IL-6 levels dominate the serum cytokine signature of severe epidermolysis bullosa: A prospective cohort study

Abstract

Background: Systemic inflammation is considered a major player in the pathogenesis of epidermolysis bullosa (EB), but its pattern has only been described in small heterogeneous cohorts. There is controversy if and how systemic inflammation should be therapeutically targeted.

Methods: We examined serum proinflammatory, anti-inflammatory, and itch related cytokines in a paediatric cohort of 29 patients with junctional and dystrophic EB. The cytokine that emerged as the most relevant was measured in a validation cohort of 42 patients during follow-up visits over 2 years.

Results: IL-6 showed the most consistent and highest aberration dominating systemic inflammation. IL-6 correlated with wound body surface area (BSA) in both, finding and validation cohorts. Patients with less than 3% wound BSA had normal IL-6, while IL-6 levels significantly increased at more than 5% and 10% of wound BSA. TGF-β was only marginally elevated in patients with severe recessive dystrophic EB, while TNF-α, IFN-γ and IL-1β varied inconsistently. Patients reporting itch showed elevations in type 2 immunity (IgE, TSLP, IL4 and/or IL-31, respectively).

Conclusions: Our data suggest a dominant skin barrier and wound healing inflammatory pattern in junctional and dystrophic EB that depends on the wound area and not on the EB type. In EB, itch mediators may be similar to other pruritic disorders.

FIGURE 1

Cytokines in the initial cohort. (a) IL‐6, (b) TGF‐β, (c) TNF‐α (d) TSLP, IL‐4 and IL‐31 (for the latter only abnormal values in patients with junctional and recessive dystrophic epidermolysis bullosa are shown). Dark grey = severe JEB, green line indicates upper normal range, horizontal bars show group median. FC, fold change; int, intermediate; JEB, junctional epidermolysis bullosa; RDEB, recessive dystrophic epidermolysis; sev, severe. *p < 0.01

FIGURE 2

IL‐6 in the validation cohort. (a) IL‐6 in the EB subtypes. (b) Correlation between IL‐6 and wound BSA. Black horizontal bars show group median; green horizontal bars indicate upper normal range (NV). BSA, body surface area; int, intermediate; JEB, junctional epidermolysis bullosa; RDEB, recessive dystrophic epidermolysis; sev, severe. **p < 0.01, ****p < 0.0001