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• 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: 14 November 2022

• Published on: 14 November 2022

  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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