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• Cardiovascular risk factors are undertreated in ORAL Surveillance trial
  Andrea D'Amuri, Piero Ruscitti and Francesco Ursini
  Published on: 25 March 2023
• Cardiovascular risk with tofacitinib in Rheumatoid Arthritis: the clinical relevance of atherosclerotic cardiovascular disease on treatment decisions.
  Fabio Cacciapaglia, Fabrizio Conti, Cristina Garufi, Vincenzo Venerito, Florenzo Iannone and Francesca Romana Spinelli
  Published on: 3 January 2023

• Published on: 25 March 2023

  Cardiovascular risk factors are undertreated in ORAL Surveillance trial

  • Andrea D'Amuri, Internal Medicine Specialist 1. General Medicine Unit, Medical Department, Azienda Ospedaliera Carlo Poma, Mantova, Italy.
  • Other Contributors:
    • Piero Ruscitti, Senior researcher
    • Francesco Ursini, Associate Professor

  Dear Editor,
  We read with great interest the article by Christina Charles-Schoeman et al. recently published in Annals of the Rheumatic Diseases, reporting the results of a post-hoc analysis of the ORAL Surveillance trial . As it is widely known to the rheumatology community, ORAL surveillance failed to demonstrate noninferiority of tofacitinib versus TNF inhibitors (TNFi) with relation to the risk of major adverse cardiovascular events (MACE) and cancer in a population of rheumatoid arthritis (RA) patients enriched for baseline cardiovascular disease (CVD) risk factors.
  In their analysis, Charles-Schoeman et al.1 stratified ORAL Surveillance participants in two main cohorts, with and without a past history of atherosclerotic cardiovascular disease (ASCVD), respectively; the latter cohort was further categorized in incremental CVD risk classes according to the ASCVD pooled cohort equations (PCE). Compared to TNFi, the risk of MACE in tofacitinib recipients at the dose currently licensed for RA (5 mg two-times-per-day) was significantly higher only in patients with a history of ASCVD (HR (95% CI): 1.96 (0.87 to 4.40)), while no statistical difference in MACE occurrence was evident in patients with no history of ASCVD, regardless the estimated 10-year ASCVD risk.
  Besides providing a better description of the subpopulation of patients who may experience a clear increase in CVD risk, this stratification revealed some interesting clues that, in our opinion, d...

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  Dear Editor,
  We read with great interest the article by Christina Charles-Schoeman et al. recently published in Annals of the Rheumatic Diseases, reporting the results of a post-hoc analysis of the ORAL Surveillance trial . As it is widely known to the rheumatology community, ORAL surveillance failed to demonstrate noninferiority of tofacitinib versus TNF inhibitors (TNFi) with relation to the risk of major adverse cardiovascular events (MACE) and cancer in a population of rheumatoid arthritis (RA) patients enriched for baseline cardiovascular disease (CVD) risk factors.
  In their analysis, Charles-Schoeman et al.1 stratified ORAL Surveillance participants in two main cohorts, with and without a past history of atherosclerotic cardiovascular disease (ASCVD), respectively; the latter cohort was further categorized in incremental CVD risk classes according to the ASCVD pooled cohort equations (PCE). Compared to TNFi, the risk of MACE in tofacitinib recipients at the dose currently licensed for RA (5 mg two-times-per-day) was significantly higher only in patients with a history of ASCVD (HR (95% CI): 1.96 (0.87 to 4.40)), while no statistical difference in MACE occurrence was evident in patients with no history of ASCVD, regardless the estimated 10-year ASCVD risk.
  Besides providing a better description of the subpopulation of patients who may experience a clear increase in CVD risk, this stratification revealed some interesting clues that, in our opinion, deserve further consideration.
  As shown in Table 2 of the article, only about 50% of patients with a history of ASCVD events were treated with antiplatelet (53.9% in tofacitinib 5 mg, 55.9% in tofacitinib 10 mg, and 50.0% in TNFi) or lipid lowering therapy (52.5% in tofacitinib 5 mg, 57.2% in tofacitinib 10 mg, and 49.1% in TNFi).
  This percentage is surprisingly low, especially in the light of the well documented tofacitinib-induced rise in cholesterol levels . Additionally, it appears contrasting with the most recent guidelines for secondary prevention of cardiovascular events , which urge treatment for all patients with a history of ASCVD.
  Even though weak adherence is a common issue with cardioprotective molecules, large studies from the general population reveal that 75–85% - and 85–90%5-6 of individuals with prior cardiovascular events are treated with lipid lowering or antiplatelet drugs, respectively.
  From the rheumatology perspective, despite the European Alliance of Associations for Rheumatology (EULAR) published its first set of recommendations 15 years ago , the management of CVD risk in inflammatory arthritis patients remains largely suboptimal as demonstrated in different studies - .
  It is already widely acknowledged that inflammation in RA patients represents a driver of accelerated atherogenesis and, accordingly, the main focus of treatment is reducing disease activity in the expectation that this may significantly ameliorate cardiovascular outcomes. However, excessive emphasis on this aspect carries the danger of neglecting the role of traditional CVD risk factors, estimated to contribute for 70% of the overall risk. In this contest, even assuming an unequivocal causal effect between tofacitinib (or other Janus kinase inhibitors, JAKi) exposure and the development of MACE, many cardiovascular events could still be prevented by improving the global CVD risk control.
  In conclusion, the findings of this post-hoc analysis of the ORAL surveillance trial could be read under a different light: the compelling need to really implement appropriate cardiovascular therapy in RA patients. In this scenario, even if confirmed in subsequent research, effective management of CVD risk factors may, at least in part, counterbalance the additional risk conferred by JAKi.

  1 Charles-Schoeman C, Buch MH, Dougados M, et al. Risk of major adverse cardiovascular events with tofacitinib versus tumour necrosis factor inhibitors in patients with rheumatoid arthritis with or without a history of atherosclerotic cardiovascular disease: a post hoc analysis from ORAL Surveillance. Ann Rheum Dis 2023; 82: 119-129.
  2 Ytterberg SR, Bhatt DL, Mikuls TR, et al. Cardiovascular and cancer risk with tofacitinib in rheumatoid arthritis. N Eng J Med 2022; 386:316-326.
  3 Souto A, Salgado E, Maneiro JR, et al. Lipid profile changes in patients with chronic inflammatory arthritis treated with biologic agents and tofacitinib in randomized clinical trials: a systematic review and meta‐analysis. Arthritis Rheumato, 2015;67:117-127
  4 Visseren FL, Mach F, Smulders YM, et al. 2021 ESC Guidelines on cardiovascular disease prevention in clinical practice: Developed by the Task Force for cardiovascular disease prevention in clinical practice with representatives of the European Society of Cardiology and 12 medical societies With the special contribution of the European Association of Preventive Cardiology (EAPC). Eu Heart J 2021; 42:3227-3337.
  5 Cannon CP, Rhee KE, Califf RM, et al. Current use of aspirin and antithrombotic agents in the United States among outpatients with atherothrombotic disease (from the REduction of Atherothrombosis for Continued Health [REACH] Registry). Am J Cardiol 2010;105:445-452.
  6 Kotseva K, Wood D, De Bacquer D, et al. EUROASPIRE IV: A European Society of Cardiology survey on the lifestyle, risk factor and therapeutic management of coronary patients from 24 European countries. Eur J Prev Cardiol 2016;23: 636-648.
  7 Peters MJL, Symmons DPM, McCarey D, et al. EULAR evidence-based recommendations for cardiovascular risk management in patients with rheumatoid arthritis and other forms of inflammatory arthriti. Ann Rheum Dis 2010;69: 325-331.
  8 van Breukelen-van der Stoep DF, van Zeben D, Klop B, et al. Marked underdiagnosis and undertreatment of hypertension and hypercholesterolaemia in rheumatoid arthritis. Rheumatology 2016;55: 1210-1216.
  9 van den Oever IA, Heslinga M, Griep EN, et al. Cardiovascular risk management in rheumatoid arthritis patients still suboptimal: the Implementation of Cardiovascular Risk Management in Rheumatoid Arthritis project. Rheumatology 2017;56:1472-1478.

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  Conflict of Interest:
  None declared.

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• Published on: 3 January 2023

  Cardiovascular risk with tofacitinib in Rheumatoid Arthritis: the clinical relevance of atherosclerotic cardiovascular disease on treatment decisions.

  • Fabio Cacciapaglia, rheumatologist Rheumatology Unit - University of Bari, Bari - Italy
  • Other Contributors:
    • Fabrizio Conti, full professor of rheumatology
    • Cristina Garufi, rheumatologist
    • Vincenzo Venerito, rheumatologist
    • Florenzo Iannone, full professor of rheumatology
    • Francesca Romana Spinelli, rheumatologist

  On October 28th, the European Medicine Agency extended to the entire class of Janus Kinase inhibitors (JAKi) the recommendation to use a JAKi only if no suitable therapeutic alternatives are available in patients older than 65 years, those at increased risk of MACE, and those who smoke or have smoked extensively in the past [1].
  The ORAL surveillance would have shown that patients with active rheumatoid arthritis (RA) aged ≥50 years and with at least one additional cardiovascular (CV) risk factor (current smoker, hypertension, low high-density lipoprotein cholesterol, diabetes mellitus, family history of premature coronary heart disease, extra-articular rheumatoid arthritis, or history of coronary artery disease) had an increased risk of major adverse cardiovascular events (MACE) with tofacitinib versus tumour necrosis factor inhibitors (TNFi) [2]. In the ORAL Surveillance not all risk factors were well balanced between the tofacitinib and TNFi arms, i.e, unstable angina was more prevalent in patients taking tofacitinib 5 mg than in those on TNFi (17/1438 vs 7/1444, respectively; Chi-square=4.174, p=0.04), as reported in the Table S2 of the main study [2]. This bias presumably influenced the higher rate of MACE observed in the tofacitinib group. Therefore, we were not surprised that the post-hoc analysis published by Charles-Schoemann et al showed that the difference between tofacitinib and TNFi in the risk of MACE was primarily seen in patients with a history of...

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  On October 28th, the European Medicine Agency extended to the entire class of Janus Kinase inhibitors (JAKi) the recommendation to use a JAKi only if no suitable therapeutic alternatives are available in patients older than 65 years, those at increased risk of MACE, and those who smoke or have smoked extensively in the past [1].
  The ORAL surveillance would have shown that patients with active rheumatoid arthritis (RA) aged ≥50 years and with at least one additional cardiovascular (CV) risk factor (current smoker, hypertension, low high-density lipoprotein cholesterol, diabetes mellitus, family history of premature coronary heart disease, extra-articular rheumatoid arthritis, or history of coronary artery disease) had an increased risk of major adverse cardiovascular events (MACE) with tofacitinib versus tumour necrosis factor inhibitors (TNFi) [2]. In the ORAL Surveillance not all risk factors were well balanced between the tofacitinib and TNFi arms, i.e, unstable angina was more prevalent in patients taking tofacitinib 5 mg than in those on TNFi (17/1438 vs 7/1444, respectively; Chi-square=4.174, p=0.04), as reported in the Table S2 of the main study [2]. This bias presumably influenced the higher rate of MACE observed in the tofacitinib group. Therefore, we were not surprised that the post-hoc analysis published by Charles-Schoemann et al showed that the difference between tofacitinib and TNFi in the risk of MACE was primarily seen in patients with a history of atherosclerotic cardiovascular disease (ASCVD), representing nearly 15% of the enrolled population [3]. Moreover, the post-hoc analysis clarifies that, despite the small number of events in the population at lower risk, there was no difference among treatment arms in patients with a high, intermediate, or low 10-year risk of CV events [3], rather highlighting the greater clinical relevance of a history of coronary artery disease (CAD), defined as myocardial infarction and unstable angina. Overall, the distribution of CV risk factors in patients enrolled in the ORAL Surveillance was significantly different in North American patients compared to those from other geographic areas, the former being significantly older, more frequently males, smokers, overweight/obese, with a higher prevalence of diabetes, hypertension, dyslipidemia (table S4 of the main study [2]): a significantly more pronounced CV risk profile in North Americans may account for their higher incidence rates of MACE [2]. Other populations, underrepresented in the study, may have a different risk profile that should be considered when prescribing tofacitinib [4].
  The results of the post hoc analysis pointed out that the history of MI or unstable angina acquires the highest relevance in the therapeutic choice of a Janus Kinase inhibitors (JAKi) [3].
  Thus, the results of the ORAL Surveillance study should be contextualized since they represent a breakthrough in the worldwide use of JAKi, a valuable treatment option for many patients with RA and other autoimmune and inflammatory diseases.
  The ongoing update of the 2019 EULAR recommendations for RA management [5], no longer putting biologic-DMARDs and JAKi on the same level, will suggest considering the latter only after considering pertinent risk factors (age over 65 years, current or past smoking history, other CV risk factors as well as risk factors for malignancies and thromboembolic events).
  This emphasizes the importance of assessing the overall CV risk rather than each individual risk factor in the treatment strategy of RA patients, and according to EULAR recommendations for CV risk management in patients with inflammatory arthritis [6], rheumatologists should be confident with CV risk stratification in their clinical practice.

  References
  1. https://www.ema.europa.eu/en/news/ema-recommends-measures-minimise-risk-...
  2. Ytterberg SR, Bhatt DL, Mikuls TR, et al. ORAL Surveillance Investigators. Cardiovascular and Cancer Risk with Tofacitinib in Rheumatoid Arthritis. N Engl J Med 2022; 386: 316-26.
  3. Charles-Schoeman C, Buch MH, Dougados M, et al. Risk of major adverse cardiovascular events with tofacitinib versus tumour necrosis factor inhibitors in patients with rheumatoid arthritis with or without a history of atherosclerotic cardiovascular disease: a post hoc analysis from ORAL Surveillance. Ann Rheum Dis 2022 Sep 22:annrheumdis-2022-222259.
  4. Cacciapaglia F, Spinelli FR, Piga M, et al. Estimated 10-year cardiovascular risk in a large Italian cohort of rheumatoid arthritis patients: Data from the Cardiovascular Obesity and Rheumatic DISease (CORDIS) Study Group. Eur J Intern Med 2022;96:60-5.
  5. Smolen JS, Landewé RBM, Bergstra SA, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2022 update. Ann Rheum Dis. 2022 Nov 10:ard-2022-223356.
  6. Agca R, Heslinga SC, Rollefstad S, et al. EULAR recommendations for cardiovascular disease risk management in patients with rheumatoid arthritis and other forms of inflammatory joint disorders: 2015/2016 update. Ann Rheum Dis 2017;76:17–28.

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  Conflict of Interest:
  FCa: speaker fees from Abbvie, Eli Lilly, Galapagos, Pfizer
  FCo: speaker fees from Abbvie, Eli Lilly, Galapagos, Pfizer
  CG: speaker fees from Eli Lilly
  VV: speaker fees from Galapagos
  FI: speaker fees from Abbvie, Eli Lilly, Galapagos, Pfizer
  FRS: speaker fees from Abbvie, Eli Lilly, Galapagos; research grant from Pfizer

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