IMPROVEMENTS IN PATIENT-REPORTED OUTCOMES AMONG PATIENTS WITH RESOLUTION OF ENTHESITIS AND/OR DACTYLITIS: POST HOC ANALYSES FROM THE KEEPSAKE 1 AND 2 TRIALS OF RISANKIZUMAB IN PATIENTS WITH ACTIVE PSORIATIC ARTHRITIS

BackgroundEnthesitis and dactylitis are associated with greater disease activity and reduced quality of life. Results from the phase 3 randomized, placebo-controlled KEEPsAKE 1 and 2 studies (NCT03675308;NCT03671148) of risankizumab in active PsA showed greater resolution of enthesitis and dactylitis with risankizumab 150 mg vs placebo at week 24.ObjectivesThis post hoc analysis evaluated improvements in patient-reported outcomes (PROs) among patients who had enthesitis (n=444), dactylitis (n=188), or both (n=128) at baseline and achieved resolution of enthesitis, dactylitis, or both with blinded risankizumab at weeks 0, 4, 16, and open-label risankizumab every 12 weeks thereafter.MethodsAssessments included achievement of minimal clinically important differences (MCID) in pain (≥10-mm decrease on visual analog scale), Health Assessment Questionnaire-Disability Index (HAQ-DI;≥0.35-unit decrease), and Functional Assessment of Chronic Illness Therapy (FACIT-Fatigue;≥4-point increase). Nonresponder imputation (with multiple imputation for COVID-19–related missing data at week 24) was used.ResultsMany patients who achieved resolution of enthesitis at week 24;week 52 also achieved MCID in pain (66.4%;71.4%), HAQ-DI (58.2%;63.4%), and FACIT-Fatigue (59.0%;72.1%). Many patients who achieved resolution of dactylitis at week 24;week 52 also achieved MCID in pain, (72.2%;81.7%), HAQ-DI (56.3%;66.2%), and FACIT-Fatigue (67.7%;69.9%). Many patients who achieved resolution of both enthesitis and dactylitis at week 24;week 52 also achieved MCID in pain (82.1%;86.4%) HAQ-DI (66.7%;69.2%), and FACIT-Fatigue (71.4%;74.6%). PRO results for patients for who did not achieve resolution of enthesitis and/or dactylitis will be presented.ConclusionMajority of patients who achieved resolution of enthesitis and/or dactylitis with risankizumab also reported improvements in pain, disability, and fatigue.AcknowledgementsAbbVie and the authors thank the patients who participated in the study and all study investigators for their contributions. Medical writing assistance, funded by AbbVie, was provided by Lisa M Pitchford, PhD, of JB Ashtin.Disclosure of InterestsShawn Kwatra Consultant of: AbbVie, Aslan Pharmaceuticals, Arcutis, Celldex, Galderma, Genzada Pharmaceuticals, Incyte, Johnson & Johnson, Novartis, Pfizer, Regeneron, and Sanofi., Grant/research support from: Galderma, Incyte, Pfizer, and Sanofi., Saakshi Khattri Speakers bureau: AbbVie, Eli Lilly, Janssen, Novartis, and UCB, Grant/research support from: Bristol Myers Squibb, LEO Pharma, Novartis, and Pfizer, Ahmad Amin Consultant of: AbbVie, Amgen, Bristol Myers Squibb, Dermavant, Eli Lilly, Janssen, LEO Pharma, Regeneron, Sanofi/Genzyme, Pfizer, and UCB, Ran Liu Shareholder of: AbbVie, Employee of: AbbVie, Byron Padilla Shareholder of: AbbVie, Employee of: AbbVie, Ahmed M. Soliman Shareholder of: AbbVie, Employee of: AbbVie, Blair Kaplan Shareholder of: AbbVie, Employee of: AbbVie, Dennis McGonagle Speakers bureau: AbbVie, Janssen, Novartis, and Pfizer., Grant/research support from: AbbVie, Janssen, Novartis, and Pfizer, UCB, BMS, Celgene.

THE LINK between INFLAMMATION and THROMBOSIS: CLINICAL and IMMUNOHISTOCHEMICAL CHARACTERIZATION of PULMONARY ARTERIAL THROMBOSIS in COVID-19 PATIENTS

Background: Coronavirus-19 disease (COVID-19) has been responsible, to date, for more than 5 million of deaths. Immunothrombosis may be a major factor contributing to mortality in COVID-19 and pulmonary arterial tree involvement that mimics multiple pulmonary embolism could be a major contributor to disease course. Immunomodulatory drugs are of some beneft but mechanism not completely clear. We investigated pulmonary arterial tree clots to better appreciate their immunothrombotic nature, in contrast to the pathological characteristics of non-infammatory thrombi (1). Objectives: The primary objective was to study in depth the arterial thrombosis in COVID-19, by characterizing the immunohistochemical nature of thrombi, performing macroscopic and microscopic analyses, and by comparing clinical, laboratory and anatomical-pathological data of these patients with other patients died for COVID-19 but without evidence of pulmonary arterial thrombosis. Methods: Autopsies were performed in patients (cases) who died for COVID-19 with evidence of pulmonary arterial thrombosis at autopsy fnding but without pathological signs of bronchopneumonia or peripheral venous thrombosis. COVID-19 positive patients without pulmonary arterial thrombosis were selected as control group. Hematoxylin and eosin stained slides were reviewed choosing those with visible pulmonary thrombi. Further histochemical and immunohisto-chemical staining were performed in selected paraffin blocks. Each component of the thrombus was evaluated with the software application QuPath in terms of fbrin, red blood cells, platelets and immune cells percentage after scanning the slides with Aperio System. Laboratory tests were recorded at 2 points: at hospital admission and at Intensive Care Unit transfer. Results: We included 13 patients (cases) and 14 controls, matched for age, gender and time from diagnosis to death. Twenty arterial thrombi were studied. By immuno-histochemistry, arterial thrombi were composed by white blood cells (WBC) [median, IQR range: 10% (5-12.25)], mainly neutrophils [58% (35.2-64.5)], red blood cells [12%, (6-34.25)], fbrin [19% (14.5-42.25)], platelets [39%, (31.75-48)] (Figure 1). Three cases had a history of previous thrombosis. All cases had received anticoagulant treatment during hospitalization, low molecular weight heparin in 12/13 (therapeutic regimen in 4/12, prophylactic in 8/12) while 1/13 continued oral anticoagulants for comorbidity. By comparing laboratory fndings between cases and controls, cases showed signifcantly higher levels of platelet count [median, IQR range: 195000/mmc (157750-274500) vs 143500 (113000-175250), p=0.011], LDH [854 U/l (731-1315) vs 539 (391.5-660), p=0.003)] at hospital admission, and D-dimer at ICU transfer [25072 FEU (6951-50531) vs 1024 (620-5501), p=0.003)]. Conclusion: Pulmonary arterial thrombosis in COVID-19 is a type of immune-mediated infammatory thrombosis, since the amount of WBC is 6-times more than normal value seen in non-infammatory thrombi. Some markers of infammation, necrosis and coagulation are much more increased in this subset of patients. Chest CT angiography rather than simple CT scan at hospital admission could be more useful in this setting, and treatments with antiplatelet agents or anticoagulants, eventually in combination with immunotherapy, might positively affect the outcome.

Mise à jour des recommandations EULAR sur l’utilisation des thérapies immunomodulatrices dans la prise en charge de la Covid-19

Introduction Les formes sévères de COVID-19 comportent à une hyperinflammation systémique intense ;ce qui a justifié des essais thérapeutiques avec des immunomodulateurs régulièrement utilisés chez les patients atteints de maladies systémiques auto-immunes ou inflammatoires Depuis février 2021 où les premières recommandations EULAR sur l’utilisation de thérapeutiques immunomodulatrices dans le COVID-19 ont été publiées [1], de nouveaux essais thérapeutiques ont été réalisés ce qui rend nécessaire une mise à jour ces recommandations. Matériels et méthodes Selon les procédures standardisées de l’EULAR [2], les résultats d’une revue de la littérature systémique réalisée jusqu’au 15 décembre 2020 puis mise à jour jusqu’au 14 juillet 2021 incluant tous types d’études ont été présentés à un groupe de travail multidisciplinaire composé d’experts internationaux comprenant des rhumatologues, des immunologistes translationnels, des hématologues, des pédiatres, des patients et des professionnels de la santé. La mise à jour des recommandations a été discutée et votée par l’ensemble du panel d’experts sur la base des résultats présentés, principalement des essais randomisés contrôlés (ECT) sur différents traitements immunomodulateurs. Résultats La mise à jour comprend deux principes généraux et dix recommandations. Les recommandations concernent uniquement la prise en charge des patients présentant des formes de COVID-19 modérées à sévères ou critiques, faute de preuves suffisantes avec très peu d’ECT concernant les patients asymptomatiques et ceux avec des formes légères de la maladie. Les molécules suivantes ont montré une efficacité dans le traitement de formes modérées à sévères ou critiques du COVID-19. L’association de glucocorticoïdes et de tocilizumab est bénéfique dans les cas de COVID-19 nécessitant une oxygénothérapie et dans les cas critiques de COVID-19. L’utilisation d’inhibiteurs de Janus kinase (baricitinib et tofacitinib) et peut-être d’Ac anti-GM-CSF est prometteuse dans les mêmes populations. Les anticorps monoclonaux anti-SARS-CoV-2 et l’utilisation de plasma convalescent pourraient trouver une application dans les phases précoces de la maladie et dans certains sous-groupes de patients immunodéprimés. D’autres immunomodulateurs comme l’hydroxychloroquine, la colchicine ou l’anakinra n’ont pas démontré leur efficacité sur la mortalité et ou sur l’aggravation clinique (évolution vers une détresse respiratoire), quel que soit le stade de la maladie. Conclusion Un nombre grandissant d’ECT soutiennent l’efficacité de l’association de glucocorticoïdes et d’autres agents immunomodulateurs tels que le tocilizumab dans le traitement de formes modérée à sévère et critique du COVID-19. De plus, certaines études en cours pourraient confirmer l’efficacité potentielle d’autres approches thérapeutiques comme les inhibiteurs de JAK ou les Ac anti-GM-CSF. L’implication des rhumatologues, en tant qu’experts des maladies inflammatoires et auto-immunes systémiques et des traitements immunomodulateurs est nécessaire dans le design des nouveaux essais cliniques et dans l’élaboration de nouvelles recommandations pour la prise en charge du COVID-19.

Higher rates of COVID-19 but less severe infections reported for patients on Dupilumab: a Big Data analysis of the World Health Organization VigiBase.

OBJECTIVE: Dupilumab (Dupixent®) is a monoclonal antibody that inhibits IL-4 and IL-13 signaling used for the treatment of allergic diseases. Whilst biologic therapy is traditionally regarded as immunosuppressive and capable to increase the infectious risk, Dupilumab does not display these characteristics and may be even protective in certain cases. We investigated the link between Dupilumab therapy and SARS-CoV-2 infection. MATERIALS AND METHODS: We carried out a comprehensive data mining and disproportionality analysis of the WHO global pharmacovigilance database. One asymptomatic COVID-19 case, 106 cases of symptomatic COVID-19, and 2 cases of severe COVID-19 pneumonia were found. RESULTS: Dupilumab treated patients were at higher risk of COVID-19 (with an IC0.25 of 3.05), even though infections were less severe (IC0.25 of -1.71). The risk of developing COVID-19 was significant both among males and females (with an IC0.25 of 0.24 and 0.58, respectively). The risk of developing COVID-19 was significant in the age-group of 45-64 years (with an IC0.25 of 0.17). CONCLUSIONS: Dupilumab use seems to reduce COVID-19 related severity. Further studies are needed to better understand the immunological mechanisms and clinical implications of these findings. Remarkably, the heterogenous nature of the reports and the database structure did not allow to establish a cause-effect link, but only an epidemiologically decreased risk in the patients subset treated with dupilumab.

Immunomodulatory therapies for severe forms of COVID-19: A systematic literature review to inform eular points to consider

Background: The severe acute respiratory syndrome coronavirus 2 (SARSCoV2) pandemic is a global health problem. Beside the specific pathogenic effect of SARS-CoV-2, a deleterious aberrant non-effective host immune response plays an important role especially in severe forms of COVID-19. There is intense investigation to explore the utility of immunomodulatory drugs commonly used in the Rheumatology arena as agents that may mitigate against COVID-19 to improve disease prognosis. Rheumatologists are used to the utilization of these immune targeted therapies. Objectives: To summarize the available information on the use of immunomodulatory agents in severe COVID-19. Methods: As part of a EULAR taskforce, a systematic literature search was conducted from January 2019 up to December 11, 2020. Two reviewers independently identified eligible studies according to the PICO framework P (population): patients with SARS-CoV-2 infection;I (intervention): any immunomodulator agent/strategy;C (comparator): any comparator;O (outcome) any clinical outcome including but not limited to mortality, admission to intensive care unit and clinical improvement. Data on efficacy and safety of immunomodulatory agents utilized therapeutically in SARS-CoV-2 infection at any stage were extracted. The risk of bias was assessed using validated tools. Results: Of 60372 records, 401 articles were eligible for inclusion. Studies were at variable risk of bias. Randomised controlled trials (RCTs) were available for the following drugs: hydroxychloroquine (N=12), glucocorticoids (N=6), tocilizumab (N= 4), convalescent plasma (N=4), interferon beta (N=2), IVIg (N=2) and N=1 each for anakinra, baricitinib, colchicine, leflunomide, ruxolitinib, interferon kappa, and vilobelimab. For glucocorticoids, dexamethasone reduced mortality only in patients requiring respiratory support;while methylprednisolone reduced mortality in patients aged 60 years or over. Data from RCTs on tocilizumab are conflicting and definite conclusions cannot be drawn at this point in time, but recent studies suggest possible benefit in patients requiring respiratory support. Hydroxychloroquine was not beneficial at any disease stage, one RCT with anakinra was negative, one RCT with baricitinib+remdesivir was positive, and individual trials testing some other compounds provided interesting, albeit preliminary, results. Conclusion: Although there is emerging evidence about immunomodulatory therapies for the management of COVID-19, conclusive data is scarce with some conflicting data. Since glucocorticoids seem to improve survival in some subsets of patients, RCTs comparing glucocorticoids alone versus glucocorticoids plus anti-cytokine/immunomodulatory treatment are warranted. This SLR informed the initiative to formulate EULAR points to consider on pathophysiology and use of immunomodulatory therapies in COVID-19.

Pathophysiology of acute respiratory syndrome coronavirus 2 infection: A systematic literature review to inform eular points to consider

Background: The severe acute respiratory syndrome coronavirus 2 (SARSCoV-2) pandemic is a global health problem. Beside the specific pathogenic effect of SARS-CoV-2, incompletely understood deleterious and aberrant host immune responses play critical roles in severe disease. Rheumatologists have the best experience of studying and treating these complicated hyperinflammatory processes. Objectives: To summarize the available information on pathophysiology of COVID-19. Methods: As part of a EULAR taskforce, two systematic literature reviews were performed one on pathophysiology and one on immunomodulatory therapies. Two reviewers independently identified eligible studies according to the following PICO framework: P (population): patients with SARS-CoV-2 infection;I (intervention): any intervention/no intervention;C (comparator): any comparator;O (outcome) any clinical or serological outcome including but not limited to immune cell phenotype and function and serum cytokine concentration. The results pertaining to pathophysiology of COVID-19 are presented here. Results: Of the 55496 records yielded, 85 articles were eligible for inclusion. Included studies were at variable risk of bias and exploring various aspects of disease pathogenesis from immune to non-immune cells (Table 1). Pro-inflammatory cytokines' expression including IL-6, was increased, especially in severe COVID-19, although not as high as other states with severe systemic inflammation. Innate and adaptative immune cell compartments were differentially affected by SARS-CoV-2 infection: neutrophils displayed an immature differentiation state and also increased neutrophil extracellular traps (NETs) formation. Dendritic cell number was reduced and classical monocytes was increased although displaying a reduced expression of HLA-DR. The lymphoid compartment was also affected: lymphopenia was present with a reduced number of CD4+ and CD8+ T lymphocytes and more frequent PD1+CD8+ T cells corresponding to an exhausted phenotype. Antibody response to SARS-CoV-2 infection showed a high variability across individuals and disease spectrum. Multiparametric algorithms showed variable diagnostic performances in predicting survival, hospitalization, disease progression or severity, and mortality. Differences in SARS-CoV-2 manifestations in adults and children were highlighted. Conclusion: Overall, SARS-CoV-2 infection affects both innate and adaptative immune responses in a variable way, according to both disease severity and individual parameters. This SLR informs the EULAR points to consider on pathophysiology and use of immunomodulatory therapies in COVID-19.

Chest pain mimicking pulmonary embolism may be a common presentation of COVID-19 in ambulant patients without other typical features of infection.

BACKGROUND: Radiological and pathological studies in severe COVID-19 pneumonia (SARS-CoV-2) have demonstrated extensive pulmonary immunovascular thrombosis and infarction. This study investigated whether these focal changes may present with chest pain mimicking pulmonary emoblism (PE) in ambulant patients. METHODS: CTPAs from outpatients presenting with chest pain to Leeds Teaching Hospital NHS Trust 1st March to 31 May 2020 (n = 146) and 2019 (n = 85) were compared. Regions of focal ground glass opacity (GGO), consolidation and/or atelectasis (parenchymal changes) were determined, and all scans were scored using British Society for Thoracic Imaging (BSTI) criteria for COVID-19, and the 2020 cohort was offered SARS-CoV-2 antibody testing. RESULTS: Baseline demographic and clinical data were similar between groups with absence of fever, normal lymphocytes and marginally elevated CRP and D-Dimer values. Evidence of COVID-19 or parenchymal changes was observed in 32.9% (48/146) of cases in 2020 compared to 16.5% (14/85) in 2019 (P = 0.007). 11/146 (7.5%) patients met BSTI criteria for COVID-19 in 2020 compared with 0/14 in 2019 (P = 0.008). 3/39 patients tested had detectable COVID-19 antibodies (2 with parenchymal changes and 1 with normal parenchyma) however 0/6 patients whose CTPA met BSTI criteria "likely/suspicious for COVID-19" and attended antibody testing were SARS-CoV-2 antibody positive. CONCLUSIONS: 32.8% ambulatory patients with suspected PE in 2020 had parenchymal changes with 7.5% diagnosed as COVID-19 infection by imaging criteria, despite the absence of other COVID-19 symptoms. These findings suggest that localized COVID-19 pneumonitis with immunothrombosis occurs distal to the bronchiolar arteriolar circulation, causing pleural irritation and chest pain without viraemia, accounting for the lack of fever and systemic symptoms.