JAK-1 Inhibitor Upadacitinib Safety Concerns Highlighted at ACR

Some concerns about safety from a recently reported clinical trial evaluating upadacitinib have emerged.

Upadacitinib is a once daily oral medicine that belongs to a new class of drugs called janus kinase or JAK inhibitors. Janus kinases are enzymes that play a role in inflammation and rheumatoid arthritis (RA). JAK inhibitors block the activity of these enzymes leading to a reduction in inflammation and are showing significant benefit in pre-approval clinical to individuals with RA.1-5

In a recently reported 12-week study evaluating two doses of upadacitinib 64 percent of patients given a 15-milligram dose and 66 percent of patients given a 30-mg dose experienced a 20 percent reduction in RA symptoms.5 In addition two other recent reports in the medical journal Arthritis & Rheumatology have confirmed the effectiveness JAK in inhibitor effectiveness in treating RA. 2,3,4

Most recently however the results of a clinical trial highlighting the safety of upadacitinib was reported. During the first 12 weeks of the study, 165 patients received once-daily upadacitinib 30 mg, 164 received once-daily upadacitinib 15 mg, and 169 received placebo. During the second 12 weeks, 84 patients in the placebo group were switched to upadacitinib 30 mg and the other 85 were switched to upadacitinib 15 mg.

The study confirmed the activity of upadacitinib in the treatment of RA and the overall safety was comparable in the 15 mg and placebo groups, but the study identified some areas of concern in the higher 30 mg treatment group.

There were more serious infections and cases of herpes zoster in the 30 mg group than in either the 15 mg group or the placebo group. And there were more discontinuations of therapy related to adverse events in the 30 mg group than in the other two groups. In addition two venous thrombotic events — pulmonary embolism or deep vein thrombosis were observed during the first 12 weeks of the trial: one at the 30 mg dose and one at the 15 mg dose. And another four such events occurred from weeks 12 to 24, bringing the total to six.

Upadacitinib will clearly play a role in the management of RA and other inflammatory arthritis conditions however patients and their physicians will clearly need to keep on eye on its side effects.


  1. American College of Rheumatology (ACR) 2017 Annual Meeting: Abstract 10L. Presented November 7, 2017.
  2. Genovese MC, Smolen JS, WEinblatt ME, et al. Efficacy and Safety of ABT-494, a Selective JAK-1 Inhibitor, in a Phase IIb Study in Patients With Rheumatoid Arthritis and an Inadequate Response to Methotrexate. Arthritis Rheumatol. 2016 Dec;68(12):2857-2866. doi: 10.1002/art.39808.
  3. Kremer JM, Emery P, Camp HS, et al. A Phase IIb Study of ABT-494, a Selective JAK-1 Inhibitor, in Patients With Rheumatoid Arthritis and an Inadequate Response to Anti-Tumor Necrosis Factor Therapy. Arthritis Rheumatol. 2016 Dec;68(12):2867-2877. doi: 10.1002/art.39801.
  4. Genovese M, Kremer J, Samani O, et al. Barcitinib in patients with refractory rheumatoid arthritis. New England Journal of Medicine. March 31, 2016. DOI: 10.1056/NEJMoa1507247.
  5. http://acrabstracts.org/abstract/a-phase-3-randomized-placebo-controlled-double-blind-study-of-upadacitinib-abt-494-a-selective-jak-1-inhibitor-in-patients-with-active-rheumatoid-arthritis-with-inadequate-response-to-convention/