Safety and efficacy of upadacitinib in patients with rheumatoid arthritis and inadequate response to conventional synthetic disease-modifying anti-rheumatic drugs (SELECT-NEXT): a randomised, double-blind, placebo-controlled phase 3 trial

This is one of two studies reported in The Lancet. The SELECT-BEYOND RCT (n=499) found upadacitinib (15 and 30mg) also led to significant improvements [ACR20 and DAS28(CRP)] compared with placebo over 12 weeks in patients with refractory rheumatoid arthritis.

A commentary suggests that these studies show the addition of yet another member to a growing family of small-molecule synthetic drugs targeting the JAK/STAT pathway, the JAKinibs. It notes tofacitinib (blocks mainly JAK1, JAK2, and JAK3) and baricitinib (blocks mainly JAK1 and JAK2) are already approved for the treatment of rheumatoid arthritis. Phase 2 studies of filgotinib, another selective JAK1 inhibitor, have been published and phase 3 studies are ongoing. It discusses how selective are the available JAK inhibitors, and how clinically important is such selectivity. It is not known yet which selective JAK inhibitor offers the maximum efficacy with the optimal side-effect profile as no head-to head studies between JAK inhibitors have been done and comparisons between the different therapeutic compounds remain tenuous. It adds that the possibility different subgroups of patients with rheumatoid arthritis might derive different benefits from JAKinibs also waits to be explored. Furthermore, it notes data have been presented for upadacitinib only up to week 24 so far, and show a numeric increase in malignancies and cardiovascular events versus placebo. Only tofacitinib, being the first JAK inhibitor to enter the market, has long-term safety data for up to 96 months. It is unclear how differing selectivity will play out in terms of long-term safety data. A 5-year follow-up period assessing the long-term efficacy and safety of upadacitinib treatment in SELECT-NEXT and SELECT-BEYOND is ongoing.