Phenotypic analysis of pyrin-associated autoinflammation with neutrophilic dermatosis patients during treatment

Objective

In 2016 specific heterozygous gain-of-function mutations in the Mediterranean fever gene MEFV were reported as causal for a distinct autoinflammatory disease coined pyrin-associated autoinflammation with neutrophilic dermatosis (PAAND). We sought to provide an extended report on clinical manifestations in PAAND patients to date and evaluate the efficacy and safety of treatment with the IL-1-blocking agent anakinra.

Methods

We undertook an open-label pilot study with anakinra. Three patients were recruited in a preliminary phase of the study with the intention to expand the treatment cohort in case of a favourable response. Acute-phase reactants and plasma cytokine levels were monitored throughout. Skin biopsies at baseline and at week 12 were stained for relevant cytokines. Available clinical data on treatment responses were retrospectively collected on additional patients.

Results

The three patients from the preliminary phase of the study [patients 1–3 (P1–P3)] demonstrated one failed and two partial treatment responses, where one patient opted to continue treatment with anakinra and the other favoured adalimumab. While a partial systemic response was observed, there was no appreciable effect of anakinra on the prominent cutaneous manifestations, reflected in residual local inflammatory cytokine expression in lesional skin. These observations did not warrant further expansion of the treatment cohort. Clinical data was retrospectively collected on an additional eight patients (P4–P11), highlighting both dominant and recessive inheritance with variable penetrance in PAAND and common gastrointestinal involvement that was not previously appreciated.

Conclusion

In our experience, while anakinra appears safe, it was not superior to biologicals targeting TNF-α in PAAND despite evidence directly implicating dysregulated IL-1β signalling.