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Star Alliance in 2020

Star Alliance in 2020 ^ W21007

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Publication Date: January 28, 2021

Source: Ivey Publishing

Industry: Transportation and distribution

Formed in 1997, Star Alliance was the first global airline network or constellation. Its aim was to shift the airline industry away from a network of loose bilateral agreements between individual airlines to a more comprehensive network of multilateral agreements between members. A wave of deregulation in the industry in the 1970s and 1980s, which opened free travel between countries, led to the creation of three major global constellations: Star Alliance, Oneworld, and SkyTeam. These networks conferred many benefits on their members, such as cost sharing, loyalty program management, and increased flight load. However, in early 2020, the outbreak of the COVID-19 pandemic had devastating effects on the airline industry. The focus of airline alliances thus shifted from greater connectivity between members to survival in the new global landscape. Would this strategy help airlines survive the COVID-19 crisis? Was group-based competition needed to thrive during a pandemic? Their main concern was whether or not the powerful frameworks they created would be able to help member airlines survive this crisis and regain their pre-pandemic financial stability. Benjamin Gomes-Casseres is affiliated with Brandeis University. Jacob Judd is affiliated with Brandeis University.

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Strategic Alliance —Case Study of Lenovo and IBM

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Alliance Design Concepts: Foreign Exchange Risk

By: Ryan Orchard

Alliance Design Concepts provided audio system solutions, which involved installing high-quality sound systems in customer facilities (such as large churches). A major cost component (60-80 per cent)…

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• Discipline: General Management
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Alliance Design Concepts provided audio system solutions, which involved installing high-quality sound systems in customer facilities (such as large churches). A major cost component (60-80 per cent) for these systems was the equipment (speakers, amplifiers, etc.), which was sourced from the United States and paid for in U.S. dollars (USD). Alliance quoted prices to customers in Canadian dollars (CAD) by converting equipment costs from USD to CAD based on the exchange rate on the day of the quotation. Since it was often months later that Alliance actually converted cash and paid the supplier in USD, it found that a change in the exchange rate during that time could directly reduce the margin on the sale. The operations manager had to devise a risk mitigation strategy and/or business process change.

Ryan Orchard is affiliated with MacEwan University.

Learning Objectives

This case could fit an introductory international business and/or finance course, where the primary use of the case would focus on foreign exchange risk and mitigation tools (including forward foreign currency exchange contracts), with a secondary focus on analyzing and improving the management of business processes and cash. This case could also fit a general management course (small business focus), where the primary use of the case would focus on analyzing and improving the management of business processes and cash, with a secondary focus on foreign exchange risk.

Oct 3, 2014 (Revised: Jul 27, 2017)

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• Efficacy and safety of targeted therapies in VEXAS syndrome: retrospective study from the FRENVEX
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• http://orcid.org/0000-0002-2520-3272 Jerome Hadjadj 1 ,
• http://orcid.org/0000-0002-0866-3824 Yann Nguyen 2 ,
• Dalila Mouloudj 1 ,
• Rim Bourguiba 3 , 4 ,
• Mael Heiblig 5 ,
• Hassina Aloui 3 ,
• Chloe McAvoy 1 ,
• Valentin Lacombe 6 ,
• Samuel Ardois 7 ,
• http://orcid.org/0000-0001-6806-3794 Corrado Campochiaro 8 ,
• Alexandre Maria 9 ,
• http://orcid.org/0000-0002-7317-2933 Cyrille Coustal 9 ,
• Thibault Comont 10 ,
• Estibaliz Lazaro 11 ,
• Francois Lifermann 12 ,
• Guillaume Le Guenno 13 ,
• Hervé Lobbes 13 ,
• Vincent Grobost 13 ,
• Roderau Outh 14 ,
• Julien Campagne 15 ,
• Anais Dor-Etienne 15 ,
• Alice Garnier 16 ,
• http://orcid.org/0000-0001-5249-3650 Yvan Jamilloux 17 ,
• Antoine Dossier 18 ,
• http://orcid.org/0000-0002-6547-232X Maxime Samson 19 ,
• Sylvain Audia 19 ,
• Barbara Nicolas 19 ,
• Alexis Mathian 20 ,
• Baptiste de Maleprade 21 ,
• Benjamin De Sainte-Marie 22 ,
• Benoit Faucher 22 ,
• Jean-David Bouaziz 23 ,
• Jonathan Broner 24 ,
• Cyril Dumain 24 ,
• Carole Antoine 25 ,
• Benjamin Carpentier 26 ,
• Brice Castel 27 ,
• Celine Lartigau-Roussin 28 ,
• http://orcid.org/0000-0002-3964-4968 Etienne Crickx 29 ,
• Geoffroy Volle 29 ,
• Damien Fayard 30 ,
• http://orcid.org/0000-0003-3388-0991 Paul Decker 31 ,
• http://orcid.org/0000-0003-4134-6086 Thomas Moulinet 31 ,
• http://orcid.org/0000-0003-1105-7662 Anael Dumont 32 ,
• Alexandre Nguyen 32 ,
• Achille Aouba 32 ,
• Jean-Philippe Martellosio 33 ,
• Matthieu Levavasseur 34 ,
• Sebastien Puigrenier 35 ,
• Pascale Antoine 35 ,
• Jean-Thomas Giraud 36 ,
• Olivier Hermine 37 ,
• Carole Lacout 6 ,
• Nihal Martis 38 ,
• Jean-Denis Karam 39 ,
• Francois Chasset 40 ,
• http://orcid.org/0000-0002-8077-8394 Laurent Arnaud 41 ,
• Paola Marianetti 42 ,
• Christophe Deligny 43 ,
• http://orcid.org/0000-0001-5114-3093 Thibaud Chazal 44 ,
• Pascal Woaye-Hune 45 ,
• Murielle Roux-Sauvat 46 ,
• Aurore Meyer 47 ,
• Pierre Sujobert 48 ,
• Pierre Hirsch 49 ,
• Noemie Abisror 1 ,
• Pierre Fenaux 50 ,
• Olivier Kosmider 51 ,
• Vincent Jachiet 1 ,
• Olivier Fain 1 ,
• http://orcid.org/0000-0001-6612-7336 Benjamin Terrier 52 ,
• http://orcid.org/0000-0003-2849-3049 Arsène Mekinian 1 ,
• http://orcid.org/0000-0001-6668-8854 Sophie Georgin-Lavialle 3
• 1 Sorbonne Université, service de médecine interne, Hôpital Saint-Antoine, AP-HP , Paris , France
• 2 Service de médecine interne, Hôpital Beaujon, AP-HP.Nord, Université Paris Cité , Clichy , France
• 3 Médecine Interne, CEREMAIA, Sorbonne Université , Hospital Tenon , Paris , France
• 4 Université Tunis el Manar, Faculté de médecine de Tunis , Tunis , Tunisia
• 5 Hématologie, Hôpital Lyon Sud - HCL , Pierre-Bénite , France
• 6 Department of Internal Medicine , University Hospital Centre Angers , Angers , Pays de la Loire , France
• 7 Médecine interne , CHU Rennes , Rennes , France
• 8 Unit of Immunology, Rheumatology, Allergy ad Rre Disesaes. IRCCS San Raffaele Hospital. Vita-Salute Vita-Salute San Raffaele University , Milan , Italy
• 9 Department of Internal Medicine - Multi-organ Diseases, St Eloi Hospital, Montpellier University Hospital, Univ Montpellier , Montpellier , France
• 10 Service de médecine interne IUCT-Oncopole, CHU Toulouse, Université Paul Sabatier , Toulouse , France
• 11 Internal Medicine , CHU de Bordeaux , Bordeaux , Nouvelle-Aquitaine , France
• 12 Service de médecine interne , Centre Hospitalier Dax , Dax , Nouvelle-Aquitaine , France
• 13 Médecine Interne , CHU Estaing , Clermont-Ferrand , Auvergne-Rhône-Alpes , France
• 14 Service de médecine interne et générale , Perpignan University , Perpignan , France
• 15 Médecine Interne , Hôpital Robert Schuman , Metz , France
• 16 Hematology Department, Nantes University Hospital , Nantes , France
• 17 Department of Internal Medicine, Hôpital Universitaire de la Croix-Rousse, Hospices Civils de Lyon, University Claude Bernard Lyon 1 , Lyon , France
• 18 Service de Médecine Interne, Hôpital Bichat-Claude-Bernard, APHP , Paris , France
• 19 Service de Médecine Interne et Immunologie Clinique, Centre de Référence Constitutif des Maladies Auto-immunes et Auto-inflammatoires Rares de l’adulte, CHU Dijon-Bourgogne, Dijon,France; Université de Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, RIGHT Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire et Génique , Dijon , France
• 20 French National Referral Center for Systemic Lupus Erythematosus, Antiphospholipid Antibody Syndrome and Other Autoimmune Disorders, Service de Médecine Interne 2, Institut E3M, Inserm UMRS, Centre d’Immunologie et des Maladies Infectieuses (CIMI-Paris) , Hôpital Universitaire Pitié Salpêtrière , Paris , Île-de-France , France
• 21 Rhumatologie , CHU de Rouen , Rouen , Normandie , France
• 22 Department of Internal Medicine, Centre Hospitalier Universitaire de La Timone , Marseille , France
• 23 Dermatology , Hopital Saint-Louis , Paris , Île-de-France , France
• 24 Internal Medicine Department , University Hospital Centre Nimes , Nimes , France
• 25 Internal Medicine , Sainte-Anne Military Teaching Hospital , Toulon , Provence-Alpes-Côte d'Azu , France
• 26 Hématologie clinique , Universite Catholique de Lille Hopital Saint-Vincent de Paul , Lille , Hauts-de-France , France
• 27 Service de Médecine Interne et d'Immunologie clinique, Centre Hospitalier de Lourdes , Lourdes , France
• 28 Internal Medicine, CH Ouest Reunion , Saint Paul , France
• 29 Centre national de référence des cytopénies auto-immunes de l'adulte, Hôpital Henri Mondor, Fédération Hospitalo-Universitaire TRUE InnovaTive theRapy for immUne disordErs, Assistance Publique Hôpitaux de Paris (AP-HP), Université Paris Est Créteil , Créteil , France
• 30 University Hospital Centre Gabriel Montpied , Clermont-Ferrand , Auvergne-Rhône-Alpes , France
• 31 Médecine interne et immunologie clinique, CHU de Nancy, UMR 7365, IMoPA, Université de Lorraine, CNRS , Nancy , France
• 32 Department of Internal Medicine , University Hospital Centre Caen , Caen , Basse-Normandie , France
• 33 Department of Internal Medicine , Centre Hospitalier Universitaire de Poitiers , Poitiers , France
• 34 Dermatologie, Centre Hospitalier Genevois , Annecy , France
• 35 Department of Internal Medicine, Centre hospitalier de Boulogne-sur-Mer , Boulogne-sur-Mer , France
• 36 Internal Medicine Unit, Tarbes Hospital , Tarbes , France
• 37 Hematology , Hopital Necker-Enfants Malades , Paris , France
• 38 Internal Medicine Department, University Hospital of Nice, Archet 1 Hospital , Nice , France
• 39 Department of Internal Medicine Amiens University Hospital , Amiens , France
• 40 Sorbonne Université, Faculté de Médecine, AP-HP, Service de Dermatologie et Allergologie , Paris , France
• 41 Department of Rheumatology. National reference Center for rare diseases (RESO). Hôpitaux Universitaires de Strasbourg et INSERM UMR-S 1109 , Strasbourg , France
• 42 Service de médecine interne, maladies infectieuses, immunologie clinique , Reims Champagne-Ardenne University , Reims , France
• 43 Service de Médecine Interne , University Hospital of Martinique , Fort-de-France , Martinique
• 44 Internal Medicine , The Fondation Adolphe de Rothschild Hospital , Paris , France
• 45 Service de Médecine interne, CHD Vendée , La Roche-sur-Yon , France
• 46 Service de médecine interne, Pierre Oudot Hospital of Bourgoin-Jallieu , Bourgoin-Jallieu , France
• 47 Service d'immunologie clinique et médecine interne , Hopitaux universitaires de Strasbourg , Strasbourg , Alsace , France
• 48 Hospices Civils de Lyon, Hôpital Lyon Sud, Service d'hématologie biologique , Pierre Bénite , France
• 49 Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, CRSA, AP-HP, SIRIC8 CURAMUS, Hôpital Saint-Antoine, Service d'Hématologie Biologique , Paris , France
• 50 Hématologie, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, Université Paris Cité , Paris , France
• 51 Service d’Hématologie Biologique, DMU BioPhyGen , APHP , Paris , France
• 52 Médecine interne, Hôpital Cochin, AP-HP.Centre, Université Paris Cité , Paris , France
• Correspondence to Dr Jerome Hadjadj, Hopital Saint-Antoine Service de Medecine Interne, Paris, Île-de-France, France; jerome.hadjadj{at}aphp.fr ; Professor Sophie Georgin-Lavialle; sophie.georgin-lavialle{at}aphp.fr

Objectives Vacuoles, E1 enzyme, X-linked, autoinflammatory and somatic (VEXAS) syndrome is an adult-onset autoinflammatory disease associated with somatic ubiquitin-like modifier-activating enzyme 1 (UBA1) mutations. We aimed to evaluate the efficacy and safety of targeted therapies.

Methods Multicentre retrospective study including patients with genetically proven VEXAS syndrome who had received at least one targeted therapy. Complete response (CR) was defined by a clinical remission, C-reactive protein (CRP) ≤10 mg/L and a ≤10 mg/day of prednisone-equivalent therapy, and partial response (PR) was defined by a clinical remission and a 50% reduction in CRP levels and glucocorticoid dose.

Results 110 patients (median age 71 (68–79) years) who received 194 targeted therapies were included: 78 (40%) received Janus kinase (JAK) inhibitors (JAKi), 51 (26%) interleukin (IL)-6 inhibitors, 33 (17%) IL-1 inhibitors, 20 (10%) tumour necrosis factor (TNFα) blockers and 12 (6%) other targeted therapies. At 3 months, the overall response (CR and PR) rate was 24% with JAKi, 32% with IL-6 inhibitors, 9% with anti-IL-1 and 0% with TNFα blockers or other targeted therapies. At 6 months, the overall response rate was 30% with JAKi and 26% with IL-6 inhibitors. Survival without treatment discontinuation was significantly longer with JAKi than with the other targeted therapies. Among patients who discontinued treatment, causes were primary failure, secondary failure, serious adverse event or death in 43%, 14%, 19% and 19%, respectively, with JAKi and 46%, 11%, 31% and 9%, respectively, with IL-6 inhibitors.

Conclusions This study shows the benefit of JAKi and IL-6 inhibitors, whereas other therapies have lower efficacy. These results need to be confirmed in prospective trials.

• Biological Therapy
• Inflammation
• Tumor Necrosis Factor Inhibitors

Data availability statement

Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information.

https://doi.org/10.1136/ard-2024-225640

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WHAT IS ALREADY KNOW ON THIS TOPIC

Vacuoles, E1 enzyme, X-linked, autoinflammatory and somatic (VEXAS) syndrome is an autoinflammatory disease caused by acquired mutations in UBA1 that requires immunosuppressive drugs to control manifestations.

Due to its recent description, current evidence in therapeutic management of patients with VEXAS comes mostly from small retrospective studies.

WHAT THIS STUDY ADDS

This retrospective multicentre study reports on the efficacy and safety of various targeted therapies for the treatment of VEXAS syndrome in the largest cohort studied to date.

We found that JAK and IL-6 inhibitors showed an overall response rate at 6 months of 30% and 26%, respectively, whereas the other targeted therapies appeared to have a lower efficacy.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

This study confirms the benefit of JAKi and IL-6 inhibitors, whereas the other targeted therapies appear to be less effective.

These results need to be confirmed in prospective therapeutic trials.

Introduction

Vacuoles, E1 enzyme, X-linked, autoinflammatory and somatic (VEXAS) syndrome is a recently described autoinflammatory monogenic disorder associated with acquired somatic mutation in the ubiquitin-like modifier activating enzyme 1 (UBA1) gene in haematopoietic progenitors, an X chromosome gene involved in ubiquitin activation and a key actor of the ubiquitin-proteasome system. 1 VEXAS syndrome mostly affects men over the age of 50 years. Patients present a broad spectrum of inflammatory manifestations and cytopenia, less commonly in the setting of myelodysplastic syndrome (MDS). 1 2 VEXAS syndrome is probably underdiagnosed with an estimated prevalence of 1/4000 in men over 50 years of age. 3 The prognosis is poor with a 5-year survival rate of 63% in the French VEXAS cohort. 2 The pathophysiology of VEXAS syndrome suggests a bias of haematopoietic stem cells towards a myeloid differentiation and an activation of multiple inflammatory pathways in the myeloid lineage. 4 Indeed, significant increased serum levels of proinflammatory cytokines such as interleukin (IL)-6 and IL-1-beta have been reported in patients. 5

Due to its recent description, the therapeutic management of patients with VEXAS is not based on high-quality data, and current evidence comes mostly from small retrospective studies. 6–10 Although glucocorticoids are used as first-line treatment and are effective when used at high doses, most patients have a glucocorticoid-dependent disease. 2 Traditional disease-modifying antirheumatic drugs (DMARDs) such as methotrexate, mycophenolate, azathioprine or hydroxychloroquine have not shown a significant steroid-sparing effect, 2 and drugs such as azathioprine should be avoided as it has been associated with therapy-related myeloid neoplasms and may promote clonal transformation. 11 12 Glucocorticoid-sparing agents currently available include biologic DMARDs (eg, IL-6, TNFα or IL-1 inhibitors), Janus kinase (JAK) inhibitors (JAKi) and azacitidine for MDS. 1 2 6 10 13 Allogeneic haematopoietic stem cell transplantation also appears to be effective for refractory disease in rare eligible patients. 14 Tocilizumab, an anti-IL6 receptor monoclonal antibody, has shown efficacy in small case series. 8 9 In a multicentre international retrospective study involving 30 patients, ruxolitinib showed superior efficacy to other JAKi with a clinical and biological response rate of 80% at 3 months. 6 However, there are currently no comparative studies between different therapies and no codified therapeutic strategy. Therefore, the aim of this study was to evaluate the efficacy and safety of targeted therapies in a cohort of patients with VEXAS syndrome.

This multicentre retrospective study was conducted within the French national VEXAS registry between November 2020 and August 2023 and included patients older than 18 years with genetically proven (ie, confirmed UBA1 mutation) VEXAS syndrome, who received at least one targeted therapy during follow-up including monoclonal antibodies and/or JAKi for relapsing disease, glucocorticoid dependence and/or inadequate response to glucocorticoids. Rheumatologists, internists and haematologists were invited to participate in this study through the French national VEXAS study group network. This study was conducted in accordance with the Good Clinical Practice protocol and the tenets of the Declaration of Helsinki principles.

Data collection

Clinical and biological data were collected retrospectively using a standardised case report form at diagnosis of VEXAS syndrome; before and at the initiation of targeted therapy: during follow-up at 3, 6, 12 months; and at the last follow-up. Clinical and biological assessments included clinical manifestations, routine laboratory tests, genetic features and treatment characteristics. Associated haematological disorders were assessed using the 2016 WHO criteria. Records were collected, and data were entered centrally. The follow-up ended with discontinuation of the biological agent or the last date at which the patient was still receiving the biological agent.

Outcome definition

The primary outcomes were complete response (CR) defined by clinical remission (absence of clinical symptom related to VEXAS syndrome), C-reactive protein (CRP) ≤10 mg/L and a ≤10 mg/day of prednisone-equivalent therapy. As a secondary outcome, also, we evaluated partial response (PR) defined by clinical remission and a 50% reduction in CRP levels and prednisone-equivalent dose as compared with baseline. Global response was defined as a CR or a PR. Treatment failure was defined by persistence of clinical activity (even if improvement was observed) and/or biological inflammatory syndrome and/or inability to reduce glucocorticoid therapy. To minimise bias from the effect of each drug on the CRP concentration, a sensitivity analysis that excluded the requirement for a normalised CRP concentration from the definition of remission was also performed. When available, we also evaluated red blood cell transfusion dependency and clonal burden of UBA1-mutated cells by measuring the UBA1 variant allele frequency in peripheral blood.

Statistical analyses

Descriptive analyses are presented as counts (percentages) for categorical variables and medians (IQR) for continuous variables. We first described the clinical characteristics at VEXAS diagnosis, the mutations and the median glucocorticoid dose and CRP levels at the initiation of each targeted therapy, overall, and according to each targeted therapy (JAKi, IL-6 and IL-1 inhibitors, TNF-α blockers and others) received during follow-up. We also described the rates of CR, PR, treatment failure or treatment discontinuation at each time point (3, 6 and 12 months), according to the specific targeted therapy. If a component of the definition of CR or PR was missing, it was imputed to the last observation carried forward (ie, missing CRP at 6 months was imputed to the 3-month value). We compared CRP, haemoglobin levels and daily glucocorticoid doses (prednisone equivalent) at each time point. We did not make statistical comparisons for these outcomes because patients could receive multiple lines of targeted therapy. We also assessed the factors associated with achieving a global response after 6 months of targeted first-line treatment. Associations were assessed using univariate logistic regression models. We compared the survival without treatment withdrawal according to each targeted therapy with Cox proportional HR models. For this analysis, patients contributed time person from the start of each targeted therapy until discontinuation, death or the end of the study period. As patients could receive multiple lines of treatment, each patient could contribute to many targeted therapy groups. We described the reasons for discontinuation of a targeted therapy and the associated side effects. P<0.05 was considered statistically significant. All analyses were performed using R V.4.1.3 (R Foundation for Statistical Computing, Vienna, Austria).

110 patients (109 (99%) male, median age 71 (68–79) years) who had received 194 targeted therapies were included. Baseline characteristics are shown in table 1 . The main clinical features of VEXAS syndrome at the initiation of targeted therapy were constitutional symptoms (82%), skin involvement (76%) and inflammatory arthralgia (60%). UBA1 mutations were p.Met41Val in 33% of cases, p.Met41Thr in 29%, p.Met41Leu in 20% and others in 15%. MDS was present in 29% of cases with no indication for specific haematological treatment. The median CRP level at treatment initiation was 60 (30–130) mg/L, and glucocorticoids were continued in 94% of cases (median prednisone dose 20 (10–40) mg/day).

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Patient characteristics at targeted therapy initiation

The reasons for starting a targeted therapy were relapsing disease in 39% of cases, glucocorticoid dependence in 27% and inadequate response to glucocorticoids as judged by the physician in 22%. 53 patients (48%) and 22 (20%) received 2 or ≥3 targeted therapies, respectively. The treatments received were JAKi in 78 (40%) of the cases (including ruxolitinib in 68, tofacitinib in 7, baricitinib in 2 and upadacitinib in 1), IL-6 inhibitors in 51 (26%; tocilizumab in 47 and sarilumab in 4), IL-1 inhibitors in 33 (17%)anakinra in 30 and canakinumab in 3), TNF-α blockers in 20 (10%; infliximab in 11, adalimumab in 7 and etanercept in 2) and other targeted therapies in 12 (6%; rituximab in 5, ustekinumab in 2, belimumab in 1, abatacept in 1, secukinumab in 1, dupilumab in 1 and omalizumab in 1). Ruxolitinib was given at a mean starting dose of 20 mg/day (range 10–40 mg/day), and IL-6 inhibitors were used intravenously in 68% of cases. Targeted therapies were associated with methotrexate in seven patients, with ciclosporin in one and with colchicine in one. JAKi and IL-6 inhibitors were mostly prescribed after 2021 (93% and 53% of cases, respectively), whereas IL-1 inhibitors, TNF-α blockers and other targeted therapies were mostly prescribed before 2021 (68%, 86% and 75% of cases, respectively) ( online supplemental figure S1 ). Overall, there were only few differences in patient’s characteristics between the biologics ( table 1 ).

Supplemental material

Efficacy of targeted therapies.

Response rates by targeted treatment received are shown in figure 1 and table 2 . At 3 months, the overall response rates (CR and PR) were 24% (CR 19% and PR 5%) with JAKi, 32% (CR 20% and PR 12%) with IL-6 inhibitors, 9% with IL-1 inhibitors and 0% with TNF α blockers or other targeted therapy. At 6 months, the overall response rates were 30% (CR 26% and PR 4%) with JAKi and 26% (CR 20% and PR 6%) with IL-6 inhibitors. Finally, at 12 months, the overall response rates were 30% (CR 26% and PR 4%) with JAKi and 26% (CR 20% and PR 6%) with IL-6 inhibitors. Twenty-four (22%) patients were treated with JAKi after IL-6 inhibitor failure or intolerance with response at 6 months in 6 (25%), whereas only 3 patients received IL-6 inhibitors after JAKi failure or intolerance without response. Sensitivity analysis that excluded the requirement for a normalised CRP concentration from the definition of remission showed CR rates of 39% with JAKi and 29% with IL-6 inhibitors at 6 months and 37% with JAKi and 21% with IL-6 inhibitors at 12 months ( table 2 ). Survival without treatment withdrawal was significantly longer with JAKi than with the other targeted therapies with a median time to discontinuation of 7.3 (3.5–12.5) months with JAKi, 5.2 (2.0–9.2) months with IL-6 inhibitors and 3.8 (2.6–6.2) months with the other therapies (p<0001, figure 2A ). Glucocorticoid sparing effect was similar between groups in patients who continued treatment, with doses decreasing from 20 (10–35) mg per day at baseline to 10 (8–15) at 3 months, to 8 (5–10) at 6 months and to 7 (5–10) at 12 months. At 6 months, 25% and 20% of patients still under treatment had prednisone-equivalent dose ≤5 mg per day in the JAKi and IL-6 inhibitor group, respectively, whereas only 9% in both groups had been completely weaned ( table 2 ). Sixteen (21%) and 10 (20%) patients were red blood cell transfusion dependent at the initiation of JAKi and IL-6 inhibitors, respectively, and 3 out of 16 (19%) with JAKi and 3 out of 10 (30%) with IL-6 inhibitors achieving transfusion independence after 6 months of treatment. Longitudinal monitoring of the clonal burden of UBA1-mutated cells, performed by measuring the UBA1 variant allele frequency in peripheral blood, was available for eight patients with JAKi and five with IL-6 inhibitors. No significant effect of both drugs was observed on clonal evolution ( online supplemental figure S2 ).

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Response rates according to treatment received.

Survival without treatment withdrawal.

Targeted-therapy response

In univariate analysis, factors significantly associated with achieving a global response to first-line targeted therapy at 6 months were older age at treatment initiation (82.6 vs 72.4 years; OR 1.07 per 1 year; 95% CI 1.03 to 1.12) and treatment with JAKi (OR 19.20; 95% CI 3.46 to 360.53) or anti-IL-6 (OR 20.95; 95% CI 3.70 to 396.26). Clinical manifestations, mutation type, CRP levels and presence of MDS were not associated with response to first-line therapy at 6 months ( table 3 ).

Factors associated with achieving a global response after 6 months of targeted first-line treatment

Safety of targeted therapies

Treatment was discontinued in 28% (n=22) of cases with JAKi with a median delay of 7.2 (3.4–12.4) months, in 69% of cases with IL-6 inhibitors with a median delay of 5.1 (2–9.1) months, in 79% of cases with IL-1 inhibitors with a median delay of 1.1 (0.9–3.0) months, in all cases with TNF α blockers with a median delay of 3.8 (1.7–6.6) months and in 92% of cases with other therapies with a median delay of 4.1 (3.2–5.0) months. The reasons for discontinuation are shown in table 4 . Among patients who stopped treatment, primary failure, secondary failure, serious adverse events and death were reported in 43%, 14%, 19% and 19% for JAKi; 46%, 11%, 31% and 9% for IL-6 inhibitors; 50%, 4%, 35% and 8% for IL-1 inhibitors; and 74%, 5%, 16% and 5% for TNF α blockers, respectively. All adverse drug reactions (ADRs) are detailed in table 5 . Any ADRs tended to be more frequent with IL-6 inhibitors than with JAKi (63% vs 46%). The most common ADRs were infections and cytopenia with JAKi and anti-IL-6 without significant differences between the two groups. Local or systemic drug reaction was the most common ADR with anti-IL-1. At the last follow-up, 24 (22%) patients died, from infections in 13 cases, from cardiac origin in 4, from cancer in 2, from hemopathy evolution in 1 and from unknown origin in 4.

Reasons for discontinuation of targeted therapy

Adverse event

This retrospective multicentre study reports on the efficacy and safety of targeted therapies for the treatment of VEXAS syndrome in the largest cohort studied to date. In total, we describe 78 exposures to JAKi, 51 to IL-6 inhibitors, 33 to IL-1 inhibitors, 20 to TNF-α blockers and 12 to other therapies in 110 patients. The study population consisted of patients with a classic VEXAS presentation, although MDS was less common (29%) than in the French initial VEXAS registry (50%), probably because inflammatory manifestations were more prominent in this cohort. 2 All patients presented with refractory/relapsing or glucocorticoid-dependent disease. JAKi and IL-6 inhibitors showed an overall response rate at 6 months of 30% and 26%,respectively (mainly CR), whereas the other targeted therapies appeared to have a lower efficacy. The better efficacy of these two drugs was confirmed in a sensitivity analysis that excluded the requirement for normalised CRP levels from the definition of remission, with a trend towards a better efficacy of JAKi. Glucocorticoid reduction was similar in patients who continued treatment, and no major differences in safety profiles were observed between JAKi and IL-6 inhibitors. Survival without treatment discontinuation was significantly longer with JAKi than with the other targeted therapies, possibly reflecting the frequent use of JAKi as a rescue treatment following the publication of Heiblig et al 6 ; 24 (22%) patients received JAKi after IL-6 inhibitors, whereas only 3 received IL-6-inhibitors after JAKi. No significant clinical or biological factors associated with response were identified.

Although not mutually exclusive, patients with VEXAS will often have either a more dominant haematological presentation (eg, cytopenias and myelodysplasia) or an autoinflammatory presentation. Consequently, the treatments used to manage VEXAS need to be considered based on the individual presentation and may need to be modified over time as the disease progresses. 12 To date, no prospective trials have been completed to guide treatment in VEXAS, and information beyond glucocorticoids is limited to observational reports or small cohort studies. In patients with a predominant inflammatory presentation, glucocorticoids are necessary and useful to control symptoms. A significant proportion of patients with VEXAS can be effectively controlled with a low, safe dose of prednisolone, but the majority of patients have a glucocorticoid-dependent disease with significant short-term and long-term toxicity, and effective steroid-sparing agents are urgently needed. 2 10 13

We confirmed that JAKi (ruxolitinib in 87% of cases) are effective therapeutic options in VEXAS syndrome. In a previous multicentre international retrospective cohort of 30 patients, ruxolitinib (JAK1/2i) was found to have a greater efficacy in terms of clinical CR at 3 months (83% vs 18%) and 6 months (87% vs 11%) compared with other JAKi commonly used in rheumatology (tofacitinib, baricitinib or upadacitinib). 6 In addition, the efficacy of ruxolitinib was similar in patients with and without myeloid neoplasms. The superior efficacy of ruxolitinib compared with other JAKi may be due to its anti-JAK2 effect that might be prominent in the pathogeny of VEXAS syndrome. 6 15 16 Response rates were significantly lower in our study than in previous studies, probably due to more restrictive response definitions that included both clinical and biological responses associated with glucocorticoid withdrawal. Indeed, response criteria are not currently consensual, and international guidelines are underway to standardise these criteria across the different VEXAS trials. We chose a ≤10 mg/day of prednisone-equivalent therapy cut-off that seemed clinically relevant to us.

IL-6 inhibitors (mainly tocilizumab) were the second most efficient drug in this study. Previous studies have reported that tocilizumab appears to have a favourable, although sometimes partial, suppressive effect on the inflammatory response. 8 9 17 18 In a systematic review, two-thirds of patients were able to achieve glucocorticoid reduction, but only 20% achieved a CR, while 40% had a PR. 9 Therefore, depending on the patient’s condition and any contraindications to each treatment (ie, cardiovascular risk or cytopenia with JAKi vs risk of bowel perforation with tocilizumab), tocilizumab may represent an alternative option to JAKi for the treatment of patients with VEXAS syndrome.

IL-1 (anakinra and canakinumab) and TNF-α blockers are commonly used in patients with autoinflammatory diseases, especially IL-1 inhibitors for inflammasomopathies. However, although high levels of TNF-α and IL-1-β with activation of inflammatory pathways at the transcriptional level have been observed in VEXAS, 4 5 the present study found reduced or no efficacy of anakinra or various TNF-α blockers. Importantly, as previously described, 12 these drugs were often associated with moderate/severe local or systemic drug reactions. Of note, only three patients were treated with canakinumab, which has previously been reported to be effective in two published cases, 19 20 and no conclusions can be drawn regarding the efficacy of this treatment.

Although discontinuation due to a serious adverse event tended to be more common with IL-6 inhibitors than with JAKi (31 vs 19%), no major differences were observed in respect to infections (23 vs 29%) and cytopenia (23 vs 29%) which were the most common ADRs or to thrombosis (12 vs 6%) or cardiovascular events (5 vs 6 %). Notably, local or systemic drug reactions were observed in 14% of cases with IL-6 inhibitors and none with JAKi. Thromboembolic events were previously observed in 20% and infections in more than a third of patients receiving JAKi, 6 complications that are also known to be associated with VEXAS activity independently of the treatment received. 2 21 22 Indeed, our group has recently shown that VEXAS is associated with a high risk of serious infections, especially in older patients carrying the p.Met41Val mutation and treated with JAKi, prompting clinicians to consider anti-infective prophylaxis in patients with VEXAS. 21

Another therapeutic strategy in VEXAS syndrome could be to target the haematological UBA1 clone by using hypomethylating agents and early haematopoietic stem cell transplantation. 5-Azacitidine has shown promising results, particularly among patients with MSD, with clinical and haematological responses ranging from 46% to 75% after a minimum of 4–6 cycles. 7 23 Haematopoietic stem cell transplantation was used in few cases for either refractory cytopenias or recalcitrant inflammatory disease and was associated with durable eradication of mutated UBA1 in the marrow. 24 25

This study has some limitations, mainly because of its retrospective design. 18 centres participated in the study, so some data were missing. However, it reports on a large cohort of patients with VEXAS in multiple centres, making it highly representative of patients with VEXAS and their management. A second limitation is the discrepancy between the number of patients included in each treatment arm due to previous much smaller retrospective studies and the general impressions of the community of physicians with clinical experience with VEXAS syndrome that suggested from the very first months after the discovery of the disease that IL-1 inhibitors and TNF-α blockers were less efficient therapeutic options. As mentioned above, response criteria for VEXAS syndrome are not currently consensual, and the criteria used in this study have not been validated. However, we used restrictive response definitions that included both clinical and biological responses associated with glucocorticoid withdrawal. The variety of biologic lines and of unmeasured factors that may have influenced biologic choice or outcomes might limit any definitive direct comparisons.

Thus, prospective studies would be needed to further examine the safety and efficacy of targeted therapies in VEXAS syndrome. In this complex and heterogeneous disease, these trials would make possible to randomise patients to the various treatment options, to standardise the dosing regimens between individual investigators and centres and the collection of laboratory data for each treatment group, to control the order of treatment options and to use consensual and validated response criteria.

In conclusion, this study confirms the benefit of JAKi and IL-6 inhibitors, whereas the other targeted therapies appear to be less effective. These results need to be confirmed in prospective therapeutic trials.

Ethics statements

Patient consent for publication.

Not applicable.

Ethics approval

This study involves human participants and was approved by Ethical Review Committee for publications of the Cochin University Hospital (CLEP decision no.: AAA-2021-08040 not required).

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Supplementary materials

Supplementary data.

This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

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Handling editor Josef S Smolen

X @Maxime_Samson21, @MoulinetThomas, @SophieGeorgin

Collaborators The FRENVEX: Isabelle Melki, Lionel Ades, Lin Pierre Zhao, Alexandra Audemard, Mikael Ebbo, Odile Beyne Rauzy, Alexandre Belot, Raphaël Borie, Ygal Benhamou, Gaetan Sauvetre, Khalil El-Karoui, François Rodrigues, Louis Terriou, Jeremie Dion.

Contributors JH is the guarantor. JH performed research, analysed results and wrote the paper. JH and SG-L designed the study. YN performed statistical analysis. JH and DM collected the data. JH, YN and SG-L analysed results and reviewed the paper. All other authors provided clinical or biological care and reviewed the paper.

Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

Competing interests None declared.

Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

Provenance and peer review Not commissioned; externally peer reviewed.

Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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