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BackgroundUpadacitinib (UPA), a Janus kinase inhibitor, was effective and well tolerated in patients (pts) with non-radiographic axial spondyloarthritis (nr-axSpA) through 14 weeks (wks) of treatment.[1]ObjectivesThis analysis assessed the efficacy and safety of UPA vs placebo (PBO) through 1 year.MethodsThe SELECT-AXIS 2 nr-axSpA study included a 52-wk randomized, double-blind, PBO-controlled period. Enrolled adults had a clinical diagnosis of active nr-axSpA fulfilling the 2009 ASAS classification criteria, objective signs of inflammation based on MRI sacroiliitis and/or elevated C-reactive protein, and an inadequate response to NSAIDs. One-third of pts had an inadequate response to biologic DMARDs. Pts were randomized 1:1 to UPA 15 mg once daily or PBO. Concomitant medications, including NSAIDs, had to be kept stable through wk 52. The study protocol outlined that pts who did not achieve ASAS20 at any two consecutive study visits between wks 24 to 52 should receive rescue therapy with NSAIDs, corticosteroids, conventional synthetic/biologic DMARDs, or analgesics. Cochran-Mantel-Haenszel (CMH) test with non-responder imputation incorporating multiple imputation (NRI-MI) was used to handle missing data and intercurrent events for binary efficacy endpoints. Mixed-effect model repeated measures (MMRM) was used to assess continuous efficacy endpoints. NRI was used for binary endpoints after rescue and as observed analysis excluding data after rescue for continuous endpoints. Treatment-emergent adverse events (TEAEs) are reported through wk 52.ResultsOf the 314 pts randomized, 259 (82%;UPA, n=130;PBO, n=129) completed wk 52 on study drug. More pts achieved an ASAS40 response with UPA vs PBO from wks 14 to 52 with a 20% treatment difference at wk 52 (63% vs 43%;nominal P <.001;Figure 1). The proportion of pts achieving ASDAS inactive disease with UPA remained higher than PBO at wk 52 (33% vs 11%;nominal P <.0001;Figure 1). Consistent improvements and maintenance of efficacy were also seen across other disease activity measures. Between wks 24 and 52, fewer pts on UPA (9%) than PBO (17%) received rescue therapy. A similar proportion of pts in each treatment group had a TEAE (Table 1). Infections were the most common TEAE;the rates of serious infections and herpes zoster were higher with UPA vs PBO, although no new serious infections were reported from wks 14 to 52. COVID-19 events were balanced between treatment groups. No opportunistic infections, malignancy excluding non-melanoma skin cancer, adjudicated major adverse cardiovascular events, inflammatory bowel disease, or deaths were reported. Two pts (1.3%) on PBO had adjudicated venous thromboembolic events.ConclusionUPA showed consistent improvement and maintenance of efficacy vs PBO through 1 year across multiple disease activity measures. No new safety risks were identified with longer-term UPA exposure. These results continue to support the benefit of UPA in pts with active nr-axSpA.Reference[1]Deodhar A, et al. Lancet. 2022;400(10349):369–379.Table 1.Safety through week 52Event, n (%)PBO (n = 157)UPA 15 mg QD (n = 156)Any AE103 (66%)107 (69%)Serious AE6 (3.8%)6 (3.8%)AE leading to D/C4 (2.5%)6 (3.8%)COVID-19-related AE22 (14%)24 (15%)Deaths00Infection60 (38%)68 (44%) Serious infection1 (0.6%)2 (1.3%) Herpes zoster1 (0.6%)5 (3.2%)Malignancy other than NMSC00NMSC1 (0.6%)0Hepatic disorder7 (4.5%)6 (3.8%)Neutropenia1 (0.6%)8 (5.1%)MACE (adjudicated)00VTE (adjudicated)2 (1.3%)a0Uveitisb3 (1.9%)2 (1.3%)Inflammatory bowel disease00aBoth patients had non-serious events of deep vein thrombosis in the lower limb with risk factors including obesity and prior deep vein thrombosis in one patient and concomitant COVID-19 infection in the other patient.bThree events of uveitis occurred in each treatment group (among n = 3 patients in the PBO group and n = 2 patients in the UPA group);two events in the PBO group and one in the UPA group occurred in patients with a history of uveitis.AcknowledgementsAbbVie funded this study and participated in the study design, res arch, analysis, data collection, interpretation of data, review, and approval of the . All authors had access to relevant data and participated in the drafting, review, and approval of this publication. No honoraria or payments were made for authorship. Medical writing support was provided by Julia Zolotarjova, MSc, MWC, of AbbVie.Disclosure of InterestsFilip van den Bosch Speakers bureau: AbbVie, Amgen, Galapagos, Janssen, Lilly, Merck, MoonLake, Novartis, Pfizer, and UCB., Consultant of: AbbVie, Amgen, Galapagos, Janssen, Lilly, Merck, MoonLake, Novartis, Pfizer, and UCB., Atul Deodhar Consultant of: AbbVie, Amgen, Aurinia, BMS, Celgene, GSK, Janssen, Lilly, MoonLake, Novartis, Pfizer, and UCB, Grant/research support from: AbbVie, Bristol Myers Squibb, Celgene, GSK, Lilly, Novartis, Pfizer, and UCB, Denis Poddubnyy Speakers bureau: AbbVie, Biocad, BMS, Galapagos, Gilead, GlaxoSmithKline, Janssen, Lilly, MSD, Medscape, MoonLake, Novartis, Peervoice, Pfizer, Roche, Samsung Bioepis, and UCB, Consultant of: AbbVie, Biocad, BMS, Galapagos, Gilead, GlaxoSmithKline, Janssen, Lilly, MSD, Medscape, MoonLake, Novartis, Peervoice, Pfizer, Roche, Samsung Bioepis, and UCB, Grant/research support from: AbbVie, Lilly, MSD, Novartis, and Pfizer., Walter P Maksymowych Consultant of: AbbVie, BMS, Celgene, Galapagos, Gilead, Janssen, Lilly, Novartis, Pfizer, and UCB, Grant/research support from: AbbVie, Novartis, Pfizer, and UCB, Employee of: Chief Medical Officer of CARE Arthritis Limited, Désirée van der Heijde Consultant of: AbbVie, Bayer, BMS, Cyxone, Eisai, Galapagos, Gilead, GSK, Janssen, Lilly, Novartis, Pfizer, and UCB, Employee of: Director of Imaging Rheumatology BV, Tae-Hwan Kim Speakers bureau: AbbVie, Celltrion, Kirin, Lilly, and Novartis., Mitsumasa Kishimoto Consultant of: AbbVie, Amgen, Asahi-Kasei Pharma, Astellas, Ayumi Pharma, BMS, Chugai, Daiichi Sankyo, Eisai, Gilead, Janssen, Lilly, Novartis, Ono Pharma, Pfizer, Tanabe-Mitsubishi, and UCB., Xenofon Baraliakos Speakers bureau: AbbVie, BMS, Celgene, Chugai, Merck, Novartis, Pfizer, and UCB, Consultant of: AbbVie, BMS, Chugai, MSD, Novartis, Pfizer, and UCB, Grant/research support from: AbbVie and Novartis, Yuanyuan Duan Shareholder of: AbbVie, Employee of: AbbVie, Kristin D'Silva Shareholder of: AbbVie, Employee of: AbbVie, Peter Wung Shareholder of: AbbVie, Employee of: AbbVie, In-Ho Song Shareholder of: AbbVie, Employee of: AbbVie.
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L'essai de phase 3 SELECT-AXIS 2 (NCT04169373) a évalué l'efficacité et la tolérance d'upadacitinib (UPA) chez des patients atteints de spondyloarthrite axiale non radiographique (nr-axSpA). Nous présentons ici une analyse en sous-groupes (ss-gpes) en fonction de la valeur de la hsCRP et de l'inflammation des sacro-iliaques (SI) à l'IRM à la sélection. Dans SELECT-AXIS 2 [1] , des patients de ≥ 18 ans ayant un diagnostic clinique de nr-axSpA remplissant les critères de classification de 2009 de l'ASAS, mais sans le critère radiologique des critères de New-York modifiés, et présentant des signes objectifs d'inflammation active à l'IRM selon la définition de l'ASAS (évaluation par 2 lecteurs et un arbitre) et/ou un taux de hsCRP supérieur à la limite supérieure de la normale (LSN, 2,87 mg/L) à la sélection, ont été randomisés selon un ratio 1/1 pour recevoir UPA 15 mg 1x/j ou un placebo (PBO). Le critère principal était la réponse ASAS40 à la semaine (S) 14. Les autres critères incluaient la faible activité de la maladie (LDA) selon l'ASDAS (≤ 2,1), la variation par rapport à l'inclusion du SPARCC-IRM articulations SI, du BASFI et de la douleur rachidienne évaluée par le patient, à S14. Les analyses en ss-gpes préspécifiées (ASAS40) et post-hoc (autres critères) ont été réalisées en fonction du statut inflammatoire à la sélection : taux de hsCRP (> LSN vs ≤ LSN) et inflammation des articulations SI à l'IRM (positive vs négative). L'imputation des non-répondeurs (NRI) avec imputation multiple (MI) pour prendre en compte des données manquantes liées au COVID-19, a été utilisée pour les variables binaires. Un modèle mixte pour mesures répétées sur les données observées (AO) a été utilisé pour les variables continues sauf pour le score SPARCC-IRM pour lequel une analyse de covariance sur les AO a été utilisée. Sur les 312 patients inclus dans l'analyse, 176 (56 %) avaient une hsCRP > LSN et une IRM négative (IRM−), 73 (23 %) une hsCRP > LSN et une IRM positive (IRM+) et 63 (20 %) une hsCRP ≤ LSN et une IRM+. Les caractéristiques démographiques et cliniques à l'inclusion étaient similaires dans les ss-gpes ;cependant, le ss-gpe hsCRP > LSN et IRM+ était plus fréquent chez les patients HLA-B27 positifs et avait un plus faible taux de traitement antérieur par DMARDs biologiques (Tableau 1). À S14, des taux plus élevés de réponse ASAS40 et ASDAS-LDA et une réduction plus importante par rapport à l'inclusion des scores SPARCC-IRM, BASFI et de douleur rachidienne ont été associés à UPA vs PBO pour tous les ss-gpes (Fig. 1). La différence UPA vs PBO était plus importante pour le groupe hsCRP > LSN et IRM+, pour tous les critères. Dans SELECT-AXIS 2, les résultats chez les patients atteints de nr-axSpA ont été améliorés pour UPA versus le PBO pour tous les sous-groupes d'inflammation à l'inclusion ;le bénéfice le plus important a été observé chez les patients ayant à la fois un taux élevé de CRP et des signes d'inflammation à l'IRM à la sélection. (French) [ FROM AUTHOR]
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Background: Severe and life threating COVID-19 pneumonia is often characterized by local and systemic immune-mediated hyperinflammation At the early disease stage activated monocytes are migrating to the lung and cause the typical opac infiltrates, which lead to an reduction of oxygen uptake. These pathophysiological observations and the fact that corticosteroids are so far the only drug, which has shown significant improvement, was the rationale use this combination anti-inflammatory drugs in severe COVID-19 disease. Interleukin (IL)-6 and IL-1 blockade alone, respectively showed contradictory results in severe COVID-19 pneumonia that might be related to the differences is patient populations (early vs. late stage) and to the fact that blockade of just one cytokine might be not sufficient against the cytokine storm. Objectives: Here we report results of an open-label treatment with a combination of an IL-6 receptor blocker tocilizumab and an IL-1 receptor antagonist anakinra in patients with early (up to 10 days since symptom onset) severe COVID-19 pneumonia with evidence of cytokine release. Methods: Adult patients with, according to World Health Organisation criteria, severe to critical COVID-19 infection associated pneumonia and cytokine release, requiring oxygen supplementation and evidence of rapid deterioration and decrease of oxygen saturation to ≤ 95% hospitalized between May 2020 and December 2020 were treated with tocilizumab 8 mg/ kg up to 800 mg intravenously and anakinra 100 to 300 mg for 3 to 5 days, starting at the same day. We excluded patients with a symptom duration of ≥ 10 days, patients with evidence of bacterial infection, indicated by an elevated procalcitonin serum level, patients with severe pre-existing lung disease such as severe COPD or heart failure of ≥ II according to the NYHA classification and patients ≥ 80 years. Laboratory parameters and chest CT were performed on initial presentation and one month after treatment. A semi-quantitative CT score was calculated based on the extent of lobar pneumonia involvement (0:0%;1, < 5%;2:5-25%;3:26-50%;4:51-75%;5, ≥ 75%;range 0-5;global score 0-25) for each time point. Results: 15 patients with severe to critical COVID-19 pneumonia and signs of cytokine release, mean age 55 (range 31-79) years, all male, with a mean symptom duration of 6 (range 4-10) days were treated. Mean oxygen saturation was 86% (range 76-95%) before initiating therapy. Mean ferritin was 1297 μg/l (range 347 -2734), mean IL-6 112 ng/L (range 2.2 -607.4) and CRP 82.4 mg/L (range 36.4 -125). In all patients we were able to prevent them from intubation and mechanic ventilation, none of our patients died. Fife patients did not need to be referred to the intensive care unit at all, while 9 patients received noninvasive ventilation and high-flow nasal oxygen support. All patients showed typical imaging features of COVID-19 pneumonia at baseline (BL) according to the Radiological Society of North America (RSNA) chest CT classification system. The mean of the global chest CT severity score at BL was 13 (range 7-20) and decreased to 6 (range 0-16) within 1 month which corresponded to a mean reduction of 58%. Chronic fibrotic pulmonary changes were not seen in any patient at BL and after 1 month mild changes were observed in 6 patients. One patient experienced lower abdominal pain, urinary tract infection, gastrointestinal bleeding due to antrum ulcers Forrest III, in another patient atrial fibrillation, urinary tract infection and apoplexy were observed. Conclusion: In our case series, all patients treated with the combination tocilizumab and anakinra recovered fast and sustained without major infectious side effects, indicating that early interruption of cytocine release might be very effective and safe in preventing patients from mechanical ventilation, death and longterm damage.