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15June2022
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ECCO Standpoint on JAK inhibitors in IBD

S. Danese, F. Magro, A. Hart, J. van der Woude, A. Armuzzi, B. Siegmund, L. Peyrin-Biroulet

In a recent randomized trial by Ytterberg and colleagues, called Oral Surveillance, patients with rheumatoid arthritis (RA) aged > 50 years and with at least an additional cardiovascular (CV) risk factor at baseline, treated with tofacitinib 5 or 10 mg twice daily experienced a higher proportion of major adverse cardiovascular events (MACE) and cancer compared with the control group (adalimumab or etanercept) [1]. 

These new data might have crucial implications in ulcerative colitis (UC) where tofacitinib, filgotinib and upadacitinib are approved.

Inflammatory bowel diseases and RA have different pathogenesis, as demonstrated by the different efficacy of drugs (e.g. etanercept, anti-IL17, antiCTLA-4, anti-CD20) or by the different risk of developing malignancies such as lymphoma [2,3]. 

Extrapolating the RA findings to other therapeutic areas may also not be appropriate as prevalence of risk factors is different across different indications. UC patients are very different from RA ones from an epidemiological standpoint and very different is the prevalence of specific risk factors, such as older age and smoking status, identified from an Oral Surveillance post hoc analysis as the most relevant to define the differential risk of tofacitinib vs TNF inhibitors [4]. UC patients are much younger [5] than RA patients and have a lower incidence of comorbidities, such as hypertension and diabetes; in addition to this, their active smoking habit is also very low (10-15%) [6], thus defining a lower baseline CV) risk [7,8]. 

Whilst specific thrombotic and cardiovascular risk assessment would require dedicated head-to-head studies in UC patients with similar characteristics to those of the surveillance trial, to date no increased risk of MACE or malignancy was identified in the overall tofacitinib-treated UC population up to 7.0 years of follow-up, suggesting a reliable safety profile [9,10].

In addition, the 3 different JAK inhibitors (JAKi), such as tofacitinib, filgotinib and upadacitinib, are very different [11] in terms of selectivity, dose, cytokine inhibition, efficacy and safety profile, including clinical experience in real world data. All JAKi have demonstrated efficacy in patients before and after biologics, needing most of the time higher doses in patients previously exposed to biologics. In conclusion, for all the reasons above and because the prevalence of risk factors is not the same for individual patients having UC, we believe that IBD specialists should have the possibility to use the proper treatment based on patient profile and individual benefit-risk profile based on the risk factors identified by the surveillance study, including age, smoking status and presence of other baseline CV , VTE or cancer risks [12].

Such a similar positioning has been also recently embraced by EULAR[13].

Positioning of JAKi should be kept before or after biologics.

References

  1. Ytterberg SR, Bhatt DL, Mikuls TR, et al. Cardiovascular and Cancer Risk with Tofacitinib in Rheumatoid Arthritis. N Engl J Med. 2022;386(4):316-326. doi:10.1056/NEJMoa2109927.
  2. Zintzaras E, Voulgarelis M, Moutsopoulos HM. The risk of lymphoma development in autoimmune diseases: a meta-analysis. Arch Intern Med. 2005;165(20):2337-2344. doi:10.1001/archinte.165.20.2337.
  3. Lewis JD, Bilker WB, Brensinger C, Deren JJ, Vaughn DJ, Strom BL. Inflammatory bowel disease is not associated with an increased risk of lymphoma. Gastroenterology. 2001;121(5):1080-1087. doi:10.1053/gast.2001.28703.
  4. Charles-Schoeman C, Buch M, DougadosM et al. Risk factors of major cardiovascular events aged >50 years with RA and > 1 additional cardiovascular risk factor: results from a phase 3b/4 randomised safety study of tofacitinib vs TNFinhibitors. Arthirtis Rheumatol 2021; 73 (suppl 10).
  5. Shivanshankar R, Tremaine W et al. Incidence and prevalence of Crohn's disease and Ulcerative colitis in Olmested County, Minnesota from 1970 through 2010. Clin Gastreonterol Hepatol 2017;15: 857-863
  6. Lakatos PL, Szamosi T, Lakatos L. Smoking in inflammatory bowel diseases: good, bad or ugly? et al. World J Gastro 2007;13:6134-6139.
  7. Fernandez-Gutierrez B, Perrotti P, Domenech E et al . Cardiovascular disease in immune-mediated inflammatory diseases: a cross sectional analysis of 6 cohorts. Medicine 2017; 96(26): e7308.
  8. Argollo M, Gilardi D, Peyrin-Biroulet C, Chabot JF, Peyrin-Biroulet L, Danese S. Comorbidities in inflammatory bowel disease: a call for action. Lancet Gastroenterol Hepatol. 2019;4(8):643-654. doi:10.1016/S2468-1253(19)30173-6.
  9. Sandborn W, Lawendy N, danese S et al. Safety and efficacy of tofacitininb for the treatment of ulcerative colitis: final anlaysis of OCTAVE open, an open label, long term extension study up to 7.0 years of treatment. Aliment Pharmacol Ther. 2022; 55:464-478.
  10. Olivera PA, Zuily S, Kotze PG, et al. International consensus on the prevention of venous and arterial thrombotic events in patients with inflammatory bowel disease. Nat Rev Gastroenterol Hepatol. 2021;18(12):857-873. doi:10.1038/s41575-021-00492-8.
  11. Roda G, Dal Buono A, Argollo M et al. JAK selectivity:more precision less troubles. Expert Review of Gastroenterology & Hepatology, 14:9, 789-796.
  12. D'Amico F, Peyrin-Biroulet L, Danese S. Cardiovascular and Cancer risk with Tofacitininb in Rheumatoid arthritis. N Engl J Med 2002; 286(18): 1767-1768.
  13. Smolen et al, presented at EULAR 2022, in press.

Posted in ECCO News, Volume 17, Issue 2