Exploring patient-reported outcomes and morbidity burden of patients with VEXAS syndrome: a scoping review.

Research in context Evidence before this study VEXAS is a recently characterized autoinflammatory syndrome that predominantly affects elderly male patients and is associated with a broad spectrum of clinical manifestations. A PubMed search revealed a lack of aggregated data on the morbidity burden associated with VEXAS syndrome, probably reflecting the novelty of the condition. Added value of this study This scoping review provides a comprehensive synthesis of the heterogeneity in VEXAS-related morbidity by aggregating symptom prevalence data from published literature. It highlights that morbidity assessments to date have been exclusively clinician-reported, underscoring a critical gap in patient-centered data. No studies assessing PROs were identified in this review. Implications of all the available evidence These findings underscore the need for prospective, patient-centered studies in VEXAS syndrome. This review supports the systematic integration of PROs in future research and provides insights to inform possible PRO assessment strategies. International efforts are needed to rapidly accumulate knowledge on health-related quality of life and symptoms of patients with VEXAS syndrome.

Introduction

VEXAS (vacuoles, E1 enzyme, X-linked, auto-inflammatory, somatic) is a recently discovered syndrome of autoinflammatory origin. 1 Somatic loss-of-function mutations in the X-linked UBA1 gene, perturbating the ubiquitylation pathway, underlie its pathogenesis. 2 , 3 , 4

This syndrome typically presents during the 6–7th decade of life in men with a diverse clinical picture encompassing a variety of conditions. 5 Skin rashes, polychondritis, fever, pulmonary infiltrates, are among the most common manifestations. Along with these, hematological features and conditions such as macrocytic anemia, myeloid vacuoles, plasma cell dyscrasia, and particularly myelodysplastic syndromes/neoplasms (MDS) are also highly prevalent. 6 , 7 , 8 , 9 Notably, morbidity and mortality can vary based on genotypic features (Met41Val being the most symptomatic subtype) with majority of patients being relapsing/refractory to multiple lines of both rheumatologic and hematologic treatment. 10 , 11 To date, the only curative treatment is allogeneic hematopoietic cell transplantation (allo-HCT), a procedure burdened by inherent mortality risk and reserved only for a minority of eligible cases. 12 , 13 , 14

Due to its highly varied clinical presentation, VEXAS has attracted broad medical interest across multiple medical specialties, highlighting its interdisciplinary nature. 15 Most of our understanding from a clinical and therapeutic standpoint is based on retrospective case series. Indeed, the majority of reported VEXAS cohorts have been so far retrospectively identified, thereby our disease knowledge is fundamentally biased by the VEXAS-agnostic part of the journey of such patients.

Currently, no guidelines exist for the management of the disease and no treatment has in-label indication for VEXAS 16 due to treatment algorithms only being proposed based on retrospective cases and literature analyses. Disease-specific treatment guidelines based on prospective data are urgently needed. 17 Hence, considering the wide spectrum of problems and symptoms at the time of clinical presentation, a key aspect that should also be factored into clinical decision-making is the health-related quality of life (HRQoL) of these patients.

While studies are still investigating the exact demographic magnitude of VEXAS, so far, the condition has been considered rare, given the little number of cases identified, also when screening large disease cohorts (about 1% of MDS, already a rare disease which is present in about 50% of VEXAS) and healthy controls. 2 The rarity of this syndrome may pose specific challenges in the assessment of HRQoL, 18 and some studies have also suggested that HRQoL of patients with rare diseases is lower than that reported by those with most common cancer diagnoses. 19

Therefore, as HRQoL and other type of patient-reported outcomes (PROs) are now critical to make more informed decisions in clinical research and routine hematology practice, 20 we performed a scoping review to describe current knowledge of PROs and morbidity burden of patients with VEXAS syndrome.

Methods

Search strategy and selection criteria

Given the novelty of the topic, a scoping review, following the guidance of Munn and colleagues, 21 was chosen as the preferred method for evidence synthesis to address the research question. This method is the most suitable when the purpose is to provide an overview of the emerging evidence and identify research gaps. 21 No review protocol exists - all information required to replicate the review is reported herein. We queried PubMed to identify published studies on VEXAS documenting HRQoL or any other type of PRO data. However, due to the novelty of the disease, and in an effort to maximize clinically relevant information from this review, we also considered studies documenting VEXAS-related morbidity burden as reported by clinicians. Publications only reporting hematologic or laboratory-based adverse events were not considered.

The search strategy was intentionally broad using only the acronym “VEXAS” without imposing any additional filters on time or other search terms. Furthermore, a backward search of references from identified systematic reviews was performed to identify further literature. The literature search, conducted without a lower date restriction, was last updated in September 2024.

Publications in English of all study types were eligible for inclusion if they reported on at least ten patients. By virtue of this strategy, we aimed to reduce the potential biases and variability inherent to smaller studies (i.e., ineligibility of one-patient case reports, and small case series). For the purpose of this review, abstracts presented at national or international meetings were not considered eligible, as deemed too limited in the reporting of relevant information. If different studies derived from the same registries, these were all included.

Reference selection in Rayyan 22 followed a two-step independent double review procedure. The first level was dedicated to screening the abstracts and the two reviewers (DK, FS) made an initial decision on the eligibility of the identified studies. In the second step, the full texts of the studies were evaluated to reach a final decision on the eligibility of the article. Discrepancies were resolved between the two reviewers; two additional reviewers (CG, FE) were consulted if consensus was not reached. To double-check the selection of articles, a comparison with a list of highly relevant articles provided by two clinical experts in the field (CG, MTV) was also performed. Our search and the reporting in this manuscript follow the recommendations stated in the PRISMA-ScR checklist. 23

Data charting process

The data charting form was developed incorporating clinical expertise, and subsequently piloted and refined before integration into RedCap. 24 Two reviewers (DK, FS) independently extracted data on study characteristics, patient characteristics, and prevalences of manifestations of VEXAS-related morbidity burden.

Study characteristics included the impact factor of the journal, sample size, year of publication, study type, and geographic location. Patient characteristics extracted comprise median age at symptom onset, comorbidities, concomitant diagnoses, and treatments received. For concomitant diagnosis, the main emphasis was on hematological malignancies like multiple myeloma (MM), MDS, and Monoclonal gammopathy of undetermined significance (MGUS). Regarding treatment types, the pre-defined categories in the case report form comprised of steroids and three types of Disease-Modifying Anti-Rheumatic Drugs (DMARDs): biological (bDMARDs), targeted synthetic (tsDMARDs), and conventional synthetic (csDMARDs).

The prevalence of the following VEXAS-related morbidity burden was captured: fever, fatigue, skin involvement, lung involvement (including dyspnea), relapsing polychondritis, arthralgia/arthritis, constitutional symptoms (other than fever and fatigue), periorbital inflammations, cardiological involvement, neurological involvement, gastrointestinal involvement, renal involvement, hearing impairment, urological involvement, liver/spleen involvement, chest pain, and infections. When different symptoms referring to the same categories (e.g., ear chondritis and nose chondritis) had distinct prevalence, we reported the highest prevalence. Additionally, it was recorded if the studies reported transfusion dependence among patients and the respective percentages. Finally, it was noted whether any PROs were assessed in the eligible studies. Any discrepancies during data charting were resolved by the two reviewers (DK, FS), with assistance from a third senior reviewer (CG or FE) in case of dissent.

Data analyses

Data was analyzed in an exclusively descriptive manner. Frequencies and percentages were calculated for categorical variables, while for continuous variables, the mean or median, along with the standard deviation or interquartile range, were reported. All analyses were executed in R (version 2024.09.0 + 375).

Role of the funding source

The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.

Results

The literature search yielded 357 records that were assessed for eligibility. We evaluated a total of 91 full papers and retrieved a total of 31 studies that fulfilled our inclusion criteria. Details of the search strategy and selection process of the articles included in this review are depicted in the PRISMA flowchart ( Fig. 1 ). Fig. 1 PRISMA flowchart.

A total of 1437 patients were analyzed in the selected studies. The median sample size of the studies was 40 patients (IQR 16·0–59·0). Since the first article published in 2020, the number of published studies on this topic has increased over time. In 2021, 4 studies (12·9%) were published, and this proportion has more than doubled in 2024 (n = 10; 32·3%). Almost all studies (n = 30; 96·8%) were non-interventional. More than one-third of the studies were conducted in France (n = 12; 38·7%), 10 (32·3%) studies were conducted in the USA, and 3 (9·7%) in Italy. No studies documenting PROs were identified. Further details on study characteristics are reported in Table 1 . Table 1 Study characteristics (N = 31, including overall N = 1437 patients). Citation Sample size Male/Female ratio (%) Geographic location Prevalence of MDS (%) Beck et al. (2020) 1 25 100/0 US 24 Bourbon et al. (2021) 25 11 100/0 France 55 Ferrada et al. (2021) 26 13 100/0 US 23 Obiorah et al. (2021) 27 16 100/0 US 37·5 Poulter et al. (2021) 28 10 100/0 UK 80 Comont et al. (2022) 29 11 100/0 France 100 Heiblig et al. (2022) 30 30 n/a France 40 Mekinian et al. (2022) 31 12 100/0 France 100 Van Der Made et al. (2022) 32 12 100/0 Netherlands 33·3 Ferrada et al. (2022) 4 83 100/0 UK 31 Georgin-Lavialle et al. (2022) 10 116 95·7/4·3 France 50 Khitri et al. (2022) 33 55 96/4 France 75 Beck et al. (2023) 34 11 81·8/18·2 US 36·4 Borie et al. (2023) 35 45 98/2 France 44 Casal Moura et al. (2023) 36 45 100/0 US 20 Gutierrez-Rodrigues et al. (2023) 37 77 100/0 US 18 Hines et al. (2023) 38 25 100/0 US 12 Mascaro et al. (2023) 39 30 100/0 Spain n/a Zakine et al. (2023) 40 59 97/3 France 37 Rabut et al. (2023) 41 17 88·2/11·8 France 31 De Valence et al. (2024) 42 124 97/3 France 54 Gurnari et al. (2024) 12 19 100/0 Italy 68 Gurnari et al. (2024) 6 41 100/0 Italy 71 Hadjadj et al. (2024) 43 110 99/1 France 29 Kosmider et al. (2024) 44 40 100/0 France 53 Maeda et al. (2024) 45 40 100/0 Japan 52·5 Sirenko et al. (2024) 2 54 94·4/5·6 US 100 Tan et al. (2024) 46 112 99/1 US 15 Vitale et al. (2024) 47 59 98·3/1·7 Italy n/a Kusne et al. (2024) 11 119 100/0 US 30 Johansen et al. (2025) 48 16 100/0 Denmark 25

The median age of patients at VEXAS symptoms onset (available in 15/31 studies) was 67 years (IQR 66·0–68·6, Table 2 ). The median prevalence of males included in the studies (available in 30/31 studies) was 100% (IQR 98·1–100). Detailed information on the presence of comorbidities was reported only in 2 (6·5%) studies. The most prevalent concomitant hematologic disease was MDS, and this was reported in at least one patient with VEXAS within 29 studies (93·6%). Monoclonal gammopathy of undetermined significance and MM were the second and third most prevalent hematologic conditions, reported for at least one patient in 15 (48·4%) and 8 (25·8%) studies, respectively. Twenty-six studies (83·9%) reported the treatment received by patients. Steroids were the most common type of treatment received (n = 24; 77·4%), followed by bDMARDS (n = 18; 58·1%), csDMARDS (n = 17; 54·8%), tsDMARDS (n = 15; 48·4%), and azacytidine (n = 13; 41·9%). Twelve (38·7%) studies analyzing 439 patients reported information on transfusion dependency. The median prevalence of patients reporting transfusion dependency in these studies was 30% (IQR 27·0–46·0). Table 2 Patient characteristics reported in the studies (N = 31). Variable Percentage of male patients included in studies (available for 30 studies) Median (IQR) 100 98·1–100 Age at symptom onset (available for 15 studies) Median (IQR) 67·0 66·0–68·6 Presence of comorbidity, n (%) Unknown 29 93·6 Yes 2 6·5 Treatment received/reported, n (%) Yes 26 83·9 No 5 16·1 Types of treatment received/reported (study-level), n (%) Steroids 24 77·4 bDMARDS 18 58·1 csDMARDS 17 54·8 tsDMARDS 15 48·4 Azacytidine 13 41·9 Ruxolitinib 9 29·0 Other b 15 48·4 Concomitant diagnosis (study-level), n (%) MDS 29 93·6 MGUS 15 48·4 MM 8 25·8 Other hematological malignancies a 9 29·0 Sweet’s syndrome 6 19·4 Polyarteritis nodosa 4 12·9 Adult-onset Still disease 3 9·7 Prevalence of concomitant diagnosis (patient-level), median (IQR) MDS (available for 29 studies) 38 39–55 MGUS (available for 14 studies) 11 9–17·8 MM (available for 7 studies) 4 3–5·5 AML = acute myeloid leukemia; bDMARDS = biological Disease-Modifying Anti-Rheumatic Drugs; CCUS = Clonal Cytopenia of Undetermined Significance; CML = chronic myeloid leukemia; CMML = chronic myelomonocytic leukemia; csDMARDS = conventional synthetic Disease-Modifying Anti-Rheumatic Drugs; DOACs = Direct Oral Anticoagulants; LMWHs = Low Molecular Weight Heparins; NSAIDs = Nonsteroidal Anti-Inflammatory Drugs; MDS = myelodysplastic syndromes; MGUS = monoclonal gammopathy of undetermined significance; MM = multiple myeloma; tsDMARDS = targeted synthetic Disease-Modifying Anti-Rheumatic Drugs. a MPN (N = 3), CMML (N = 2), CML (N = 2), Monoclonal B-cell lymphocytosis (N = 2), AML (N = 1), B-cell lymphoma (N = 1), CCUS (N = 1). b DMARDs (not specified which type) (N = 2), Intravenous immunoglobulins (N = 2), Thalidomide (N = 2), Transfusion (N = 2), Allogenic stem cell transplantation (N = 2), Dapsone (N = 1), Decitabine (N = 1), Disulone (N = 1), DOACs (N = 1), Erythropoietin (N = 1), Hypomethylating agent (N = 1), Lenalidomide (N = 1), LMWHs (N = 1), NSAIDs (N = 1), Potassium iodure (N = 1), Salazopyrin (N = 1).

The data summarized in Table 3 display the type of symptom groups identified across the eligible studies, showcasing the clinical heterogeneity of VEXAS syndrome as documented in the literature. Notably, seven symptom groups were consistently reported in at least half of the evaluated studies, illustrating that, albeit diverse, patterns of clinical manifestations may be recognized. Among these, skin involvement and pulmonary involvement emerged as the most frequently reported manifestations, appearing in 100% and 96·8% of studies, respectively. Other prevalent symptoms included relapsing polychondritis, documented in 90·3% of studies, followed closely by arthralgia or arthritis (83·9%), fever (77·4%), periorbital inflammation (77·4%), and constitutional symptoms (51·6%). The multi-systemic inflammatory nature of VEXAS is further emphasized by six additional symptom clusters affecting different key organ systems (i.e., cardiovascular involvement, neurological involvement, gastrointestinal involvement, renal involvement, hearing impairment, and urological involvement) being reported in at least a quarter of eligible studies. All reported data were based on clinician-reported information, as no study documented PRO data. See Table 3 for a comprehensive list of symptoms reported in the VEXAS literature. Table 3 VEXAS-related morbidity burden at study-level. N of studies % Skin involvement 31 100·0 Pulmonary/Lung involvement 30 96·8 Relapsing polychondritis 28 90·3 Arthralgia/Arthritis 26 83·9 Fever 24 77·4 Periorbital inflammation 24 77·4 Constitutional symptoms 16 51·6 Cardiovascular/Heart involvement 14 45·2 Neurological involvement 12 38·7 Gastrointestinal involvement 10 32·3 Renal involvement 10 32·3 Hearing impairment 10 32·3 Urological involvement 9 29·0 Liver/spleen involvement 7 22·6 Fatigue 5 16·1 Chest pain 2 6·5 Infections 2 6·5 Other 5 16·1

The results presented in Table 4 and partly visualized in Fig. 2 (for descriptive purposes only), provide insight into the prevalence of symptoms reported among VEXAS patients across the respective evaluated studies. Skin lesions emerged as a standout symptom cluster, appearing in all eligible studies and exhibiting the highest average prevalence (median = 83·6%, IQR 76·0–90·0), followed by fever (median = 81·2%, IQR 67·5–89·0), and constitutional symptoms in general (median = 76%, IQR 54·8–85·3). Table 4 Prevalence of VEXAS-related morbidity burden at patient-level. N of studies N of study participants Mean prevalence (SD) Median prevalence (IQR) Skin involvement 31 1437 81·3 (15·7) 83·6 (76·0–90·0) Pulmonary/Lung involvement 30 1396 57·6 (23·1) 56·0 (43·8–73·6) Relapsing polychondritis 28 1337 51·2 (17·0) 47·5 (40·5–53·1) Arthralgia/Arthritis 26 1248 57·9 (20·0) 58·0 (47·0–67·0) Fever 24 901 76·9 (18·9) 81·2 (67·5–89·0) Periorbital inflammation 24 1274 39·8 (13·5) 38·0 (31·0–47·5) Constitutional symptoms 16 806 68·1 (22·3) 76·0 (54·8–85·3) Cardiovascular/Heart involvement 14 714 17·2 (13·2) 12·0 (9·5–18·6) Neurological involvement 12 626 15·4 (14·2) 10·5 (5·8–16·5) Gastrointestinal involvement 10 516 18·9 (14·3) 11·4 (10·3–28·8) Renal involvement 10 384 10·4 (6·8) 8·5 (7·1–9·9) Hearing impairment 10 551 32·4 (15·2) 29·5 (22·8–46·5) Urological involvement 9 344 16·6 (8·6) 13·0 (11·9–18·8) Liver/spleen involvement 7 248 22·2 (15·5) 16·0 (13·4–23·7) Fatigue 5 167 66·8 (22·1) 62·5 (55·0–75·0) Chest pain 2 104 10·3 (11·7) 10·3 (6·2–14·5) Infections 2 135 48·0 (17·0) 48·0 (42·0–54·0) Fig. 2 Median prevalence of VEXAS-related morbidity burden among VEXAS patients in evaluated studies. The manifestations of VEXAS-related morbidity burden highlighted in red have a median prevalence exceeding 50% among VEXAS patients in the eligible studies.

Pulmonary involvement was also frequent, affecting more than half of the evaluated patients on average (median = 56%, IQR = 43·8–73·6). In contrast, symptoms involving other organ systems were observed less commonly, with median prevalences generally around 10% - such as cardiovascular symptoms (12·0%), renal involvement (8·5%), gastrointestinal manifestations (11·4%), and urological symptoms (13·0%). These findings underline the variability in symptom presentation across different organ systems.

For a detailed breakdown of the prevalence of each reported symptom, see Table 4 , which consolidates data extracted from the VEXAS literature. This table underscores the heterogeneity of symptom distribution, highlighting both common and rare manifestations of the VEXAS syndrome.

Discussion

We have identified a notable gap in our knowledge of VEXAS syndrome owing to the lack of any PRO data stemming from current scientific literature. None of the studies identified assessed HRQoL or symptoms as reported by patients themselves, or even reported qualitative data from patients’ interviews. Considering the rare condition of this disease, international collaboration may be critical to maximize efforts to rapidly bridge this gap. For example, the setting-up of an international registry with standardized PRO data collection methods could be instrumental to accelerate our knowledge on the actual burden experienced by patients with VEXAS.

In the meanwhile, our findings provide some initial insights on possible PRO assessment strategies for this rare condition. For example, the identification of symptoms noted in our review (with skin problems representing the most prevalent) may suggest which symptomatic areas can be potentially relevant for these patients. In this respect, we note there are now PRO libraries which include a wide spectrum of symptoms, such as the ones by the MDASI, 49 EORTC, 50 FACIT 51 and the PRO-CTCAE 52 that could be used, for example, for devising a customized (patient-reported) symptoms list to complement traditional safety data in future clinical trials.

However, considering that none of the studies identified in our review included any sort of PRO information, studies to elicit the unique patients’ and caregivers’ perspective on symptoms and other more general HRQoL aspects will be important to start developing a VEXAS patient-centric research agenda. To illustrate, in the studies found in our review it was observed that, on average, nearly half of patients with VEXAS had a concomitant diagnosis of MDS and it is known that this disease, per se, is associated with substantial HRQoL impairments. 53 , 54 , 55 A real-world MDS study found that more than 50% of patients reported clinically relevant problems with physical functioning already at the time of diagnosis, and that this was the case for patients with both lower- and higher-risk disease. 53 However, physical limitations were not documented in the studies identified in our review. Given the high prevalence of anemia in this population, 56 future PRO studies should elucidate its potential impact in terms of physical limitations. Also, considering the auto-inflammatory manifestations of VEXAS which often involve joints, skin and cartilage of ear and nose, the spectrum of the symptomatology experienced by these patients with VEXAS and its impact on HRQoL could be even more substantial than that reported by patients with MDS.

To the best of our knowledge, the only available PRO data for patients with VEXAS has been recently published in an abstract form being presented at the last Annual Conference of the American Society of Hematology (ASH). In a sample of 45 patients with VEXAS, Patel BA and colleagues 57 found that neither UBA1 genotype nor mutational burden was associated with health domains assessed by the Medical Outcomes Survey Short Form (SF)-36 questionnaire. The authors also observed that younger patients suffering from VEXAS syndrome experienced significantly more impact on their mental health than older individuals. This data may be associated with a higher concern about the consequence of a serious disease, and with yet unknown effective therapies, expressed by younger patients who are likely to have more active daily life and family commitments. Another interesting result (albeit not statistically significant) from this valuable abstract 57 was that physical functioning score was lower in those patients who ultimately died during the study period. This data deserves close attention in future research with VEXAS as there is now ample evidence from the cancer literature that self-reported health status information, including physical functioning, provides prognostic information for survival beyond traditional clinical and laboratory exams. 58 , 59

However, the SF-36 questionnaire used in the study by Patel BA and colleagues 57 is a generic PRO measure, thereby unlikely to capture, yet unknown, relevant health aspects for these patients. Efforts should therefore be made to put in place more refined strategies to assess HRQoL of patients with VEXAS in future studies, including clinical trials eagerly needed to expand in-label drug access to patients.

For example, the development of a VEXAS-specific PRO measure could be valuable in order to capture the most relevant symptoms and functional aspects of these patients, and thereby facilitating patient-centered care. In contrast to generic PRO measures, disease-specific questionnaires are purposely devised to assess functional aspects or symptoms that matter most to patients with a particular health condition or diagnosis. 60 In any case, future efforts to devise a PRO-specific measure should include the patient input from the very beginning of the development process. 61

However, it should also be noted that developing new disease-specific HRQoL measures for patients with rare diseases may be challenging for several reasons including, for example, the small sample size available for study validation. 18 , 61 Previous works 18 , 61 have comprehensively addressed this issue providing practical suggestions for alternative approaches, such as using item-banks or adapting existing PRO measures that may also be considered in the setting of rare diseases.

The issue of how to best capture the patient’s voice in this context remains a major challenge but of crucial importance to speed up our knowledge on how to best assist these patients during their treatment journey. This aspect also has implications from a regulatory standpoint. The U.S. Food and Drug Administration (FDA) recently issued a draft guidance to industry that addresses “Rare Diseases: Considerations for the Development of Drugs and Biological Products” by also emphasizing the value of patient-centricity. 62 Indeed, this document notes that “Patient input can provide important information about patients' experiences, perspectives, needs, and priorities that can be incorporated throughout the drug development process”. 62 Therefore, along with ongoing efforts to devise effective treatment strategies, research efforts should also aim to understand how to best harness the patients’ voice into clinically relevant information.

Our review has limitations. Some articles identified were derived from the same registries, therefore some patients might overlap between the selected articles, which could lead to an overestimation of the prevalence of some clinical manifestations. Furthermore, the way of collecting VEXAS-related morbidity burden across the studies was not consistent. Additionally, using a threshold of at least ten patients for inclusion criteria may have resulted in the exclusion of smaller studies that could have been relevant to our review. Finally, considering the scoping nature of this review and that we only searched PubMed and excluded non-English articles, it is possible that we eventually missed potentially relevant studies.

In conclusion, we advocate for urgent international concerted efforts to ensure a rapid uptake of PRO evidence-based data that may inform the development of patient-centric VEXAS clinical trials and therapies.

Contributors

FE supervised the project, contributed to the data collection, data analysis, data interpretation, figure making, manuscript writing and revision. DK contributed to the literature search, literature review, data interpretation, figure making, data analysis, and manuscript writing. FS contributed to the literature search, literature review, data interpretation, and manuscript writing. PF and MTV contributed to manuscript editing and provided expert advice on the content matter. CG supervised the project, contributed to the data collection, data analysis, data interpretation, figure making, manuscript writing and revision. FE, DK, FS, and CG accessed and verified the underlying data. All authors have seen and approve of the final version of this manuscript.

Data sharing statement

The authors confirm that the data supporting the findings of this study are available within this article.

Declaration of interests

FE: Research support (institution): Daiichi Sankyo; Consulting fees: AbbVie, Incyte, Novartis.

MTV: Consulting fees: JAZZ Pharmaceuticals, Daiichi Sankyo; Speaker’s Bureau: Celgene/BMS, Astellas, JAZZ Pharmaceuticals, AbbVie, Novartis, Daiichi Sankyo, Servier, Advisory Board: Celgene/BMS, JAZZ Pharmaceuticals, Servier.

CG: Consulting fees: Genesis Therapeutics, Advisory board: Novartis & Sobi.

The other authors declare no competing interests.

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