Free special edition 2023

ADVERSE EFFECTS

Janus kinase inhibitors: higher incidence of serious adverse effects and death thanwith TNF-alpha inhibitors

● The EMA recommends using the Janus kinase (JAK) inhibitors abrocitinib , baricitinib , filgotinib , tofacitinib and upadacitinib , authorised mainly for chronic inflammatory diseases, only as a last resort, in certain patients. J anus kinase (JAK) inhibitors are immunosuppressants. Some have been authorised in the European Union for oral use in various chronic inflammatory rheumatological, intestinal or cutaneous disorders, without evidence that they represent a therapeutic advance over the immunosuppressants already available, in particular TNF-alpha inhibitors. These JAK inhibitors are: abrocitinib (Cibinqo°), baricitinib (Olumiant°), filgotinib (Jyseleca°), tofacitinib (Xeljanz°) and upadacitinib (Rinvoq°) (1). Two other JAK inhibitors, fedratinib (Inrebic°) and ruxolitinib (Jakavi°), are authorised for use in cancer, in particu lar myelofibrosis (1,2). JAK inhibitors have the adverse effects common to all im munosuppressants, including serious infections and cancer, but they can also provoke venous or arterial thromboembolism, hypertension, hypercholesterolaemia, weight gain, haem atological disorders, etc. (1). In 2019, the “interim” results of a clinical trial in 4362 patients aged 50 years or over (including about one-third aged 65 years or older) with rheumatoid arthritis, showed that tofacitinib exposes patients to a greater risk of cancer and thromboembolic events, in particular myocardial infarction, than TNF-alpha inhibitors. These risks were increased with both authorised doses of tofacitinib : 5 mg or 10 mg, twice daily (1-3). Higher incidence of serious infections, hepatic disorders and all-cause death than with TNF-­ alpha inhibitors. Other data from this trial, made public in 2022, also showed that, compared with TNF-alpha inhibitors, tofacitinib was associated with a higher incidence of: – serious infections (9.7% of patients in the tofacitinib 5 mg twice daily group, 11.6% in the tofacitinib 10mg twice daily group, versus 8.2% in the TNF-alpha inhibitor group); – hepatic disorders (3.2%, 4.9%, versus 2.4%, respectively); – death from any cause (1.8%, 2.7%, versus 1.2%, respectively). For each of these adverse effects, the difference between the tofacitinib 10 mg twice daily group and the TNF-alpha in hibitor group was statistically significant (2,3). In 2022, data from a clinical trial of baricitinib in patients with rheumatoid arthritis also suggested a higher incidence of car diovascular and venous thromboembolic adverse events than with TNF-alpha inhibitors (2).

In light of these data, the European Commission requested a review of the harm-benefit balance of the five JAK inhibitors authorised for use in chronic inflammatory disorders. The Commission considered that the characteristics of the patients concerned justified examining JAK inhibitors authorised for cancer separately, even though a class effect is suspected (2). As of 1 February 2023, the European Medicines Agency (EMA) website makes no mention of fedratinib and ruxolitinib being under review. Effects common to all of these substances. In late 2022, the EMA considered that there was a “ class effect ”, meaning that the increased incidence of certain adverse effects identified with tofacitinib and baricitinib compared with TNF-­ alpha inhibitors in the two above-mentioned clinical trials is shared by the three other JAK inhibitors authorised for use in chronic inflammatory diseases (4). The EMA therefore recom mended that abrocitinib , baricitinib , filgotinib , tofacitinib and upadacitinib only be prescribed as a last resort in patients: aged 65 years or over; at increased risk of serious cardiovascular events, such as stroke or myocardial infarction; who smoke or are ex-smokers; or are at increased risk of cancer. The EMA also recommended using these drugs “ with caution ” in patients with risk factors for venous thromboembolism (in cluding pulmonary embolism). It recommended reducing the doses of JAK inhibitors for all of these patients, without speci fying by howmuch (4). IN PRACTICE  The increased incidence of serious adverse effects associated with tofacitinib and baricitinib , and probably also the three other JAK inhibitors used in chronic inflammatory diseases, raises questions about the harm-benefit balance of drugs of this class, especially since they have not been demon strated to have tangibly greater efficacy thanTNF-alpha inhibitors. In addition, their most serious adverse effects (infections and thromboembolism) are difficult to predict, even when patients are carefully monitored. ©Prescrire References 1- “Inhibiteurs de Janus kinases: ruxolitinib, etc.” Interactions Médica menteuses Prescrire 2023. 2- EMA “Notification to the PRAC/EMA secretariat of a referral under article 20 (…)” 28 January 2022 + “Addendum to notification to the PRAC/EMA secretariat of a referral under article 20 (…)” 13 June 2022: 6 pages. 3- Ytterberg SR et al. “Cardiovascular and cancer risk with tofacitinib in rheumatoid arthritis” N Engl J Med 2022; 386 (4): 316-326. 4- EMA “EMA confirms measures to minimise risk of serious side effects with Janus kinase inhibitors for chronic inflammatory disorders” 11 November 2022 + 27 January 2023 + “Alignment of dose recommendations for Janus kinase inhibitors in patients with certain risk factors” 13 January 2023: 7 pages. ▶ Translated from Rev Prescrire March 2023 Volume 43 N° 473 • Pages 180-181

Prescrire Int • May 2023

Prescrire International Special Edition 2023 • Page 11