Tadashi Terui1, Satomi Kobayashi2, Yukari Okubo3, Masamoto Murakami4, Keiichiro Hirose5, Hiroshi Kubo5. 1. Department of Dermatology, Nihon University School of Medicine, Tokyo, Japan. 2. Department of Dermatology, Seibo International Catholic Hospital, Tokyo, Japan. 3. Department of Dermatology, Tokyo Medical University, Tokyo, Japan. 4. Department of Dermatology, Ehime University School of Medicine, Ehime, Japan. 5. Janssen Pharmaceutical K.K., Tokyo, Japan.
Abstract
Importance: Palmoplantar pustulosis (PPP) is a recalcitrant skin disease with no biologics currently approved for treatment. The involvement of interleukin 23 (IL-23) and cytokines of the type 17 helper T cell lineage in the pathogenesis of PPP has been recently postulated. Objective: To evaluate the efficacy and safety of guselkumab, an anti-IL-23 monoclonal antibody, in Japanese patients with PPP. Design, Setting, and Participants: This double-blind, randomized, placebo-controlled, parallel-group, 24-week trial was conducted between May 14, 2013, and September 27, 2014, at 11 centers in Japan. Participants were patients with moderate to severe PPP that did not respond adequately to conventional treatments. Interventions: Patients were randomized 1:1 to receive guselkumab, 200 mg, by subcutaneous injection or matching placebo at weeks 0 and 4. Main Outcomes and Measures: Changes in total scores of skin-related outcomes from baseline at the end of week 16 (primary clinical cutoff) and through week 24 were measured. Serum biomarker analyses were performed at baseline, week 4, and week 16, and safety was monitored through week 24. Results: Of 49 randomized patients (35 [71%] women; median [range] age, 52 [28-77] years), 41 completed the study at week 24. Mean (SD) PPP severity index total scores (primary end point) improved significantly from baseline in guselkumab-treated patients (-3.3 [2.43]) vs placebo (-1.8 [2.09]) (least squares mean difference, -1.5; 95% CI, -2.9 to -0.2; P = .03). At week 16, PPP area and severity index scores (least squares mean difference, -5.65; 95% CI, -9.80 to -1.50; P = .009) and proportion of patients achieving 50% reduction in these scores (difference in proportion, 39.2; 95% CI, 14.0-64.3; P = .009) improved significantly. A numerically higher proportion of patients had a physician's global assessment score of 1 or less in the guselkumab group vs placebo. Improvement in efficacy scores was maintained through week 24 in the guselkumab group. Significant reductions from baseline in serum IL-17A and IL-17F cytokine levels were observed at weeks 4 and 16. Frequency of treatment-emergent adverse events was comparable between the guselkumab group (19 of 25 patients [76%]) and the placebo group (18 of 24 patients [75%]). Frequent adverse effects included nasopharyngitis (14 patients [29%]), headache (3 patients [6%]), contact dermatitis (3 patients [6%]), and injection site erythema (3 patients [6%]). No major safety concerns emerged during the study. Conclusions and Relevance: Targeting IL-23 and its associated immune cascade with guselkumab may be a safe and useful therapeutic option for treatment of PPP. Trial Registration: clinicaltrials.gov Identifier: NCT01845987.
RCT Entities:
Importance: Palmoplantar pustulosis (PPP) is a recalcitrant skin disease with no biologics currently approved for treatment. The involvement of interleukin 23 (IL-23) and cytokines of the type 17 helper T cell lineage in the pathogenesis of PPP has been recently postulated. Objective: To evaluate the efficacy and safety of guselkumab, an anti-IL-23 monoclonal antibody, in Japanese patients with PPP. Design, Setting, and Participants: This double-blind, randomized, placebo-controlled, parallel-group, 24-week trial was conducted between May 14, 2013, and September 27, 2014, at 11 centers in Japan. Participants were patients with moderate to severe PPP that did not respond adequately to conventional treatments. Interventions: Patients were randomized 1:1 to receive guselkumab, 200 mg, by subcutaneous injection or matching placebo at weeks 0 and 4. Main Outcomes and Measures: Changes in total scores of skin-related outcomes from baseline at the end of week 16 (primary clinical cutoff) and through week 24 were measured. Serum biomarker analyses were performed at baseline, week 4, and week 16, and safety was monitored through week 24. Results: Of 49 randomized patients (35 [71%] women; median [range] age, 52 [28-77] years), 41 completed the study at week 24. Mean (SD) PPP severity index total scores (primary end point) improved significantly from baseline in guselkumab-treated patients (-3.3 [2.43]) vs placebo (-1.8 [2.09]) (least squares mean difference, -1.5; 95% CI, -2.9 to -0.2; P = .03). At week 16, PPP area and severity index scores (least squares mean difference, -5.65; 95% CI, -9.80 to -1.50; P = .009) and proportion of patients achieving 50% reduction in these scores (difference in proportion, 39.2; 95% CI, 14.0-64.3; P = .009) improved significantly. A numerically higher proportion of patients had a physician's global assessment score of 1 or less in the guselkumab group vs placebo. Improvement in efficacy scores was maintained through week 24 in the guselkumab group. Significant reductions from baseline in serum IL-17A and IL-17F cytokine levels were observed at weeks 4 and 16. Frequency of treatment-emergent adverse events was comparable between the guselkumab group (19 of 25 patients [76%]) and the placebo group (18 of 24 patients [75%]). Frequent adverse effects included nasopharyngitis (14 patients [29%]), headache (3 patients [6%]), contact dermatitis (3 patients [6%]), and injection site erythema (3 patients [6%]). No major safety concerns emerged during the study. Conclusions and Relevance: Targeting IL-23 and its associated immune cascade with guselkumab may be a safe and useful therapeutic option for treatment of PPP. Trial Registration: clinicaltrials.gov Identifier: NCT01845987.
Authors: Kenneth B Gordon; Kristina Callis Duffin; Robert Bissonnette; Jörg C Prinz; Yasmine Wasfi; Shu Li; Yaung-Kaung Shen; Philippe Szapary; Bruce Randazzo; Kristian Reich Journal: N Engl J Med Date: 2015-07-09 Impact factor: 91.245
Authors: Kristian Reich; April W Armstrong; Peter Foley; Michael Song; Yasmine Wasfi; Bruce Randazzo; Shu Li; Y-K Shen; Kenneth B Gordon Journal: J Am Acad Dermatol Date: 2017-01-02 Impact factor: 11.527
Authors: Adam A Pettey; Rajesh Balkrishnan; Stephen R Rapp; Alan B Fleischer; Steven R Feldman Journal: J Am Acad Dermatol Date: 2003-08 Impact factor: 11.527
Authors: S Cro; V R Cornelius; A E Pink; R Wilson; A Pushpa-Rajah; P Patel; A Abdul-Wahab; S August; J Azad; G Becher; A Chapman; G Dunnil; A D Ferguson; A Fogo; S A Ghaffar; J R Ingram; S Kavakleiva; E Ladoyanni; J A Leman; A E Macbeth; A Makrygeoegou; R Parslew; A J Ryan; A Sharma; A R Shipman; C Sinclair; R Wachsmuth; R T Woolf; A Wright; H McAteer; J N W N Barker; A D Burden; C E M Griffiths; N J Reynolds; R B Warren; H J Lachmann; F Capon; C H Smith Journal: Br J Dermatol Date: 2021-08-19 Impact factor: 11.113
Authors: Farzan Solimani; Robert Pollmann; Thomas Schmidt; Ansgar Schmidt; Xiang Zheng; Rajkumar Savai; Stefan Mühlenbein; Julia Pickert; Verena Eubel; Christian Möbs; Rüdiger Eming; Michael Hertl Journal: Front Immunol Date: 2019-07-31 Impact factor: 7.561
Authors: Mohamed A Alfaleh; Hashem O Alsaab; Ahmad Bakur Mahmoud; Almohanad A Alkayyal; Martina L Jones; Stephen M Mahler; Anwar M Hashem Journal: Front Immunol Date: 2020-08-28 Impact factor: 7.561