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Introduction
Cutaneous lupus erythematosus (CLE) is a potentially disfiguring and debilitating manifestation of lupus erythematosus, a heterogeneous autoimmune disease with a broad spectrum of organ system involvement and clinical presentations. Despite CLE’s demonstrated impact on patients’ quality of life, no drugs for treatment of CLE have been approved by the Food and Drug Administration. One proposed driver of this gap is a focus on SLE rather than its cutaneous counterpart in therapeutic development programmes. Another challenge is the lack of regulatory acceptance of and clarity on existing endpoints, which has inhibited some expansion into this area of the field.
To address an urgent unmet need for guidance around a standardised outcome measurement set in CLE research, a steering committee comprised of dermatologists and rheumatologists proposed a working core outcome set (COS) for randomised controlled trials and longitudinal observational studies. A COS comprises outcomes that must be assessed and documented in every clinical trial related to a specific medical condition.1 This ensures uniformity in assessing and reporting outcomes across different clinical studies.
Following the Outcome Measures In Rheumatology (OMERACT) Filter 2.1 Onion framework,2 the steering committee first classified candidate outcomes as ‘core domains’ (ie, relevant domains and subdomains that should be measured in every study for a given disease), ‘important but optional’ domains and ‘research agenda’ domains. Subsequently, they recommended candidate outcome measures for each core domain based on review of the literature (table 1).3 The proposed COS (ie, core domain set and corresponding outcome measurement set) represents a ‘working’ set to bridge an urgent need while allowing more rigorous methodological approaches to continue in parallel via COMET (Core Outcome Measures in Effectiveness Trials) Initiative and OMERACT standards, with ongoing work by groups such as the International Dermatology Outcome Measures (IDEOM) Initiative.4 This study aimed to assess the endorsement of the working COS by an international sample of CLE leaders and experts
Working core outcome measurement set
Methods
The proposed COS was presented at the recent Fifth International Conference on Cutaneous Lupus Erythematosus (ICCLE) (JFM). Subsequently, the ICCLE meeting attendees were invited to complete a six-survey assessing consensus on the proposed working COS, including endorsement of the ‘core domain’, ‘full domain’ (ie, core domains, optional important domains and research agenda domains) and ‘core outcome measurement’ sets. Additionally, they were asked to vote on their preferred CLASI (Cutaneous Lupus Erythematosus Disease Area and Severity Index) primary endpoint with regard to percentage change compared with baseline (CLASI50, CLASI70 or CLASI90) and the complementary Cutaneous Lupus Activity Investigator’s Global Assessment (revised version) (CLA-IGA-R) instrument as key secondary (vs co-primary endpoint). Appropriate patient-reported outcome measures were also considered, as outlined in table 1. Demographic data were collected, and descriptive statistics were calculated.
Results
Survey results were collected from 46 out of 114 emailed meeting attendees (40.3% response rate). Respondents primarily identified themselves as dermatologists (95.6%), but also included one rheumatologist (2.2%) and one researcher (2.2%). The majority of respondents reported residency in Asia (65.2%), with smaller subsets from North America (26.1%) and Europe (8.7%). All 46 respondents endorsed the proposed working ‘core domain set’, and all but one (97.8%) endorsed the ‘full core domain set’. All respondents voted to endorse the ‘core outcome measures set’, including the CLASI and CLA-IGA/CLA-IGA-R. Preference for CLASI percentage change from baseline endpoint was mixed; 43.5% voted in favour of CLASI50, while 39.1% preferred CLASI70 and 17.4% preferred CLASI90.
Discussion
This report demonstrates strong consensus among an international cohort of CLE experts endorsing the use of the working COS proposed by Guo et al3 for the much-needed standardisation of outcome measures used in CLE research. This effort is part of a wider effort by the lupus research community to develop organ-specific endpoints to combat the regulatory and trial design challenges of demonstrating treatment efficacy and safety in a complex, heterogeneous disease with highly variable manifestations across organ systems.5
CLE is a lupus manifestation for which an organ-specific approach to measuring treatment success is particularly needed. CLE often occurs without features of SLE and extrapolating CLE treatment effects from SLE clinical trials that fail to include CLE-specific measurement can be problematic. For example, measures such as the SLE Disease Activity Index only capture presence or absence of inflammatory rash, thus missing the granular detail required to detect meaningful therapeutic effects on skin disease.6
The working COS proposed by Guo et al and endorsed by experts during the Fifth ICCLE specifically serves as a direct response to the pressing need for more precise evaluation of CLE outcomes. It accomplishes this by standardising the assessment of multiple relevant domains of disease, including skin-specific disease activity and damage, investigator global assessment of disease activity, CLE symptoms, health-related quality of life and patient global assessment of disease activity. Adopting the proposed working COS should minimise heterogeneity in CLE outcome reporting in clinical trials which has historically hindered regulatory approval in CLE.
While consensus about measuring outcomes in CLE has been achieved, there is still disagreement regarding preferred CLASI endpoint as a per cent change from baseline. Multiple large clinical trials have used CLASI50 as a cut-off representing clinically meaningful improvement in patients with at least moderate skin involvement at baseline, and there is evidence that a 6-point or a 50% reduction in CLASI score reflects meaningful improvement in patients’ quality of life.7 8 This may explain why CLASI50 was preferred by more experts than more stringent endpoints, CLASI70 and CLASI90. Future studies may seek to clarify why some experts prefer more stringent CLASI endpoints.
This report establishes evidence of expert support for the working COS, which serves as timely, practical guidance for CLE researchers and regulators. A noted limitation of these findings is the lack of representation from patients, industry and other CLE stakeholders. Next steps include the development of a formal CLE COS following COMET Initiative methodology, which involves a wider range of stakeholders. The working COS may serve as a much-needed stopgap while more rigorous COS research is underway, including in the context of an ongoing IDEOM Initiative.
Ethics statements
Patient consent for publication
Ethics approval
This study involves human participants. As this study reports results from a minimally interactive anonymous online survey of lupus experts, no identifiable personal information was obtained and no intervention was made.
Acknowledgments
We would like to thank the International Conference on Cutaneous Lupus Erythematosus (ICCLE) and its meeting chair, Professor Minoru Hasegawa, for hosting this study.
Footnotes
VPW and JFM are joint senior authors.
Twitter @ariannazhang6
Contributors JFM and VPW conceptualised and provided supervision for the study. All authors were involved in the design of the survey and methodology. AJZ performed survey administration and data analysis. AJZ and LMP-C wrote the original draft manuscript. Substantial manuscript edits and review were performed by all authors.
Funding This project has no direct funding sources. AJZ receives a predoctoral stipend from an NIH T32 (T32TR004418). LMP-C has received grant funding from the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis.
Competing interests All authors declare no support from any organisation for the submitted work. JFM is a consultant and/or investigator for Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, AbbVie, Dermavant, Eli Lilly, Incyte, Moonlake, Novartis, Janssen, UCB, Sanofi-Regeneron, Sun Pharma, Biogen, Pfizer and Leo Pharma. VPW discloses receiving grants from: Celgene, Amgen, Janssen, Biogen, Gilead, Viela, Horizon Therapeutics and Ventus; consulting for: AstraZeneca, Pfizer, Biogen, Celgene, Resolve, Janssen, Gilead, Lilly, BMS, Nektar, AbbVie, Viela, GSK, EMD Serona, Sanofi, Anaptysbio, Amgen, Merck Kyowa Kirin, Rome Therapeutics and Xencor; serving on the medical advisory board for: Lupus Foundation of America. LMP-C discloses receiving honoraria from the International Dermatology Outcome Measures. AJZ has no competing interests to disclose.
Provenance and peer review Not commissioned; externally peer reviewed.