Anakinra for neutrophilic pustular skin disease

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Individuals >17 years old with histopathologically-confirmed Pustular Psoriasis (PP) involving 5% body surface area or palmoplantar involvement were enrolled from January 1, 2013 to October 31, 2019. Anakinra (100mg daily) was initiated with dose escalation every 4 weeks for 12 weeks up to 300mg daily, followed by treatment withdrawal and week 16 assessment. Primary endpoint was change in total body surface area involvement (TBSAI) at week 12. Secondary endpoints included changes in Disease Activity Index for Psoriatic Arthritis (DAPSA), Dermatology Life Quality Index (DLQI), and Adverse Events (AEs). This study was approved by the NIH Institutional Review Boards (13-C-0071/13-AR-0071). Informed consent was obtained. Eighteen participants were enrolled. Fifteen were female and median interquartile range (IQR) age was 47.8 years (43.3, 55.0). Seven of 14 evaluable participants achieved clinical response as determined by 50% reduction in TBSAI after 12 weeks of anakinra (median -0.9, IQR (- 1.8, 0.0), p=0.033). Response was maintained 4 weeks after withdrawal of anakinra therapy by TBSAI (median 0.3, IQR (0.0, 1.8), p=0.074). Baseline biopsies showed intense staining of IL-36 which persisted at week 12, whereas intense myeloperoxidase (MPO) staining decreased in 7/8 patients at week 12, regardless of response. DAPSA (median -9.7, IQR (-16.4, -4.7), p=0.0005) and DLQI (median, -7.0, IQR (-9.0, -5.0), p=0.0001) improved at week 12. All systemic inflammatory markers were reduced at week 12 and increased 4 weeks after drug discontinuation. Anakinra was associated with vascular inflammation reduction after cardiovascular risk factor 188 adjustment (beta=0.18, p<0.001). Genetic variants previously associated with PP were identified in 16/18 patients. Most adverse events were grade 1-2, including injection site reactions, headaches, nausea, infection, pruritus, and pain. We demonstrate that anakinra up to 300mg daily is a safe and effective treatment for some patients with PP. Objective and self-reported measures improved following anakinra therapy, and anakinra was well-tolerated at all dose levels. All but one responder demonstrated >5-point improvement in DLQI score (2 to 5-point change suggests a clinically-important difference). Additionally, we systematically describe the burden and therapeutic response of joint and vascular inflammation in pustular psoriasis. Our results, which include localized and generalized PP patients, contrast with the APRICOT study, in which palmoplantar pustulosis participants treated with anakinra 100mg daily for 8 weeks did not achieve clinical response. This difference may be attributable to lower doses used and/or shorter treatment duration, and underscores the potential requirement for higher doses of anakinra for pustular psoriasis. This study is limited by its small sample size and uncontrolled open-label design. Larger studies are needed to confirm anakinra efficacy in PP and to explore genetic contributions. This manuscript, entitled 'Anakinra for Refractory Pustular Psoriasis: A Phase II, Open Label, Dose-Escalation Trial' was accepted for publication to the J Am Acad Dermatol. July 27, 2022 and is in press.