Canakinumab in adults with steroid‐refractory pyoderma gangrenosum

Abstract

SummaryBackground Pyoderma gangrenosum (PG) is a rare, neutrophilic, ulcerative skin disease that is difficult to treat, especially when unresponsive to steroids. Objectives To determine whether canakinumab is an effective and safe treatment in PG. Methods Five adult patients with clinically and histologically confirmed steroidrefractory PG were enrolled in this prospective open-label study. They received canakinumab 150 mg subcutaneously at week 0 with an optional 150 mg at week 2 in case of an inadequate response [Physician's Global Assessment (PGA) ≥ 2], and an optional 150-300 mg at week 8 depending on PGA. The primary clinical end point was clinical improvement (PGA at least À1 from baseline) and/or complete remission (PGA 0 or 1) at week 16. Real-time quantitative polymerase chain reaction was performed on skin samples to quantify cytokine mRNA levels. Results Interleukin (IL)-1b and its known target genes IL6, CXCL8 and IL36A were significantly increased in lesional skin of PG. Under canakinumab therapy, four of five patients showed a decrease in target-lesion size, PGA and Dermatology Life Quality Index (DLQI), and three of five achieved complete remission. The mean diameter of target lesions decreased from 4Á32 AE 2Á6 cm at visit 1 to 0Á78 AE 1Á3 cm at visit 7 (P = 0Á03). Mean DLQI decreased from 15 AE 5 at visit 1 to 8 AE 4 by visit 7 (P = 0Á01). Adverse effects were reported in two patients: fatigue in one and worsening of disease at a nontarget lesion in the other. Conclusions Our data indicate that IL-1b plays a key pathogenic role in PG and canakinumab may represent a therapeutic option for steroid-refractory PG.

Potential of IL-1, IL-18 and Inflammasome Inhibition for the Treatment of Inflammatory Skin Diseases

“…PG is frequently associated with systemic diseases. Increased expression of IL-1β was found in lesional skin of PG patients compared to healthy skin (Marzano et al, 2014b; Kolios et al, 2015). In an open-label, proof of concept study evaluating the anti-IL-1β monoclonal antibody Gevokizumab, six patients with active ulcers received three subcutaneous injections once every 4 weeks and four out of six patients had a complete clearance of the target ulcer, 1 a partial (90%) closure of the ulcer and 1 did not respond (ClinicalTrials.gov Identifier: NCT01882504) (Huang et al, 2014, poster).…”

“…In an open-label study, five steroid-refractory PG patients were treated with Canakinumab once with 150 mg at onset and then optionally at weeks 2 and 8 if response was suboptimal. At the week 16 study endpoint 80% of the patients showed decreased size of target ulcers and 60% were in complete remission (ClinicalTrials.gov Identifier: NCT01302795) (Kolios et al, 2015). A case report described complete healing of a PG patient that received a Canakinumab monthly at a 150 mg dose for 3 months (Galimberti et al, 2016).…”

Epidemiology of pyoderma gangrenosum: Results from an Italian prospective multicentre study

“…With regard to systemic drugs, steroids were the mainstay of treatment; second choices were cyclosporine and dapsone. Following the recent expansion on the use of biological drugs, 15.6% of patients have been treated with anti‐TNFα with good results, but further studies and trials must be performed before considering these drugs (included IL‐1 antagonist and IL‐12/23) the first choice in treating PG. Finally, Japanese authors report the use of granulocyte and monocyte adsorption apheresis (GCAP) to treat steroid‐resistant PG, but we have no experience with such therapies.…”

Acne and hidradenitis suppurativa

“…As the PSTPIP1 gene is associated with the inflammasome pathway, IL‐1β blockade has been a successful therapy for PAPA syndrome. Recently, isolated pyoderma gangrenosum was also found to have increased IL‐1β and was treated successfully in an investigator‐initiated trial with anti‐IL‐1β blockade, resulting in an 80% response rate …”