors for MS. Multiple sclerosis is prevalent in patients between the ages of 20 and 40 years, and is more common in women\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. According to the latest MS Atlas, a joint project of the International Multiple Sclerosis Federation and WHO, 2.8\u0026nbsp;million people worldwide suffered from MS. Since 2013, there has been an increase of 500,000 new cases of MS global. The prevalence and incidence of MS has been steadily increasing worldwide, including in the Middle East and North Africa (MENA) region, over the past few decades\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. The prevalence of MS varies according to geographic regions, with the highest incidence rates (111\u0026ndash;300 cases per 100,000 population) reported in the WHO European Region and the Americas\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eThere is no definitive cure for MS, but a number of disease-modifying therapies (DMTs) that primarily target the inflammatory milieu have been designed to reduce the rate of relapses and the accumulation of disability in patients with MS\u003csup\u003e6\u003c/sup\u003e. Sphingosine-1-phosphate receptor modulators (S1PRMs), a class of disease-modifying therapies (DMTs), are structurally similar to Sphingosine 1-phosphate (S1P). S1P is a biologically active soluble hemolytic phospholipid signaling molecule. Under normal homeostatic conditions, erythrocytes and endothelial cells are thought to be the major sources of S1P in plasma, whereas mast cells and platelets lead to a localized increase in S1P under noninflammatory and prethrombotic conditions\u003csup\u003e\u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. Sphingosine-1-phosphate receptors (S1PRs) are expressed throughout the body and mediate a wide range of biological functions. However, due to the widespread expression of S1PRs on cardiomyocytes and vascular endothelial cells, all drugs related to them will have some cardiovascular effects\u003csup\u003e\u003cspan additionalcitationids=\"CR10\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. Fingolimod, the first approved S1PRMs, non-selectively targets S1PR1, S1PR3, S1PR4 and S1PR5. Some arrhythmic adverse events (AEs) of fingolimod, such as atrioventricular block and sinus bradycardia, have been reported. In early clinical trials of fingolimod, it was found that patients experienced a transient decrease in mean measured heart rate 4\u0026ndash;5 h after the first dose of the drug\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. Since studies have shown that this cardiovascular effect may be mediated by transient agonism of S1PR1 or S1PR3, second-generation S1PRMs with low affinity for S1PR3 have been widely developed. However, similar cardiovascular AEs were observed in MS patients receiving siponimod, ozanimod, and other second-generation drugs that reduce S1PR3 binding\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e. Currently, for proved S1PRMs, 6 hours of continuous cardiac monitoring after the first dose is recommended to somewhat minimize these side effects\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. However, to date, there was few studies with data from the real world have elucidated the risk of arrhythmic adverse events in MS patients treated with S1PRMs. The FDA Adverse Drug Event Reporting System (FAERS), established in 2012, is one of the largest pharmacovigilance databases in the world, harboring a large number of drug-related AEs to monitor the safety of drugs once they reach the market. Therefore, this study utilized the FAERS database of S1PRMs-related arrhythmia adverse reactions using proportional imbalance method to provide a comprehensive and systematic study.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eData sources and procedures\u003c/h2\u003e\u003cp\u003eThis study is a retrospective, observational pharmacovigilance study using data from the FAERS database. The reports of S1PRMs-related adverse reactions submitted from the forth quarter of 2010 when the first approved S1PRM listed to the first quarter of 2024 were extracted from the FAERS database. FAERS was queried by using the generic names \u0026ldquo;fingolimod\u0026rdquo; \u0026ldquo;siponimod\u0026rdquo; ozanimod\u0026rdquo; and \u0026ldquo;ponesimod\u0026rdquo; with primary suspect, after removing duplicate reports (with the same ISR number), the reports were analyzed. Two researchers used SMQ-narrow and PTs to classify S1PRMs-related cardiac arrhythmias and extracted patient and drug information from reports.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003eData analysis\u003c/h2\u003e\u003cp\u003eStatistical analysis is based on the proportional imbalance method, we used the Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi Item Gamma Poisson Shrinker (MGPS) algorithm to study the association between drugs and a specific AE. The equations and criteria for these four algorithms are given in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eROR, PRR, BCPNN, and EBGM methods, formulas, and criterias\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"3\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAlgorithms\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCalculation formula\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCriteria\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eROR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cspan class=\"InlineEquation\"\u003e\u003c/span\u003e\u003cspan class=\"InlineEquation\"\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(1) a\u0026thinsp;\u0026ge;\u0026thinsp;3\u003c/p\u003e\u003cp\u003e(2) 95%CI\u0026thinsp;\u0026gt;\u0026thinsp;1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePRR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cspan class=\"InlineEquation\"\u003e\u003c/span\u003e\u003cspan class=\"InlineEquation\"\u003e\u003c/span\u003e\u003c/p\u003e\u003cp\u003en\u0026thinsp;=\u0026thinsp;a\u0026thinsp;+\u0026thinsp;b\u0026thinsp;+\u0026thinsp;c\u0026thinsp;+\u0026thinsp;d\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(1)\u003cspan class=\"InlineEquation\"\u003e\u003c/span\u003e\u003c/p\u003e\u003cp\u003e(2) PRR\u0026thinsp;\u0026ge;\u0026thinsp;2\u003c/p\u003e\u003cp\u003e(3)\u003cspan class=\"InlineEquation\"\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eBCPNN\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cspan class=\"InlineEquation\"\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(1) a\u0026thinsp;\u0026ge;\u0026thinsp;3\u003c/p\u003e\u003cp\u003e(2) IC-2SD\u0026thinsp;\u0026gt;\u0026thinsp;0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003e\u003cspan class=\"InlineEquation\"\u003e\u003c/span\u003e\u003cspan class=\"InlineEquation\"\u003e\u003c/span\u003e\u003cspan class=\"InlineEquation\"\u003e\u003c/span\u003e\u003cspan class=\"InlineEquation\"\u003e\u003c/span\u003e\u003cspan class=\"InlineEquation\"\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eEBGM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eEBGM=\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:\\frac{a\\left(a+b+c+d\\right)}{\\left(a+b\\right)\\left(a+c\\right)}\\)\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003cp\u003e\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:95\\text{\\%}\\text{C}\\text{I}={\\text{e}}^{\\text{l}\\text{n}\\left(\\text{E}\\text{B}\\text{G}\\text{M}\\right)\\pm\\:1.96\\sqrt{(\\frac{1}{\\text{a}}+\\frac{1}{\\text{b}}+\\frac{1}{\\text{c}}+\\frac{1}{\\text{d}})}}\\)\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eEBGM05\u0026gt;2\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003eAll data were analysed using IBM\u0026reg; SPSS\u0026reg; statistical software. p-value less than 0.05 was considered statistically significant.\u003c/p\u003e\u003c/div\u003e"},{"header":"Results and Discussion","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\u003ch2\u003eDescriptive analysis\u003c/h2\u003e\u003cp\u003eWe extracted all reported cases from the FAERS database, after deduplication and screening totaling 2059 cases of S1PRMs-related cardiac arrhythmias were reported, 1860 of Fingolimod, 153 of Siponimod, 38 of Ozanimod, 8 of Ponesimod. In this study, the reported data were analysed, and the demographic characteristics of the AEs associated are shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. Among the adverse events reported, the proportion of women was slightly higher than that of men. In terms of age distribution, although the proportion of patients with unknown age reached 30.69%, the highest proportion of AEs was in the age group of 18\u0026ndash;65 years (64.50%). The median age of the four drugs was 45, 56, 43, 60. The country with the most reports is the United States (45.12%), followed by the United Kingdom(20.12%), Germany (6.31%), Canada(2.78%), etc. The number of cases peaked in 2018 with fingolimod. A total of 282 serious adverse events were mainly reported by fingolimod, including 5 deaths, 257 hospitalization-initial or prolonged, and 18 life-threatening.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eClinical characteristics of reports with S1PRMs-related cardiac arrhythmias from the FAERS database\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colspan=\"4\" nameend=\"c5\" namest=\"c2\"\u003e\u003cp\u003eReports\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003echaracteristics\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eFingolimod\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eSiponimod\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eOzanimod\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003ePonesimod\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eN\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1860\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e153\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e38\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026lt;18\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e44\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e18\u0026ndash;65\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1197\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e101\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e27\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026gt;65\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e35\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e19\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMissing\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e584\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e33\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGender\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFemale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1302\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e103\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e25\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e440\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e44\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMissing\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e118\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCountry of the reporter\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUnited States\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e655\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e121\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e38\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUnited Kingdom\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGermany\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e96\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCanada\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e62\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eReported years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2010\u0026ndash;2015\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e493\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2016\u0026ndash;2020\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1067\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e49\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2020\u0026ndash;2024\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e300\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e104\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e38\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOutcomes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDeath\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHospitalization-Initial or Prolonged\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e257\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLife-Threatening\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e18\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDisability\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOther\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eStandardized signal detection\u003c/h2\u003e\u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e shows the signal intensity of S1PRMs-associated AEs classified by SMQ. Based on our statistical analysis, a total of 22 Standardised MedDRA Queries (SMQ) were affected by adverse events related to fingolimod, 14 by Siponimod, 10 by Ozanimod and 8 by Ponesimod, respectively. Two of the SMQs involved in all four drugs are haematopoietic leukopenia and tachyarrhythmia, term nonspecific. In this study, adverse reactions related to arrhythmias are highlighted \u003cb\u003e(\u003c/b\u003eTable\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Based on our statistical analysis, fingolimod was most strongly associated with the occurrence of adverse arrhythmias, which may be related to its poor selectivity for S1PR receptors. Fingolimod non-selectively targets S1PR1, S1PR3, S1PR4 and S1PR5, and is widely expressed in cardiomyocytes and vascular endothelial cells.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eROR of S1PRMs-associated SMQ\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSMQ\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eFingolimod\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eSiponimod\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eOzanimod\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003ePonesimod\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eskin premalignant disorders\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3.70(3.58)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.98(2.57)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eoptic nerve disorders\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3.27(3.17)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003egastrointestinal premalignant disorders\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2.62(2.43)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003egastrointestinal ulceration\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2.01(1.91)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ehaematopoietic leukopenia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.56(2.53)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.39(2.38)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.46(1.30)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.00(0.21)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eskin tumours of unspecified malignancy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.28(1.81)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.27(2.04)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003econditions associated with central nervous system haemorrhages and cerebrovascular accidents\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.48(2.37)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.93(1.55)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eoptic nerve disorders\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.17(1.79)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.44(0.88)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ereproductive premalignant disorders\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.38(1.81)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003edisorders of sinus node function\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.39(2.23)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eretinal disorders\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.20(2.13)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.72(1.49)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eimmune-mediated/autoimmune disorders\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.89(1.86)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.67(1.58)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2.01(1.91)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ebreast tumours of unspecified malignancy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.68(1.03)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eskin malignant tumours\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.94(1.85)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.39(0.27)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eliver related investigations signs and symptoms\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.73(1.68)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003evestibular disorders\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.75(1.65)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.45(1.13)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003econduction defects\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.75(1.66)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.09(0.77)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003etachyarrhythmia terms nonspecific\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.43(1.21)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.45(0.86)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.69(1.09)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.28(0.16)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ehypertension\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.59(1.46)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.04(0.85)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003enoninfectious meningitis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.43(1.21)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eocular motility disorders\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.43(1.26)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003euterine and fallopian tube malignant tumours\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.23(1.02)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003edepression (excl suicide and self injury)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.17(1.12)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003enoninfectious encephalitis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.02(0.69)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eliver neoplasms benign (incl cysts and polyps)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.98(0.53)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.11(0.94)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003egastrointestinal nonspecific inflammation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.96(0.57)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.57(0.79)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ecOVID-19\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.35(2.21)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.61(1.42)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.57(0.79)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003einterstitial lung disease\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.03(0.10)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eComparison of the Constituent Ratio of Caused arrhythmias by S1PRMs\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"6\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCase number\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eROR (95%CI)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePRR (χ\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eIC(IC\u003csub\u003e025\u003c/sub\u003e)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eEBGM(EBGM\u003csub\u003e05\u003c/sub\u003e)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFingolimod\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e350\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e4.11(3.70,4.57)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e4.05(800.69)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e2.00(1.87)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e4.03(3.93)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSiponimod\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e3.18(1.95,5.20)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e3.18(21.72)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1.45(0.86)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e3.17(2.68)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOzanimod\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e3.97(2.39,6.60)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e3.96(3.27)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1.69(1.09)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e3.96(3.45)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePonesimod\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e6.40(2.64,15.53)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e6.29(17.32)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1.62(0.59)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e6.29(5.40)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003ePT level signal detection\u003c/h3\u003e\n\u003cp\u003eFigure\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e shows the PTs for each S1PRMs. Fingolimod involves 30 PTs, with higher signal values primarily including electrocardiogram PR shortened (ROR\u0026thinsp;=\u0026thinsp;30.54, 95% CI\u0026thinsp;=\u0026thinsp;20.45, 45.62), heart rate decreased (ROR\u0026thinsp;=\u0026thinsp;21.39, 95% CI\u0026thinsp;=\u0026thinsp;20.47, 22.34), atrioventricular block first degree (ROR\u0026thinsp;=\u0026thinsp;21.30, 95% CI\u0026thinsp;=\u0026thinsp;18.97, 23.93), atrioventricular block second degree (ROR\u0026thinsp;=\u0026thinsp;18.85, 95% CI\u0026thinsp;=\u0026thinsp;16.16, 21.98), electrocardiogram PR prolongation (ROR\u0026thinsp;=\u0026thinsp;13.04, 95% = 9.06, 18.79), and sinus arrhythmia (ROR\u0026thinsp;=\u0026thinsp;10.76, 95% CI\u0026thinsp;=\u0026thinsp;8.18, 14.17). Siponimod was associated with 7 PTs including atrioventricular block first degree (ROR\u0026thinsp;=\u0026thinsp;24.23, 95% = 18.04, 32.55), heart rate decreased (ROR\u0026thinsp;=\u0026thinsp;20.77, 95% = 18.41, 20.77), cardiac flutter (ROR\u0026thinsp;=\u0026thinsp;7.65, 95% = 4.87, 12.02), extrasystoles (ROR\u0026thinsp;=\u0026thinsp;4.68, 95% = 2.72, 8.07). Ozanimod demonstrated 4 PTs involved cardiac flutter (ROR\u0026thinsp;=\u0026thinsp;9.38, 95% = 5.44, 16.17), heart rate decreased (ROR\u0026thinsp;=\u0026thinsp;7.35, 95% = 5.65, 9.57), heart rate abnormal (ROR\u0026thinsp;=\u0026thinsp;3.59, 95% = 1.35, 9.58), and palpitations (ROR\u0026thinsp;=\u0026thinsp;2.36, 95% = 1.82,3.05). Ponesimod has 4 PTs heart rate decreased (ROR\u0026thinsp;=\u0026thinsp;8.85, 95% = 2.83, 27.67), arrhythmia (ROR\u0026thinsp;=\u0026thinsp;7.99, 95% = 2.979, 21.48), palpitations(ROR\u0026thinsp;=\u0026thinsp;3.62, 95% = 1.34, 9.72), and loss of consciousness (ROR\u0026thinsp;=\u0026thinsp;3.24 (1.21,8.72). Notably, all four S1PRMs exhibited significant heart rate decreased (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e), consistent with the results of previous RCT (Randomized Controlled Trial) experiments. Based on these findings, clinical guidelines emphasize stringent electrocardiographic monitoring protocols during treatment initiation, including baseline ECG evaluation (focusing on PR interval and QTc duration), continuous cardiac monitoring\u0026thinsp;\u0026ge;\u0026thinsp;6 hours after initial dosing, and contraindication in patients with baseline heart rate\u0026thinsp;\u0026lt;\u0026thinsp;55 bpm or history of atrioventricular block.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\n\u003ch3\u003eUnivariate logistic regression analysis\u003c/h3\u003e\n\u003cp\u003eTo investigate the effects of age and gender on the adverse reaction of arrhythmia, a univariate logistic regression analysis was performed (Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e). The analysis results showed that gender had no significant effect on the adverse reaction of arrhythmia caused by the four drugs. Except for ponesimod, the use of S1PRMs was more likely to cause arrhythmia adverse reactions with increasing age. This may be related to the fact that elderly individuals often have cardiovascular underlying diseases such as hypertension and coronary heart disease, as well as the situation of multiple drug combinations. Therefore, when administering medications to elderly patients, it is necessary to fully understand the patients' medical history, and active electrocardiogram monitoring of heart rate is required after drug administration.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003elogistic regression analysis\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"9\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eFingolimod\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003eSiponimod\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003eOzanimod\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e\u003cp\u003ePonesimod\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eOR(CI%)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eP\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eOR(CI%)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eP\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eOR(CI%)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eP\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eOR(CI%)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eP\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.26\u003c/p\u003e\u003cp\u003e(1.21,1.31)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e๤0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.17\u003c/p\u003e\u003cp\u003e(1.11,1.24)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e๤0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1.26\u003c/p\u003e\u003cp\u003e(1.21,1.31)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e๤0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e1.09\u003c/p\u003e\u003cp\u003e(0.99,1.21)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0.077\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGender\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.50\u003c/p\u003e\u003cp\u003e(0.24,1.04)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.064\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.28\u003c/p\u003e\u003cp\u003e(0.36,4.53)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.704\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.50\u003c/p\u003e\u003cp\u003e(0.24,1.04)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.064\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.91\u003c/p\u003e\u003cp\u003e(0.08.9.80)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0.939\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eSince fingolimod was approved by the U.S. Food and Drug Administration in 2010 as the first sphingosine-1-phosphate receptor modulator for the treatment of relapsed multiple sclerosis, the development of such novel therapeutic compounds has become a pharmacological target of great concern in clinical trial\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. However, S1PR is expressed in a variety of body tissues to regulate multiple physiological and pathological cellular responses involving innate and adaptive immunity, cardiovascular and neurological functions. Due to their widespread expression in cardiomyocytes and vascular endothelial cells, drugs associated with S1PRMs can all produce certain cardiovascular effects. To alleviate this adverse reaction, selective second-generation S1PRMs were subsequently developed\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. Nevertheless, similar cardiovascular adverse events were also observed in multiple sclerosis patients treated with siponimod, ozanimod and other second-generation drugs that reduce the binding of S1PR3.\u003c/p\u003e\u003cp\u003eMost of the previous studies have focused on the exploration of the mechanism of adverse reactions. So there is a lack of adverse reaction studies from the real-world data. In this study, we identified 2,059 arrhythmia-related adverse events associated with S1PRMs, including 1,860 cases for fingolimod, 153 for siponimod, 38 for ozanimod, and 8 for ponesimod. The proportion of reports from women is higher, and the proportion of patients aged 18\u0026ndash;65 is even greater. This may be related to the fact that the prevalence of multiple sclerosis varies by gender, with epidemiological studies finding a total ratio of 3:1 for women to men. In addition, the study described a high proportion of AEs in the United States (45.12%), United Kingdom (20.12%), Germany (6.31%), which may be related to the fact that is currently mainly listed in Western countries.\u003c/p\u003e\u003cp\u003eBased on our statistical analysis, a total of 22 SMQs were affected by adverse events related to fingolimod, 14 to \u003cb\u003eSiponimod\u003c/b\u003e, 10 and 8 to \u003cb\u003eOzanimod, Ponesimod, respectively\u003c/b\u003e. Two of the SMQs involved in all four drugs are haematopoietic leukopenia and tachyarrhythmia terms nonspecific. In this study, we investigated the adverse effects associated with arrhythmias caused by S1PRs in detail. The results showed that fingolimod has the strongest association with arrhythmia, while there was no significant difference in the association strength between selective second-generation S1PRMs and arrhythmia. The PTs with the highest signal value for fingolimod were bradycardia and first- and second-degree AV block. This is consistent with the adverse reactions observed in clinical trials\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eAfter the first administration of fingolimod, the heart rate usually shows a brief decrease, with the lowest point typically occurring 4 to 5 hours after administration. The pooled data analysis of the phase III trial of fingolimod showed that only 0.6% of the patients had symptomatic bradycardia. The incidence of first-degree atrioventricular block was 4.7%, while the incidence of second-degree atrioventricular block (Mobitz type I) was lower, at 0.2%\u003csup\u003e19\u003c/sup\u003e. Five months after the marketing of fingolimod, a death case was reported. The deceased patient was 48 years old\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e. The autopsy results showed that ventricular arrhythmia was the main cause of death. Therefore, for those taking fingolimod for the first time, their vital signs and electrocardiograms should be closely observed. Studies have found that bradycardia occurs in 4.4% of users of siponimod. It is usually asymptomatic and resolves spontaneously within 24 hours without the need for intervention. The five-day dose escalation method can be adopted for the use of siponimod to alleviate the reducing effect of siponimod on heart rate in the initial stage of use. If the patient has no history of heart disease, there is no need for monitoring in a medical institution during treatment\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e. Ozanimod and ponesimod are relatively safe. The overall incidence of serious adverse events was low. No clinically significant cardiac conduction abnormalities were reported, but it could still cause a decrease in heart rate. To mitigate the impact on heart rate during the first administration, the same dose-escalation regimen could be used\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eFurthermore, this study explored the impact of age and gender on adverse reactions to arrhythmia. The results of the univariate logistic regression analysis showed that gender did not significantly affect the adverse reactions of arrhythmia caused by the four drugs. Except for ponosimod, the risk of arrhythmia increased with age when using S1PRMs, possibly due to the presence of cardiovascular conditions such as hypertension and coronary heart disease, as well as the use of multiple medications. This suggests that clinicians should conduct a comprehensive assessment of potential risk factors before prescribing these drugs and closely monitor the patient's heart rate and blood pressure during treatment.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn summary, this study systematically analyzed the arrhythmia-related adverse event signals after the use of S1PRMs based on real-world data from FAERS. Through comprehensive studies, arrhythmia-related adverse reactions have been found to occur mainly in women and patients around 45 years of age. Fingolimod involves a relatively large number of PTs, and the new generation of S1PRMs has a shorter time to market than fingolimod, so it is necessary to conduct research through multi-dimensional real-world databases to further reveal its arrhythmia adverse events associated with multiple sclerosis.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was performed using the FAERS source that was provided by the FDA. The information, results, or interpretation of the current study do not represent any opinion of the FDA.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePan Ma conceived the study; Siqi Wang collected the report; Xie Linli and Siqi Wang wrote the manuscript and edited the manuscript. All authors have approved publishment of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe work was supported by Chongqing Clinical Pharmacy Key Specialties Construction Project (425Z2M2).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll information was obtained via the public FDA Adverse Event Reporting System database. DOI: 10.6084/m9.figshare.29900117\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclarations Conflict of interest\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no conficts of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e Not applicable.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u0026nbsp;\u003c/strong\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eMarcus, R. (2022). What Is Multiple Sclerosis? \u003cem\u003eJama 328\u003c/em\u003e (20), 2078.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eOh, J., Vidal-Jordana, A., \u0026amp; Montalban, X. (2018). 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T., Zhang-Auberson, L., Tang, D., Collins, W., \u0026amp; Kappos, L. (2014). First-dose effects of fingolimod: Pooled safety data from three phase 3 studies. \u003cem\u003eMultiple Sclerosis and Related Disorders\u003c/em\u003e, \u003cem\u003e3\u003c/em\u003e(5), 629\u0026ndash;638.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAbdar, M., Ebrahimifar, P., \u0026amp; Etemadifar, M. (2016). The outbreak fingolimod cardiovascular side effects in relapsing-remitting multiple sclerosis patient: A longitudinal study in an Iranian population. \u003cem\u003eARYA atherosclerosis\u003c/em\u003e, \u003cem\u003e12\u003c/em\u003e(6), 274\u0026ndash;280.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKappos, L., Radue, E. W., O'Connor, P., Polman, C., Hohlfeld, R., Calabresi, P., Selmaj, K., Agoropoulou, C., Leyk, M., Zhang-Auberson, L., \u0026amp; Burtin, P. (2010). 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Safety and efficacy of the selective sphingosine 1-phosphate receptor modulator ozanimod in relapsing multiple sclerosis (RADIANCE): a randomised, placebo-controlled, phase 2 trial. \u003cem\u003eThe Lancet Neurology\u003c/em\u003e, \u003cem\u003e15\u003c/em\u003e(4), 373\u0026ndash;381.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"S1PRMs, Cardiac arrhythmias, FAERS, Signal detection, Drug safety","lastPublishedDoi":"10.21203/rs.3.rs-7912836/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7912836/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003eBackground\u003c/b\u003e Sphingosine-1-phosphate receptor modulators (S1PRMs) are an effective class of disease-modifying therapies (DMTs) for the treatment of multiple sclerosis (MS). But its clinical application is limited due to its adverse reactions.\u003c/p\u003e\u003cp\u003e\u003cb\u003eMethods\u003c/b\u003e In this study we mined cardiac arrhythmias adverse event signals of S1PRMs based on the Food and Drug Administration Adverse Event Reporting System (FAERS) from the first quarter of 2004 to the first quarter of 2024, using the Reported Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confdence Propagation Neural Network (BCPNN) and Multi-item Gamma Poisson Shrinker (MGPS) methods to provide a reference for the safe clinical use of the drug.\u003c/p\u003e\u003cp\u003e\u003cb\u003eResults\u003c/b\u003e We identified 2,059 arrhythmia-related adverse events associated with S1PRMs, including 1,860 cases for fingolimod, 153 for siponimod, 38 for ozanimod, and 8 for ponesimod. Patients aged 18\u0026ndash;65 and female patients were at a higher risk. High risk signals in the report include heart rate decreased, cardiac flutter, extrasystoles.\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusion\u003c/b\u003e Mining the adverse reaction signal study of S1PRMs based on the FAERS database provides some support for the clinical monitoring and risk identification of this drug.\u003c/p\u003e","manuscriptTitle":"Cardiac arrhythmias associated with S1RPMs: a pharmacovigilance study based on real-world data","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-13 14:48:49","doi":"10.21203/rs.3.rs-7912836/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"69db56a1-c9d9-42a9-a163-71d30eee6081","owner":[],"postedDate":"November 13th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-02-10T02:23:44+00:00","versionOfRecord":[],"versionCreatedAt":"2025-11-13 14:48:49","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7912836","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7912836","identity":"rs-7912836","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}