Serum Immunoglobulin G Levels and Nicastrin Variation in Hidradenitis Suppurativa

Variation in nicastrin (NCSTN) is associated with a monogenic subtype of hidradenitis suppurativa. Dysregulation of humoral immunity has been suggested as a potential mechanistic link between NCSTN variation and hidradenitis suppurativa. There is a paucity of biomarkers that can predict disease-associated variation.

To investigate whether serum immunoglobulin levels, as a surrogate marker of humoral immunity, can identify individuals with hidradenitis suppurativa who have a specific disease-associated NCSTN variant.

Maltese individuals with hidradenitis suppurativa genotyped for a disease-associated NCSTN in-frame deletion prevalent in the local patient cohort were invited to participate in this cross-sectional study from January to July 2023. Participation was restricted to adult individuals with hidradenitis suppurativa without known or suspected pathologies that would be associated with serum immunoglobulin levels. Data were analyzed between October 2023 and December 2023.

Serum immunoglobulin G levels and other hematological paraments were analyzed.

Main outcomes were the associations between serum immunoglobulin levels and an underlying NCSTN variation in individuals with hidradenitis suppurativa.

A total of 125 individuals (64 female individuals [51.2%]) with hidradenitis suppurativa of Maltese ethnicity were recruited in the study, of whom 17 (13.6%) who were from 7 genealogically unrelated families were heterozygous for the disease-associated NCSTN variant. Deletion carriers had a higher serum immunoglobulin G level (1370 mg/dL vs 1140 mg/dL [to convert to g/L, multiply by 0.01]; P < .001). The association between NCSTN variation and elevated immunoglobulin G levels retained significance despite adjusting for multiple confounders, including markers of disease severity, age of recruitment, age of disease onset, treatment with adalimumab, and liver transaminase levels. Serum immunoglobulin G demonstrated a strong discriminatory capacity in identifying patients who were heterozygous for the NCSTN variant.

The results of this cross-sectional study suggest an altered humoral immune state in patients harboring a specific NCSTN variant and support the role of serum immunoglobulin G levels as a potential predictive biomarker of monogenic hidradenitis suppurativa. This may aid in identifying and prioritizing individuals with monogenic hidradenitis suppurativa.