Identification of Biomarkers and Critical Evaluation of Biomarker Validation in Hidradenitis Suppurativa

Abstract

IMPORTANCEThe identification and validation of biomarkers in hidradenitis suppurativa (HS) has potential to improve the understanding and management of this chronic, burdensome disease.OBJECTIVE To systematically identify all known HS biomarkers, categorize them by biomarker type, and critically evaluate their validity according to established criteria.EVIDENCE REVIEW Eligibility criteria for this review (PROSPERO Registration 230830) included randomized clinical trials, uncontrolled clinical trials, cohort studies, case-control studies, and other observational studies with no restrictions of patient age, sex, race or ethnicity, or language of publication up until December 31, 2020. All articles were categorized into biomarker type, defined using the US Food and Drug Administration Biomarkers, Endpoints, and other Tools (BEST) glossary. Assessment of each identified biomarker was undertaken in line with the US Food and Drug Administration and European Medicines Agency guidelines for the validation of proposed biomarkers. Assessment of the strength of overall data regarding individual biomarkers was undertaken using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) approach.FINDINGS A total of 3953 nonduplicate articles were screened, of which 1429 articles were retrieved based on the include/exclusion criteria applied. After full-text screen and data extraction, 106 articles were included in this review. The evidence of strength of 6 categories of biomarkers (susceptibility/risk, diagnostic, monitoring, predictive, prognostic, and pharmacodynamic/response biomarkers) was assessed using GRADE criteria. A total of 48 biomarkers were identified with a minimum GRADE rating of moderate. Only 1 diagnostic (serum IL-2R), 1 monitoring (dermal Doppler vascularity), and 2 predictive biomarkers (epithelialized tunnels and positive family history of HS) achieved a GRADE rating of high. None of the identified biomarkers had sufficient clinical validity to be recommended for routine use in the clinical setting. CONCLUSIONS AND RELEVANCEMajor barriers to the identification, validation, and introduction of routine biomarkers in the management of HS include lack of independent biomarker validation studies (especially assumption-free "omics"-based techniques); insufficient assessment of collinearity between identified or proposed biomarkers; and a lack of routine integration of biomarkers into the structure of clinical trials. International consensus among researchers, clinicians, and pharmaceutical stakeholders is required to standardize goals and methods and encourage biomarker integration into future HS clinical trials. This systematic review presents a number of priorities for near-term future research to overcome such barriers and limitations of biomarkers in HS.

Case Report: Comorbid Hyper-IgD Syndrome and Hidradenitis Suppurativa – A New Syndromic Form of HS? A Report of Two Cases

“…Despite turning down genetic assessment, the patient's sibling discussed in case one suffered from Crohn's disease, which is associated with HS (PMC8130070). In both cases, we observed a lack of response to standard HS treatment modalities, which albeit a frequent occurrence, may be more significant in patients with underlying genetic variation and can be considered a negative predictive biomarker (9). Of note, several inactivating mutations have also been reported in genes located downstream to the MVK gene in the isoprenoid synthesis pathway.…”

“…Interestingly, rare autoinflammatory syndromes have HS as a key cutaneous manifestation (8). Patients with syndromic HS typically suffer from severe forms of HS with unusual skin location and signs of systemic inflammation, and resistance to conventional treatments is often reported (9). Treatment of syndromic HS is challenging and should be personalized (10).…”

The Genomic Architecture of Hidradenitis Suppurativa—A Systematic Review

“…Such endeavors require large-scale multicenter, collaborative genomic efforts ( Daxhelet et al, 2021 ; Jabbour et al, 2021 ) which will allow for endotyping ( González-Manso et al, 2020 ), deep phenotyping and, ultimately precision medicine ( Robinson, 2012 ; Delude, 2015 ) for HS patients. Genetic variables also have the propensity to act as diagnostic and predictive HS biomarkers ( Der Sarkissian et al, 2022 ). The evidence outlined in this review suggests that considering HS as a single disease may be misleading.…”

New and Emerging Targeted Therapies for Hidradenitis Suppurativa

“…Clinically relevant biomarkers could be helpful. A recent systematic review critically evaluated biomarkers in HS, and showed that only one diagnostic (serum IL-2R), one monitoring (dermal Doppler vascularity), and two predictive biomarkers (epithelialized tunnels and positive family history of HS) achieved a high GRADE (grading of Recommendations, Assessment, Development, and Evaluation), but none of them had sufficient clinical validity to be recommended for routine use in the clinical setting [ 196 ].…”