Upadacitinib for the treatment of active non-radiographic axial spondyloarthritis (SELECT-AXIS 2): a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Upadacitinib, a Janus kinase inhibitor, has been shown to be effective in patients with ankylosing spondylitis. We aimed to assess the efficacy and safety of upadacitinib in non-radiographic axial spondyloarthritis. METHODS: The SELECT-AXIS 2 non-radiographic axial spondyloarthritis study was a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial at 113 sites across 23 countries (Argentina, Australia, Belgium, Brazil, Bulgaria, Canada, China, Czech Republic, France, Germany, Hungary, Israel, Japan, Mexico, Poland, Russia, Slovakia, South Korea, Spain, Taiwan, Turkey, Ukraine, and the USA). Eligible adults had active non-radiographic axial spondyloarthritis, with objective signs of inflammation based on MRI or elevated C-reactive protein and an inadequate response to non-steroidal anti-inflammatory drugs. Patients were randomly assigned (1:1) to receive oral upadacitinib 15 mg once daily or placebo using interactive response technology. Random treatment assignment was stratified by MRI inflammation in the sacroiliac joints and screening high-sensitivity C-reactive protein status (MRI-positive and C-reactive protein-positive, MRI-positive and C-reactive protein-negative, and MRI-negative and C-reactive protein-positive) and previous exposure to biologic disease-modifying antirheumatic drugs (yes vs no). Treatment assignment was masked from patients, investigators, study site personnel, and the study sponsor. The primary endpoint was the proportion of patients with an Assessment of SpondyloArthritis international Society 40 (ASAS40) response at week 14. Analyses were performed on the full analysis set of patients, who underwent random allocation and received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT04169373. FINDINGS: Between Nov 26, 2019, and May 20, 2021, 314 patients with active non-radiographic axial spondyloarthritis were enrolled into the study, and 313 received study drug (156 in the upadacitinib group and 157 in the placebo group); 295 (94%) patients (145 in the upadacitinib group and 150 in the placebo group) received treatment for the full 14 weeks. A significantly higher ASAS40 response rate was achieved with upadacitinib compared with placebo at week 14 (70 [45%] of 156 patients vs 35 [23%] of 157 patients; p<0·0001; treatment difference 22%, 95% CI 12-32). The rate of adverse events up to week 14 was similar in the upadacitinib group (75 [48%] of 156 patients) and placebo group (72 [46%] of 157 patients). Serious adverse events and adverse events leading to discontinuation of study drug occurred in four (3%) of 156 patients in the upadacitinib group and two (1%) of 157 patients in the placebo group. Few patients had serious infections or herpes zoster in either treatment group (each event occurred in two [1%] of 156 patients in the upadacitinib group and one [1%] of 157 patients in the placebo group). Five (3%) of 156 patients in the upadacitinib group had neutropenia; no events of neutropenia occurred in the placebo group. No opportunistic infections, malignancies, major adverse cardiovascular events, venous thromboembolic events, or deaths were reported with upadacitinib treatment. INTERPRETATION: Upadacitinib significantly improved the signs and symptoms of non-radiographic axial spondyloarthritis compared with placebo at week 14. These findings support the potential of upadacitinib as a new therapeutic option in patients with active non-radiographic axial spondyloarthritis. FUNDING: AbbVie.

Successful treatment of severe COVID-19 pneumonia, a case series with simultaneous interleukin-1 and interleukin-6 blockade with 1-month follow-up.

Interleukin (IL)-6 and IL-1 blockade showed beneficial results in patients with severe COVID-19 pneumonia and evidence of cytokine release at the early disease stage. Here, we report outcomes of open-label therapy with a combination of blocking IL-6 with tocilizumab 8 mg/kg up to 800 mg and IL-1 receptor antagonist anakinra 100-300 mg over 3-5 days. Thirty-one adult patients with severe COVID-19 pneumonia and signs of cytokine release, mean age 54 (30-79) years, 5 female, 26 male, and mean symptom duration 6 (3-10) days were treated. Patients with more than 10 days of symptoms, evidence of bacterial infection/elevated procalcitonin and other severe lung diseases were excluded. Computed tomography (CT) scans of the lung were performed initially and after 1 month; inflammatory activity was assessed on a scale 0-25. Twenty-five patients survived without intubation and mechanical lung ventilation, two patients died. C-reactive protein decreased in 19/31 patients to normal ranges. The mean activity CT score decreased from 14 (8-20) to 6 (0-16, n = 16). In conclusion, most of our patients recovered fast and sustained, indicating that early interruption of cytokine release might be very effective in preventing patients from mechanical ventilation, death, and long-term damage.

Twenty years of clinical trials in axial spondyloarthritis: what can we learn for the future?

PURPOSE OF REVIEW: We have now about 20 years of experience with the treatment of axial spondyloarthritis with biologics, which raises the question what we can learn from past experience, and which open questions should be addressed in future investigations. RECENT FINDINGS: Many studies have shown that axSpA patients - both patients in their nonradiological and radiological stage - respond similarly well to biologic treatment and these patients should be seen as having the same disease at different stages. AxSpA respond best to TNF-blocker - and probably also to other biologics - if the disease duration is short and if objective parameters of inflammation, such as C-reactive protein or MRI are positive. Primary aim of treatment is to reach and maintain clinical remission. Once remission is achieved, it can be maintained by continuing treatment, and in a proportion of yet not well defined patients the drug dose can be reduced without inducing a flare. The recent demonstration of a good efficacy, in addition to TNF blockers, also of IL-17 inhibitors and JAK-inhibitors in axSpA patients raises the question how to select the best patients for the best treatment. Radiographic progression can best be stopped by effectively suppressing inflammation, whether different drugs have here a different effect has still to be defined. More sensitive measurements of radiographic progression are urgently needed. SUMMARY: Reaching and maintaining clinical remission and preventing structural bony damage is the primary treatment target in patients with axSpA. How to reach this aim best has to be further explored in the future.