In active UC, upadacitinib induced and maintained remission
JAK inhibitors, such as upadacitinib, represent an advance in the management of patients with ulcerative colitis (UC); however, it remains unclear whether the balance of efficacy versus risk favors one drug over the others, according to an ACP Journal Club commentary.
Three industry-funded trials—two placebo-controlled randomized induction trials (U-ACHIEVE substudy 2 and U-ACCOMPLISH) and a randomized placebo-controlled maintenance trial (U-ACHIEVE substudy 3)—found that upadacitinib induced clinical remission at eight weeks and maintained it through 52 weeks in patients with moderately to severely active ulcerative colitis (UC). The most commonly reported adverse events in the induction trials were nasopharyngitis, creatine phosphokinase elevation, and acne.
Results from the trials were published May 26 by The Lancet. The following commentary by Geoffrey M. Forbes, MBBS, MD, was published in the ACP Journal Club section of the October Annals of Internal Medicine.
Upadacitinib, tofacitinib, and filgotinib inhibit JAKs, molecules that facilitate cell signaling following cytokine-cell interaction for many cytokines. JAK inhibitor use is evolving in inflammatory bowel disease for which evidence of efficacy is established in UC but less so in Crohn disease.
The trials reported by Danese and colleagues assessed the effects of upadacitinib, which is putatively more selective for JAK1 inhibition than other JAK inhibitors, in UC. More patients in the upadacitinib groups than in the placebo groups achieved clinical remission and maintenance of remission. The tighter outcome measure of endoscopic remission at 8 weeks was achieved in 14% to 18% of patients in the upadacitinib group vs. 1% to 2% in the placebo group. Clinical (<20%) and endoscopic (<10%) remission were achieved and maintained in small proportions of patients.
Included patients had disease phenotypes that were difficult to treat. They had moderately to severely active disease despite a median disease duration of 6 years, 38% were receiving concomitant corticosteroids, and 52% had received biologic therapy. It is unknown whether patients with less difficult or earlier stage UC would benefit more from upadacitinib.
Implementing upadacitinib treatment earlier in the disease course is partially contingent on an acceptable side effect profile. Investigators and regulators remain cognizant of this, to the extent that the U.S. Food and Drug Association has required warning statements of the possibility of serious cardiovascular events, cancer, and death. In the current trials, 4.0% of patients developed herpes zoster.
JAK inhibitors represent an advance in the management of UC; it remains to be determined whether the balance of efficacy vs. risk favors one over the others.