Abstract
Background:
Palmoplantar pustulosis is a rare, debilitating, chronic skin disease involving the hands and feet, and there are limited treatment options. Mechanistic findings suggest that interleukin 1 may be a pathogenic driver.
Objective:
To determine whether or not anakinra [Sobi (Swedish Orphan Biovitrum AB), Stockholm, Sweden], an interleukin 1 receptor antagonist, delivers therapeutic benefit in palmoplantar pustulosis.
Design:
A Phase IV, randomised, double-blind, placebo-controlled study with two stages and an adaptive element (24 participants in stage 1, 64 participants in total) with an open-label extension.
Setting:
Sixteen hospitals across England, Scotland and Wales.
Participants:
Adults (aged ≥ 18 years) with a diagnosis of palmoplantar pustulosis and a disease duration of > 6 months and of sufficient impact and severity to require systemic therapy.
Interventions:
Participants were randomised (1 : 1) to daily self-administered subcutaneous injection of either anakinra or a placebo for 8 weeks.
Main outcome measures:
The primary outcome was the Palmoplantar Pustulosis Area and Severity Index score measured at 0, 1, 4, 8 and 12 weeks, with the primary end point at 8 weeks adjusted for baseline. Secondary outcomes included other investigator-assessed efficacy measures of disease severity, safety measures and participant-reported measures of efficacy and impact.
Results:
A total of 64 participants (mean baseline Palmoplantar Pustulosis Area and Severity Index score of 17.8, standard deviation 10.5) received anakinra (n = 31) or the placebo (n = 33). In the primary intention-to-treat analysis, which estimated the effect of the treatment policy, the mean treatment group difference at 8 weeks after adjustment for baseline Palmoplantar Pustulosis Area and Severity Index score was –1.65 (95% confidence interval –4.77 to 1.47; p = 0.300), in favour of anakinra relative to placebo, but was not statistically significant. Similarly, secondary investigator-assessed outcomes did not show statistical superiority of anakinra: the baseline-adjusted mean difference in fresh pustule count (palms and soles) between the anakinra group and the placebo group was 2.94 (95% confidence interval –26.44 to 32.33), in favour of placebo, and the mean difference in total pustule count was –30.08 (95% confidence interval –83.20 to 23.05), in favour of anakinra. Participant-assessed outcomes were consistent with these objective findings: the baseline-adjusted mean difference in Dermatology Life Quality Index between the anakinra group and the placebo group was 0.52 (95% confidence interval –2.04 to 3.07), in favour of placebo, and the mean difference in Palmoplantar Quality-of-Life Index was 1.27 (95% confidence interval –3.04 to 5.57), in favour of placebo. However, the proportion of participants who strongly agreed that treatment was worthwhile was greater in the anakinra group (12/29, 41%) than in the placebo group (4/28, 14%), a difference in proportion of 27% (95% confidence interval 5% to 49%). In the complier-average causal effect analysis, the baseline-adjusted mean treatment group difference in the week 8 Palmoplantar Pustulosis Area and Severity Index score in individuals who received ≥ 50% of injections was –2.30 (95% confidence interval –6.54 to 1.93; p = 0.287) and in those who received ≥ 90% of injections was –3.80 (95% confidence interval –10.76 to 3.16; p = 0.285), in favour of anakinra. No serious infections, significant neutropenia or other serious adverse events occurred. Injection site reactions were more frequent for those receiving anakinra (19/31, 61%) than for those receiving placebo (1/33, 3%).
Conclusions:
There was no evidence that anakinra was superior to placebo. For the treatment of palmoplantar pustulosis, interleukin 1 blockade is not a useful intervention.
Limitations:
The sample size was calculated to detect a large effect size. Treatment adherence was lower than expected. It cannot be ruled out that there was some selection bias towards less severe or unstable participants entering the trial given that the trial was placebo controlled with a required washout period.
Future work:
Palmoplantar pustulosis remains an area of high unmet need and further research is recommended to (1) identify new drug targets, (2) determine the contributory role of drug exposure (including pharmacokinetics and adherence) and (3) validate outcome measures in palmoplantar pustulosis.
Trial registration:
This trial is registered as ISCRTN13127147 and EudraCT 2015-003600-23.
Funding:
This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a MRC and National Institute for Health Research (NIHR) partnership. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 9, No. 2. See the NIHR Journals Library for further project information.
About the Series
Efficacy and Mechanism Evaluation
ISSN (Print): 2050-4365
ISSN (Electronic): 2050-4373
Declared competing interests of authors: Suzie Cro reports grants from the National Institute for Health Research (NIHR) during the conduct of the study. Victoria Cornelius reports being an Efficacy and Mechanism Evaluation (EME) Funding Committee member (2019–20) outside the submitted work. Francesca Capon reports grants from Boehringer Ingelheim (Ingelheim am Rhein, Germany) and consultancy fees from AnaptysBio (San Diego, CA, USA) outside the submitted work. Jonathan Barker reports personal fees from Amgen Inc (Thousand Oaks, CA, USA), Almirall S.A. (Barcelona, Spain), AbbVie (Lake Bluff, IL, USA), Celgene Ltd (Summit, NJ, USA), Novartis Pharmaceuticals UK Ltd (London, UK), Lilly UK (Basingstoke, UK), Boehringer Ingelheim, Bristol-Myers Squibb (New York, NY, USA), Janssen Pharmaceuticals (Beerse, Belgium), Sun Pharmaceutical Industries Ltd (Mumbai, India) and UCB (Slough, UK), and grants from AbbVie, Lilly, Boehringer Ingelheim and Janssen, outside the submitted work. David Burden reports personal fees from Boehringer Ingelheim, Novartis, Janssen and AbbVie outside the submitted work. Christopher Griffiths reports grants from Almirall S.A., Celgene, Eli Lilly and Company (Indianapolis, IN, USA), Janssen, Novartis, Sandoz UK Ltd (Camberley, UK) and UCB, and personal fees from Almirall S.A., Amgen, Celgene, BMS, LEO Pharma UK (Maidenhead, UK), Eli Lilly, Janssen, Novartis, AbbVie and Boehringer Ingelheim during the conduct of the study. Helen Lachmann reports Swedish Orphan Biovitrum AB (Stockholm, Sweden) funds for a research nurse. Helen McAteer reports grants from AbbVie, Almirral, Amgen, Celgene, Dermal Laboratories (Hitchin, UK), Eli Lilly, Janssen, LEO Pharma UK, UCB and from T&R Derma (Linthwaite, UK) outside the submitted work. Prakash Patel reports grants from EME programme (part of NIHR) during the conduct of the study. Andrew Pink reports personal fees from AbbVie, Lilly UK, Sanofi (Paris, France), LEO Pharma UK, Novartis, Almirall, UCB, Janssen and from BMS outside the submitted work. Nick Reynolds reported receiving lecture fees from AbbVie (to Newcastle University), payment for medical advisory board meeting and lectures fees from Almirall (to Newcastle University), contributing to a clinical trial from AnaptysBio (to Newcastle upon Tyne Hospital), lecture fees from Celgene (to Newcastle University), lecture fees from Janssen (to Newcastle University), grants and serving as a paid member of a medical advisory board from Novartis, and lecture fees from UCB Pharma Ltd (to Newcastle University) outside the submitted work. Richard Warren reports grants from AbbVie, Almirall, Amgen, Celgene, Janssen, LEO Pharma UK, Lilly, Medac Pharma (Stirling, UK), Novartis, Pfizer Inc. (New York, NY, USA) and UCB, and personal fees from AbbVie, Almirall, Amgen, Celgene, Janssen, LEO Pharma UK, Lilly, Medac, Novartis, Pfizer, UCB, Avillion LLP (Uxbridge, UK), Boehringer Ingelheim, Bristol Myers Squibb and Sanofi, outside the submitted work. Catherine Smith reports non-personal pecuniary relationships with AbbVie, GlaxoSmithKline plc (Brentford, UK), Janssen, Novartis, Pfizer Inc., Regeneron® (Tarrytown, NY, USA), Sanquin (Amsterdam (the Netherlands), Qiagen (Crawley, UK), MedImmune, LLC (Gaithersburg, MD, USA), Celgene, LEO Pharma, UCB Pharma, Sanofi, Boehringer Ingelheim and grants from Boehringer Ingelheim outside the submitted work.
Last reviewed: December 2020; Accepted: June 2021.
