JAK inhibitors and Comorbidities

Sanat Phatak MD, DM, MRCP
Associate Consultant, Rheumatology & Immunology, KEM Hospital, Pune, Maharashtra

JAK inhibitors, chiefly baricitinib and tofacitinib received US-FDA approval for use in multiple rheumatological illnesses including rheumatoid arthritis and psoriatic arthritis. There has been a recent increase in the use of tofacitinib by rheumatologists, physicians, and orthopaedic surgeons in India; this coincided with the availability of generic tofacitinib in November 2020 at a much lower cost. In a low-middle income country where the vast majority of healthcare is privately paid for by patients, the cost and the convenience of oral therapy is a major reason for physicians’ decisions to switch to JAK inhibitors. These are effective medicines and provide excellent relief in patients. Each effective medication comes with a double edge, and it is up to the treating doctor to weigh these adverse effects.

Like with all medications modulating the immune system, an increase in infection risk remains a concern. With experience, JAK inhibitors seem to be generally safe. A recent meta-analysis of subjects from 20 trials showed a two-and-a-half times risk of serious infections, mainly in those receiving 20 mg per day. This is a dose rheumatologists scarcely use. India is endemic to tuberculosis and in studies, TB has been a concern. It is common practice to screen for latent tuberculosis infection (LTBI) before starting ts DMARD and b DMARD therapy, although clear guidelines for the former are lacking. In a follow-up of clinical trials, Indian patients had the highest incidence of TB; interestingly all those who developed TB did not have a positive IGRA at screening, suggesting a new infection rather than activation. In two retrospective case series from Western India, 4 and zero out of a hundred patients respectively developed TB; tofacitinib was not stopped in those who developed it. These data give us a sense of confidence about the safe use where TB is concerned; until formal guidelines become available, a sense of caution and clean clinical observation for new onset TB is practical.

Non-communicable issues of concern include metabolic adverse effects and a higher risk of malignancy. Despite having a low body mass index, the body composition of Indians is adipose and thus we have a higher and earlier susceptibility to metabolic diseases such as diabetes mellitus, lipid abnormalities and coronary heart disease. Studies including trials and observational follow-ups report weight gain, an average of 1 kg with a subset of patients gaining much more. Most patients also have an elevation in serum cholesterol and LDL cholesterol values. It is unclear if this dyslipidemia translates to a higher event risk of coronary artery disease, especially since it needs to be weighed against the increased risk attributed to uncontrolled inflammatory disease. The ORAL Surveillance study did show a higher risk of cardiovascular events as compared to TNF inhibitor therapy; the post hoc analysis only showed this in patients with prior atherosclerotic cardiovascular disease. Thus, patients need to be counseled about this possibility, and involving a metabolic physician early helps. Malignancy has also been a concern, but a large meta-analysis of more than 80 thousand person-years exposure did not find a higher risk as compared to placebo. Malignancy risk in these patients is multifactorial and thus it is important to be aware. However, current data does not suggest that any of these adverse effects are true deal breakers. 

Suggested reading:

  1. Russell MD, Stovin C, Alveyn E, et al. JAK inhibitors and the risk of malignancy: a meta-analysis across disease indications. Ann Rheum Dis. 2023;82(8):1059-1067.
  2. Shawky AM, Almalki FA, Abdalla AN, Abdelazeem AH, Gouda AM. A Comprehensive Overview of Globally Approved JAK Inhibitors. Pharmaceutics. 2022;14(5):1001.
  3. Ytterberg SR, Bhatt DL, Mikuls TR, Koch GG, Fleischmann R, Rivas JL et al; ORAL Surveillance Investigators. Cardiovascular and Cancer Risk with Tofacitinib in Rheumatoid Arthritis. N Engl J Med. 2022;386(4):316-326.