International consensus definition of disease flare in hidradenitis suppurativa

Dear Editor, Greater than 80% of patients with HS experience periodic worsening, or flare, at least monthly.¹ Though flares are a dominant aspect of disease course and patient experience, no consistent definition of HS flare exists in the medical literature.² This poses a challenge for clinical researchers evaluating disease flare in HS and is a barrier to standardized assessment of this important outcome. This project sought to build consensus among an international group of researchers, clinicians, and patients living with HS on a definition of HS flare that is appropriate for clinical trial research.

Using the Delphi technique, an anonymous survey was designed by the workgroup and distributed to participants via REDCap.³ A purposive sample of participants from Hidradenitis Suppurativa core outcomes set international collaboration (HiSTORIC) group were invited to participate, including physicians, industry representative, and patients with a physician-confirmed HS diagnosis. All participants were required to be at least 18 years of age, fluent English speakers, and have reliable internet access. Survey items were generated from the literature and survey instruments. Data from each round was summarized for participants, who were asked to assign a score from 1– 9 to indicate how important the construct was to the definition of HS flare (1–3: not important; 4–6: important but not critical; 7–9: critically important). Five members of the workgroup formed a steering group. Consensus “in” was reached when ≥70% of participants scored the item between 7–9 and <15% scored the item between 1–3. Conversely, consensus “out” was reached when ≥70% of participants scored the item between 1–3 and <15% scored the item between 7–9. Only responses with >90% completion were included in the statistical analyses, which were performed using SAS Version 9.4 (SAS Institute Inc., Cary, NC). Stability of consensus was not assessed. Approval was granted by the Penn State Institutional Review Board.

The study began in April 2019 with the distribution of the Round 0 survey, which was used to develop items for the remaining rounds. Rounds 1–5 sought consensus “in” or “out” for words or phrases relevant to HS flare. The number of items and results for each Round are summarized in Table 1. The survey was shortened by the steering committee before Round 3 due to feedback regarding survey length. Round 3 consisted of 11 statements based on items with consensus or near-consensus in prior rounds. Rounds 6–7 focused on gaining consensus on definition statements, rather than fragments. In Round 6, 62% of participants reported high levels of agreement with the following statement: ‘HS Flare is new or worsening clinical signs and symptoms significant to the patient.’ In Round 7, participants rated their level of agreement on each of four proposed definitions; 83% reported high levels of agreement with the statement: “HS flare is a new or substantial worsening of clinical signs or symptoms.”

Table 1.

Summary of Delphi process, participants, and results

Study phase	Delphi Round	Participants	Results
Preparation Phase	Round 0
Consensus Building Phase	Round 1	n=65	47 items 3 Consensus “in”	Consensus in: a new lesion reactivation of a lesion at the site of a prior lesion worsening of a lesion that has remained active flare is a worsening pain flare is a new drainage flare is a new abscess flare is both more symptoms and lesions Consensus out: flare means a change in treatment that is NOT prescribed or administered by a physician flare is a new non-inflamed cyst; flare is a new non-inflamed nodule
	Round 2	n=54	47 items 6 Consensus “in;” 3 Consensus “out”
	Round 3	n=54	13 items 4 Consensus “in”	Consensus in: flare is worsening of a persistently active HS lesion flare is a new or worsening pain related to HS lesions flare is a new or worsening drainage related to HS lesions flare can be limited (localized) or widespread new or worsening swelling should be in the flare definition flare is a new or worsening inflammatory nodule flare is a new or worsening tunnel (fistula or sinus tract) Consensus out: flare is defined by a change in prescription HS therapy
	Round 4	n=52	9 items 1 Consensus “out”
	Round 5	n=53	11 items 3 Consensus “in”
	Round 6	n=50	6 items	Statements with highest levels of agreement: HS Flare is new or worsening clinical signs and symptoms significant to the patient. (Highly Agree: 62.0% [31/50]) HS Flare is new or worsening clinical signs or symptoms. (Highly Agree: 61.2% [30/49]) HS Flare is new or worsening clinical signs and symptoms. (Highly Agree: 60.0% [30/50]) Statement with highest levels of agreement: HS Flare is a new or substantial worsening of clinical signs OR symptoms. (Definitely Agree: 83.33% [45/54])
	Round 7	n=54	4 items
Conclusion	Round 8			Consensus Statement: “HS flare is new or substantial worsening of clinical signs or symptoms.”

In summary, the consensus definition of HS flare derived in this work states that HS manifestations may be “new or worsening.” This is consistent with prior studies, which found that a single new lesion or worsening of an existing active lesion met criteria for flare.⁴ Indeed, during the process of this study, items related to quantitative scoring consistently lacked consensus. The definition of flare as “≥25% increase in the abscess and/or nodule (AN) count with a minimum increase of 2 relative to baseline,” commonly used in ongoing clinical trials, has multiple issues: first, the validity of this flare measurement has not been established;⁵ second, this outcome risks low sensitivity as it would not detect flares that consist of worsening existing lesions; and third, data have shown that the AN count has only poor to moderate interrater reliability.^{6 7}

Relevant limitations of this study include voluntary response bias and respondent fatigue. From this work, metrics for flare severity and duration can be determined and there is an opportunity to use valid and reliable HS flare assessments to define ‘remission’ and ‘low disease activity’ for HS.

Assessment of durable efficacy of a treatment depends on a valid and reproducible measurement of HS flares. This study has taken an important first step to measuring HS flare and establishes a definition with high face validity. Future studies will investigate the measurement properties of existing, and perhaps novel, outcome measures to assess flare. Additionally, there is an opportunity to use valid and reliable HS flare assessments to define ‘remission’ and ‘low disease activity’ for HS, which are defined for other inflammatory diseases (e.g. systemic lupus erythematosus) on the basis of absent or diminished flares.⁸