Establishing a consensus definition of VEXAS flare for clinical research

Abstract

Objective:

VEXAS syndrome is a severe systemic haemato-inflammatory disease with heterogeneous clinical presentations. Most patients experience recurrent inflammatory flares despite anti-inflammatory therapy. The lack of accepted definitions of flare in these patients is preventing development of disease activity tools that are essential for conducting clinical trials. We aimed to develop a consensus definition of a VEXAS flare for use in clinical trials.

Methods:

A 9-member international expert advisory committee established a consensus definition of VEXAS flare using modified Delphi methodology. Clinical inflammatory manifestations of VEXAS syndrome were identified through a systematic literature review. Committee members developed a conceptual framework for flare definition, proposed revisions, and voted on changes until consensus (≥75% concurrence) was reached.

Results:

Consensus defined VEXAS flare as active inflammatory manifestation(s) of VEXAS syndrome requiring escalation in glucocorticoid therapy. Three flare categories were established: A) recurrence of a prior documented VEXAS manifestation; B) development of a new VEXAS-defining inflammatory manifestation; or C) emergence of a new inflammatory manifestation not meeting criteria for A or B. The panel endorsed an independent adjudication committee to assess Category C flares in clinical trials.

Conclusions:

This study proposes a standardized definition of VEXAS flare, providing uniform criteria for identifying VEXAS disease activity. Future research will evaluate its performance in clinical trials.

Graphical Abstract

Introduction

Vacuoles, E1 enzyme, X-linked, Autoinflammatory, and Somatic (VEXAS) syndrome (hereafter, VEXAS) is a recently recognized systemic disease driven by somatic haematopoietic mutations in the UBA1 gene. The most common reported mutations are missense or splice site mutations at exon 3. These mutations result in loss of the active cytoplasmic ubiquitin-like modifier-activating enzyme 1 (UBA1) isoform. Clinical manifestations in VEXAS are heterogenous, including chondritis, arthritis and arthralgias, cutaneous, ocular, and respiratory involvement, and progressive bone marrow failure [1–3].

Persistent systemic inflammation, often requiring long-term glucocorticoid therapy, is common in patients with VEXAS. Although steroid-sparing agents are often used in conjunction with glucocorticoids, these therapies have not been studied prospectively, and efficacy has been limited. Treatment for VEXAS continues to be challenging, and there are no approved treatments, leaving glucocorticoids as the mainstay of therapy for patients with inflammatory manifestations [4]. In the absence of effective targeted therapies, patients experience severe and debilitating side effects and complications of long-term steroid use.

A major barrier to advancing clinical research in this area is the lack of established endpoints. Efforts to assess disease activity in VEXAS have relied on adapting instruments developed for other diseases, which fail to fully capture VEXAS-specific disease activity. Retrospective analyses have applied International Working Group response criteria for myelodysplastic neoplasms (MDS) to assess response to hypomethylating agents [5, 6], though these criteria do not capture auto-inflammatory manifestations central to VEXAS. Inflammation-oriented response has been described in several retrospective analyses, measured by subjective resolution of clinical manifestations, time to next steroid-sparing therapy and normalization of acute phase reactants [5, 7–9]. However, neither haematologic nor inflammation-related response criteria have been implemented prospectively, and no consensus definition of VEXAS flare or treatment response has been established.

In established rheumatologic diseases, validated disease activity indices (DAI), such as Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI), American College of Rheumatology 20% response criteria (ACR20; for rheumatoid arthritis), Birmingham Vasculitis Activity Score (BVAS), and Psoriasis Area and Severity Index (PASI), standardize disease assessment and guide treatment. For VEXAS, defining disease flare is a critical first step toward developing a validated DAI and will facilitate clinical research in this area of unmet need. We present a detailed VEXAS flare definition, developed through a Delphi exercise with an international cohort of VEXAS experts. This definition will serve as the foundation for future clinical trials, providing a framework for measuring flare frequency or flare-free survival, while also improving disease monitoring and patient care.

Methods

Panel selection and establishment of a hypothetical framework for flare definition

An international physician expert advisory committee, including sub-specialists in haematology, immunology, rheumatology and medical genetics, was selected based on clinical experience and publication record on VEXAS. VEXAS patients, psychometricians, and statisticians were not included in the panel.

Panel members held a 4-hour virtual group meeting to develop a hypothetical framework for defining VEXAS flare and to initiate a drafting definition. Moderators facilitated an open-ended discussion and prepared a draft definition based on panel feedback. While it is possible that this initial pre-consensus meeting could introduce bias into the eventual definition by promoting groupthink (undermining diversity of thought that the Delphi method is designed to preserve) and anchoring bias (opinions shared during this meeting may influence subsequent voting), the meeting was considered a necessary step to develop a model for flare definition and to identify key areas of divergency or uncertainty to be explored in the Delphi rounds.

Literature review of VEXAS flare manifestations

To generate a comprehensive list of flare manifestations (“concepts”) for potential inclusion in the definition, a systematic literature review of English language articles published on PubMed between December 2020 and February 2024 containing the term ‘VEXAS’ was performed (search string: VEXAS). Studies were included if they (1) described at least three patients (e.g., isolated case reports excluded), (2) did not select patients based on specific manifestations and (3) did not contain overlapping data with another included publication. Titles and abstracts were screened by one author, with final inclusion based on full manuscript review by one author (BGH). A second author (SAB) additionally reviewed all abstracts for selection; cases of disagreement on whether an article should be included were resolved through discussion between BGH and SAB.

The following data were extracted from each publication: sample size (number of patients with VEXAS syndrome), study type and non-haematological manifestations reported in ≥10% of patients. Manifestations were summarized by organ system involvement.

Development of the VEXAS flare definition

A modified Delphi methodology was used to iteratively refine the VEXAS flare definition via multiple rounds of organized feedback. Panel members provided semi-anonymous feedback, with moderators aware of commenters’ identities, but voting results were only shared in aggregate.

In the first round, panellists voted on inclusion and exclusion of concepts identified in the systematic review. In each round, members voted on proposed modifications, with the option to suggest additional changes in an open-ended format. After each round, moderators summarized responses, updated the definition and generated questions for further voting. This process continued until a consensus was achieved and no further modifications were proposed. A consensus was defined as agreement by ≥75% of voting members, provided ≥85% had voted.

Results

Panel composition

Of ten physicians identified as VEXAS experts who were invited for panel participation, nine agreed to participate. The medical specialties of these panellists were haematology (n=5), rheumatology/immunology (n=3) and medical genetics (n=1). One additional physician with experience in clinical research in haematology was invited as a non-voting panel member.

Framework for VEXAS flare definition

Panellists agreed that a VEXAS flare should be broadly defined as ‘an active inflammatory manifestation of disease for which escalation in glucocorticoid therapy is indicated.’ While acute phase reactants such as C-reactive protein (CRP) were considered sensitive biomarkers of disease activity, they were recognized as non-specific. Further, concern was raised around requiring CRP elevation for flare determination in the setting of a clinical trial, as patients may be treated for a flare without having bloodwork at symptom onset. Thus, while assessment of inflammatory biomarkers was recommended during a flare, panellists concluded that the definition of flare should not be contingent upon these.

Inflammatory manifestations were classified into three categories (Table 1). Most manifestations were considered evaluable by the treating physician without requiring independent adjudication, such as flares that present as a stereotyped recurrence of prior inflammatory manifestations (Category A) and flares that involve VEXAS-defining manifestations (Category B). However, some manifestations were considered sufficiently ambiguous (Category C) that the panel recommended use of an independent adjudication committee to reduce inter-rater variability in flare assessment. While the panel recognized that some clinical trials may require independent adjudication for all flares, establishing a clear criterion for when independent review is necessary could reduce barriers to clinical research, ensuring both feasibility and consistency.

Table 1.

VEXAS flare categories

Flare category	Description	Example	Adjudication Recommended
A	Flares that present as recurrence of a prior disease manifestation	A patient with VEXAS syndrome who has historically presented with fever and polyarthritis during flares presents again with a similar constellation of signs and symptoms in the absence of infection	No
B	Flares that present with VEXAS-defining manifestations	A patient with VEXAS syndrome who has not previously had cutaneous involvement now presents with a rash. Biopsy is consistent with neutrophilic dermatosis	No
C	Flares that present without a VEXAS-defining manifestation and that do not meet Category A criteria	A patient with VEXAS syndrome whose prior flares consisted of chondritis now presents with fatigue, night sweats and myalgias in the absence of infection. CRP is elevated	Yes

CRP, C-reactive protein; VEXAS, Vacuoles, E1 enzyme, X-linked, Autoinflammatory, and Somatic.

Literature review

The literature search yielded 288 results, of which 200 were initially excluded: 59 were review articles, 113 were case reports describing fewer than three patients and 28 were focused on other diseases, leaving 88 for consideration for inclusion. Of these, 57 were excluded based on lack of clinical data (e.g., a focus on genetic data only), lack of unique data (e.g., overlapping cohorts) or a focus on a specific disease phenotype (Supplemental Figure S1). Ultimately, 31 publications were included (Supplemental Table S1), from which 19 groups of inflammatory manifestations were documented (Table 2), each of which was considered for inclusion in the VEXAS flare definition.

Table 2.

Inflammatory manifestations of VEXAS syndrome based on literature review

Systemic involvement and examples
Fatigue	Reduced ability to perform physical or mental activities
Constitutional symptoms	Fever, chills, night sweats, unintended weight loss
Thrombosis	Venous or arterial thrombosis/thromboembolism
Organomegaly	Lymphadenopathy, splenomegaly
Systemic vasculitis	Polyarteritis nodosa, large vessel arteritis
End-organ involvement and examples
Cutaneous	Neutrophilic dermatosis, erythema nodosum, leukocytoclastic vasculitis, pustular dermatosis
Pulmonary	Pulmonary infiltrates, pleural effusion, interstitial lung disease, pulmonary nodules, cough
Joint	Arthritis, joint effusion, arthralgia
Cartilage	Relapsing polychondritis, nasal chondritis, auricular chondritis
Cardiac	Myocarditis, pericarditis, pericardial effusion
Ocular	Uveitis, scleritis, episcleritis
Periorbital	Periorbital oedema, orbital pseudotumour, palpebral oedema, facial swelling
Nervous system	Demyelinating polyneuropathy, sensory neuropathy, axonal polyneuropathy
Gonadal	Orchitis, epididymitis, testicular pain
Gastrointestinal	Peritonitis
Musculoskeletal	Myalgia, polymyalgia rheumatica, connective tissue disease
Renal	Tubulointerstitial nephritis
Oropharyngeal	Odynophagia, aphthous ulcers, retropharyngeal phlegmon
Inner ear	Labyrinthitis, hearing loss

VEXAS, Vacuoles, E1 enzyme, X-linked, Autoinflammatory, and Somatic.

VEXAS flare definition

A total of four revision rounds were conducted electronically between May and July of 2024, with consensus reached following endorsement by all nine voting members. The complete VEXAS flare definition is provided in Table 3. Here, we present each component of the definition, along with voting results and key discussions that shaped the final consensus. Note that the denominator for all votes reflects the number of members responding to each question.

• “A VEXAS flare is defined as an active inflammatory manifestation of VEXAS syndrome fulfilling at least one of the criteria below, for which an escalation in glucocorticoid therapy is indicated.”

Table 3.

VEXAS flare consensus definition

Definition of VEXAS flare
A VEXAS flare is defined as an active inflammatory manifestation of VEXAS syndrome fulfilling at least one of the criteria below, for which an escalation in glucocorticoid therapy is indicated*†
Category A
Recurrence of one or more of the patient’s prior documented VEXAS-related inflammatory manifestations
Category B
Development of one or more of the following inflammatory signs considered by the
Investigator to be directly attributable to VEXAS syndrome:
a) Skin rash with biopsy-proven diagnosis of neutrophilic dermatosis, erythema nodosum, leukocytoclastic vasculitis, panniculitis or neutrophilic urticarial dermatosis
b) Auricular and/or nasal chondritis
c) Biopsy- or imaging-proven vasculitis of any calibre vessel
d) Ocular inflammation, including orbital inflammation, dacryoadenitis, uveitis, scleritis or episcleritis.
e) Persistent periorbital oedema
Category C ‡
Development of any of the following inflammatory manifestations directly attributable to
VEXAS syndrome per an independent adjudication committee§:
a) Recurrent or persistent fevers >38.0°C documented on at least two occasions within the span of at least two weeks in the absence of infection or alternative aetiology evident after comprehensive clinical investigation
b) Night sweats on multiple occasions over at least two weeks in the absence of infection or alternative aetiology after comprehensive clinical investigation
c) Arthritis, arthralgias or myalgias
d) New onset non-infectious cough or clinically significant dyspnoea in the setting of pulmonary infiltrates lasting at least one week without an alternative aetiology
e) Other inflammatory end-organ involvement that is considered directly attributable to VEXAS syndrome and that does not meet Category B criteria

^*Chronic organ damage or impairment resulting from VEXAS syndrome does not constitute evidence of a disease flare.

^†While arterial or venous thrombosis may occur in the setting of a disease flare, the isolated diagnosis of new thrombosis is insufficient to constitute a VEXAS syndrome flare.

^‡Independent adjudication committee recommended.

^§Documentation of the relevant manifestations and results of clinical, laboratory and radiographic investigations undertaken to exclude alternative aetiologies (including infection), accompanied by longitudinal CRP, ESR and ferritin values (including values drawn while the manifestation is active) should be provided to the adjudication committee.

CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; VEXAS, Vacuoles, E1 enzyme, X-linked, Autoinflammatory, and Somatic.

This definition is based on unanimous agreement (100%, 9/9) among panellists that a flare should be defined by inflammatory manifestations and by need for clinical action – specifically escalation in glucocorticoid therapy. While other non-glucocorticoid anti-inflammatory or disease-targeting therapeutic interventions may be used for symptomatic management, flare prevention, or treatment of underlying disease, panellists agreed that escalation in glucocorticoid therapy is the mainstay of treatment of an acute flare, and thus this escalation may be used to aid in the differentiation of flare versus non-flare event. It was acknowledged that a clinician’s determination of what signs and symptoms qualify as ‘inflammatory’ is inherently subjective. While treatment escalation also depends on individual clinician judgement, this requirement was considered valuable for minimizing heterogeneity in flare reporting.

Implicit within this definition is that the manifestations result directly from VEXAS. However, differentiating flare from infection can be challenging as patients with VEXAS are highly susceptible to atypical infections that may mimic flares [10]. A prime example is non-tuberculous mycobacterial infections, commonly identified in skin lesions of patients with VEXAS. When disseminated, these infections can also present with fever and pulmonary infiltrates, hallmark features of VEXAS flares [11]. Due to this diagnostic challenge, a flare should only be confirmed once alternative aetiologies have been ruled out to ensure accurate classification.

Consensus was not reached on whether isolated cytopenia without other inflammatory manifestations should constitute a flare, though most panellists (67%, 6/9) did not consider this presentation to reflect a flare. Progressive cytopenias may indicate progression of bone marrow pathology, which is not necessarily directly associated with active inflammation. Several alternative aetiologies could contribute to progressive cytopenias in VEXAS, including worsening of underlying bone marrow failure, development of MDS or plasma cell dyscrasia, opportunistic infections and drug-related cytopenias [12]. While cytopenias may occur during flares, they are usually accompanied by other inflammatory manifestations. Two panellists (22%) would consider isolated cytopenias to be potentially indicative of flare, particularly in the setting of elevated inflammatory markers, but both indicated a degree of ambiguity in their assessment. For example, whether cytopenias could constitute a flare may depend on degree of blood count reduction and whether multiple cell lines were reduced. Guidance around classification of flare based on cytopenias was not included in the flare definition.

• “Footnotes: Chronic organ damage or impairment resulting from VEXAS syndrome does not constitute evidence of a disease flare” and “While arterial or venous thrombosis may occur in the setting of a disease flare, the isolated diagnosis of new thrombosis is insufficient to constitute a VEXAS syndrome flare.”

Panellists agreed (100%, 9/9) that chronic organ damage should not be considered when assessing an acute flare.

There was agreement that isolated thrombosis or thromboembolic disease, occurring in the absence of other inflammatory signs or symptoms, should not be considered an acute flare. While thrombosis is a prominent feature in VEXAS and may occur secondary to inflammation, it would be uncommon to have thrombosis in the absence of any other signs or symptoms of inflammation during a flare.

VEXAS flare definition categories

• “Category A: Recurrence of one or more of the patient’s prior documented VEXAS-related inflammatory manifestations.”

  Category A flares, characterized by recurrent inflammatory disease for which an increase in glucocorticoid therapy is indicated, may be determined by the clinical investigator without need for independent adjudication. If a prior manifestation included a constellation of findings and only one recurred, most panellists (75%, 6/8) agreed that this would constitute a Category A flare. A comprehensive history of prior inflammatory manifestations should be documented prior to study enrollment to effectively ascertain Category A flares in clinical trials.

• “Category B: Development of one or more of the following inflammatory signs considered by the investigator to be directly attributable to VEXAS Syndrome: Skin rash with biopsy-proven diagnosis of neutrophilic dermatosis, erythema nodosum, leukocytoclastic vasculitis, panniculitis or neutrophilic urticarial dermatosis; auricular and/or nasal chondritis; biopsy- or imaging-proven vasculitis of any calibre vessel; ocular inflammation, including orbital inflammation, dacryoadenitis, uveitis, scleritis or episcleritis; persistent periorbital oedema.”

Panellists outlined specific inflammatory manifestations that would be considered VEXAS flare-defining in a patient with VEXAS. Even if new (non-recurrent), these manifestations could be ascertained without independent adjudication.

Panellists agreed that a new inflammatory rash is diagnostic of VEXAS flare provided that the diagnosis has been confirmed by skin biopsy (100%, 8/8). While visual confirmation alone may be sufficient for diagnosis of a recurrent rash (Category A), new rashes generally warrant biopsy. If a new rash is treated presumptively with glucocorticoid dose escalation without pathological confirmation, or if the biopsy is inconclusive or insufficient to rule out alternative causes, independent adjudication would be required (Category C).

Panellists concurred (100%, 8/8) that auricular and nasal chondritis in a patient with diagnosed VEXAS constitutes a flare. Other types of chondritis (e.g., costochondritis or upper airway chondritis) are less frequently reported and may be less diagnostically apparent; such manifestations could be associated with a flare, but independent adjudication would be required (Category C).

Vasculitis often involves cutaneous tissue in patients with VEXAS and would thus fall under the broader category of inflammatory skin rash. Panellists concurred that, like evaluation of rash, biopsy-proven vasculitis could be considered indicative of disease flare in the absence of independent adjudication (75%, 6/8). In contrast, independent adjudication would be required for new cases where diagnostic ambiguity remains despite workup, or where urgency to initiate empirical treatment precludes biopsy (e.g., vision-threatening giant cell arteritis).New ocular inflammation in a patient with VEXAS is considered diagnostic of a flare based on panel consensus (100%, 8/8), provided alternative aetiologies such as infection are ruled out. Panellists concurred that new periorbital oedema in a patient with VEXAS is diagnostic of flare (78%, 7/9), as this is a classical and readily visualized finding in VEXAS. To differentiate VEXAS-associated periorbital oedema from alternative causes (e.g., sinus congestion), the term ‘persistent’ was added to the criterion, with interpretation of what constitutes persistence left to the physician.

Other inflammatory manifestations were considered for Category B but did not achieve consensus. Gonadal involvement (e.g., epididymitis or orchitis in the absence of infection) was considered uncommon and non-specific, and 87.5% (7/9) recommended removal from Category B. Similarly, fever of unknown origin (FUO) was considered diagnostically challenging, and thus 56% (5/9) recommended that it be moved to Category C.

• Category C: Development of any of the following inflammatory manifestations directly attributable to VEXAS syndrome per an independent adjudication committee. Footnote: Documentation of the relevant manifestations and results of clinical, laboratory, and radiographic investigations undertaken to exclude alternative aetiologies (including infection), accompanied by longitudinal CRP, erythrocyte sedimentation rate (ESR) and ferritin values (including values drawn while the manifestation is active) should be provided to the adjudication committee.”

Panellists agreed that Category C flares – new manifestations that are not considered flare-defining – should be independently adjudicated by a committee of physicians experienced in VEXAS. The independent committee must be provided with sufficient clinical detail and results of inflammatory biomarkers obtained during the potential flare. Most panellists (67%, 6/9) considered CRP to be the most relevant biomarker, while one (11%, 1/9) voted that multiple inflammatory markers should be provided to the adjudication committee, as the relative value of CRP compared to other biomarkers has not been rigorously demonstrated.

• “(Category C): Recurrent or persistent fevers >38.0°C documented on at least two occasions within the span of at least two weeks in the absence of infection or alternative aetiology evident after comprehensive clinical investigation; night sweats on multiple occasions over at least two weeks in the absence of infection or alternative aetiology after comprehensive clinical investigation; arthritis, arthralgias or myalgias; new onset non-infectious cough or clinically significant dyspnoea in the setting of pulmonary infiltrates lasting at least one week without an alternative aetiology; other inflammatory end-organ involvement that is considered directly attributable to VEXAS syndrome and that does not meet Category B criteria.”

The diagnostic criteria for FUO have evolved over time. The original definition, proposed in 1961, required fever lasting longer than three weeks with at least one week of evaluation in the hospital [13]. More recent definitions, however, require that an elevated temperature be documented on several separate occasions where an appropriate diagnostic workup fails to reveal an aetiology [14, 15]. Here, fever criteria have been adapted from these more recent definitions and require that the associated clinical workup be submitted for independent adjudication. Panellists agreed on inclusion of night sweats as a Category C manifestation (87.5%, 7/8). Though challenging to assess directly, night sweats are a prognostically relevant marker in haematologic malignancies [16, 17] and can likewise occur in patients with VEXAS.

Panellists recommended including arthritis as a flare manifestation, though some (33%, 3/9) were concerned that monoarticular involvement could reflect alternate aetiologies such as gout or septic arthritis. As an arthritis flare would be independently adjudicated, however, it was decided to keep the broad term of ‘arthritis’ as a potential flare manifestation. Both arthralgias and myalgias raised concern with the panel, with 22% (2/9) recommending against inclusion as these manifestations could occur for many alterative reasons, including adrenal insufficiency in the setting of a protocol-directed glucocorticoid taper and, as a result, could be seen as ‘glucocorticoid responsive.’ If such manifestations occur, the adjudication committee, in consideration of the full clinical picture and accompanying inflammatory biomarkers, would be the arbiters of whether these symptoms constitute a true flare. Clinicians may be cautioned against escalating glucocorticoid doses for isolated arthralgias or myalgias in the absence of other inflammatory manifestations. Ultimately, arthritis, arthralgias and myalgias were included as Category C manifestations, based on 87.5% (7/8) consensus.

Pulmonary involvement is common in VEXAS, and 75% (6/8) of panellists agreed with inclusion of symptoms such as cough and dyspnoea occurring in the setting of non-infectious pulmonary infiltrates. There are many causes of respiratory symptoms in patients with VEXAS, including infection, anaemia and thromboembolism, which should be considered prior to designating an episode as a flare.

Consensus was not achieved on adding fatigue (22%, 2/9) or weight loss (11%, 1/9), as these were considered non-specific. While fatigue and weight loss may be present in patients experiencing a flare, and while fatigue is common in both chronic inflammatory illnesses and myeloid neoplasms [18, 19], these findings are unlikely to be isolated during a flare.

Panellists were asked to vote on whether to list other VEXAS-associated manifestations captured as part of the literature review under Category B or C. For the following manifestations, a majority recommended that the manifestation be captured under a final criterion of “other inflammatory end-organ involvement”: lymphadenopathy, cardiac/pericardial involvement, neuropathy, organomegaly, peritonitis, colitis, oral ulceration and renal involvement. These are less common VEXAS manifestations, therefore requiring further workup to rule out other more likely aetiologies. Thus, these manifestations could qualify as a VEXAS flare but would require independent adjudication.

Discussion

These VEXAS flare criteria provide a standardized foundation for use in clinical trials. By clearly defining what constitutes a flare, they will help decrease variability in assessment, support the development of meaningful clinical endpoints and improve consistency between studies. This unified approach is essential for comparing therapeutic outcomes and advancing care for patients with VEXAS.

An advantage of this definition of VEXAS flare is that it is broad enough to include any potential disease manifestation. While the initial systematic review documenting inflammatory manifestations of VEXAS syndrome was limited to English-language publications from a single search engine (PubMed), the review served as a starting point for input by panellists, and the flare definition was thus not limited to manifestations derived from the literature. The addition of Category C manifestations, including “other inflammatory end-organ involvement”, allows for broad discretion on the part of the treating physician in determining whether a flare has occurred. In fact, the items noted on systematic review closely match the non-hematologic inflammatory manifestations noted in a separate systematic review subsequently published by Al-Hakim et al. [20], further supporting the content validity of this flare definition.

The integration of flare into trial endpoints will depend on the study design, the therapeutic mechanism of action and the target population. For example, in a clinical trial evaluating a new therapy in the setting of a glucocorticoid taper, flare-free interval may be relevant. Trials enrolling patients with active disease may measure time to flare resolution or number of flare-free days.

The performance of this definition in a clinical trial will also depend on study design. In studies involving patients on long-term glucocorticoid therapy, most flares may fall under Category A (recurrence). In newly diagnosed patients, flares may be defined more by Category B manifestations or those needing adjudication (Category C). Prospective validation will clarify when independent adjudication is necessary, though if all Category C events are consistently judged as true flares, adjudication may not be critical.

A limitation of this definition is that it groups a wide range of inflammatory events, from mild to severe. It may miss minor inflammatory manifestations or isolated haematological issues that do not trigger glucocorticoid escalation. As a result, a remission definition based solely on absence of flare might still include low-grade disease activity. Although this definition does not assess flare severity, it lays the groundwork for a VEXAS-specific DAI, which is currently in development.

Future research efforts should focus on studying the performance characteristics of this flare definition. For example, this flare definition is incorporated into the primary endpoint of the ongoing PAXIS trial (NCT06782373, CTIS 2024–516347-41–00), in which flare-free survival after successful glucocorticoid taper will be assessed based on investigator determination of flare, with independent adjudication required for Category C events. The construct validity of this flare definition can be evaluated by examining its association with other markers of disease activity, including levels of inflammatory biomarkers, patient-reported outcomes, and performance status.

While inflammatory biomarker levels are omitted from this definition of flare for logistical reasons (i.e., levels may not be captured prior to initiating treatment for flare in clinical practice), these markers are often used to support flare assessment [21]. CRP is increased in most untreated patients and can trend with acute inflammation [22]. Similarly, a normal CRP may rule out acute inflammation, although false negative results may be observed during treatment with specific classes of therapy (e.g., IL-6 inhibition) or if levels are checked after flare-directed treatment has already been initiated. Further efforts should be made to establish the role of CRP as a biomarker of flare assessment.

The primary utility of this definition is for retrospective assessment of whether a flare has occurred, following an appropriate diagnostic workup. Importantly, this definition is not intended to inform real-time clinical decision-making during or outside a clinical trial. For example, clinicians must determine modifications of glucocorticoid dosing based on the best information at hand and in the best interest of their patients. Ultimately, decisions regarding glucocorticoid dose alteration remain the responsibility of the patient’s physician and should not be contingent on an adjudication committee. In clinical practice, this flare definition may serve as a guide for clinicians in their assessment of flares, but it should not be a substitute for clinical judgement and consideration of all available data, including biomarkers, patient-reported data, and the exclusion of alternative aetiologies.

There is an urgent need for clinical research to identify effective treatments for VEXAS. Standardized flare criteria are a critical step toward defining reliable trial endpoints and comparing therapeutic outcomes. This definition is an important foundation for improving how we capture and study disease activity in VEXAS, and future prospective studies will test its real-world utility.

Key messages:

• A standardized definition of VEXAS flare using a modified Delphi method was developed by a panel of international experts for use in clinical research.

• Three categories of VEXAS flare were described: recurrent, VEXAS-defining, and other.

• This definition provides a framework for measuring flare-related outcomes, facilitating clinical research in VEXAS syndrome.

Data availability statement:

The datasets analysed during the current study are available from the corresponding author on reasonable request. Sobi is committed to responsible and ethical sharing of data on the participant level and summary data for medicines and indications approved by the European Medicines Agency and/or Food and Drug Administration, while protecting individual participant integrity and compliance with applicable legislation. Data access will be granted in response to qualified research requests. All requests are evaluated by a cross-functional panel of experts within Sobi and a decision on sharing will be based on the scientific merit and feasibility of the research proposal, maintenance of personal integrity and commitment to publication of the results. To request access to study data, a data sharing request form (available on www.sobi.com) should be sent to medical.info@sobi.com. Further information on Sobi’s data sharing policy and process for requesting access can be found at: https://www.sobi.com/en/policies.