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Anakinra for palmoplantar pustulosis: results from a randomized, double-blind, multicentre, two-staged, adaptive placebo-controlled trial (APRICOT).

ABSTRACT: Palmoplantar pustulosis (PPP) is a rare, debilitating, chronic inflammatory skin disease that affects the hands and feet. Clinical, immunological and genetic findings suggest a pathogenic role for interleukin (IL)-1. To determine whether anakinra (an IL-1 receptor antagonist) delivers therapeutic benefit in PPP. This was a randomized (1 : 1), double-blind, two-staged, adaptive, UK multicentre, placebo-controlled trial [ISCRTN13127147 (registered 1 August 2016); EudraCT number: 2015-003600-23 (registered 1 April 2016)]. Participants had a diagnosis of PPP (> 6 months) requiring systemic therapy. Treatment was 8 weeks of anakinra or placebo via daily, self-administered subcutaneous injections. Primary outcome was the Palmoplantar Pustulosis Psoriasis Area and Severity Index (PPPASI) at 8 weeks. A total of 374 patients were screened; 64 were enrolled (31 in the anakinra arm and 33 in the placebo arm) with a mean (SD) baseline PPPASI of 17·8 (10·5) and a PPP investigator's global assessment of severe (50%) or moderate (50%). The baseline adjusted mean difference in PPPASI favoured anakinra but did not demonstrate superiority in the intention-to-treat analysis [-1·65, 95% confidence interval (CI) -4·77 to 1·47; P = 0·30]. Similarly, secondary objective measures, including fresh pustule count (2·94, 95% CI -26·44 to 32·33; favouring anakinra), total pustule count (-30·08, 95% CI -83·20 to 23·05; favouring placebo) and patient-reported outcomes, did not show superiority of anakinra. When modelling the impact of adherence, the PPPASI complier average causal effect for an individual who received ≥ 90% of the total treatment (48% in the anakinra group) was -3·80 (95% CI -10·76 to 3·16; P = 0·285). No serious adverse events occurred. No evidence for the superiority of anakinra was found. IL-1 blockade is not a useful intervention for the treatment of PPP.

SUBMITTER: Cro S

PROVIDER: S-EPMC9255857 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Palmoplantar pustulosis (PPP) is a rare, chronic inflammatory skin disease. It is known to affect quality of life at a level comparable to that from major medical and psychiatric illness, yet current treatment options are remarkably limited. Recent evidence however suggests that interleukin-1 (IL-1) blockade with anakinra will deliver therapeutic benefit in PPP. METHODS:Anakinra for Pustular psoriasis: Response in a Controlled Trial (APRICOT) is a two-staged, adaptive, double-blind, randomised placebo-controlled trial which aims to test the hypothesis that IL-1 blockade with anakinra will deliver therapeutic benefit in PPP. During stage 1 a total of 24 patients will be randomised (1:1) to receive either placebo or anakinra. The two candidate primary outcomes are fresh pustule count (across palms and soles) and the Palmoplantar Pustulosis Area and Severity Index (PPPASI) score, recorded at baseline and at weeks 1, 4 and 8. Analysis at the end of stage 1 will compare treatment arms to ensure sufficient efficacy and safety in order to progress to stage 2. The primary outcome for stage 2 will also be identified following an assessment of the reliability and discriminative ability of fresh pustule count and PPPASI. The trial is powered to detect efficacy and will recruit an additional 40 patients in stage 2 (n?=?64 in total). Analysis will follow the intention-to-treat principle and analyse patients as randomised. DISCUSSION:This manuscript describes the important features of the small population trial design for APRICOT and the pre-specified statistical analysis plan for stage 1. The statistical analysis plan has been developed prior to data extraction and in compliance with international guidelines. It will increase the transparency of the data analysis for the APRICOT trial. The findings of the trial will help to clarify the role of anakinra in the treatment of PPP. TRIAL REGISTRATION:ISCRTN, ISCRTN13127147 . Registered on 1 August 2016. EudraCT Number 2015-003600-23 . Registered on 1 April 2016.

Project description:BACKGROUND:Multicentre trials investigating food allergies by double blind placebo controlled food challenges (DBPCFC) need standardized procedures, challenge meals and evaluation criteria. We aimed at developing a standardized approach for identifying patients with birch related soy allergy by means of DBPCFC to soy, including determination of threshold levels, in a multicentre setting. METHODS:Microbiologically stable soy challenge meals were composed of protein isolate with consistent Gly m 4 levels. Patients sensitized to main birch allergen Bet v 1 and concomitant sensitization to its soy homologue Gly m 4 underwent DBPCFC. Outcome was defined according to presence and/or absence of ten objective signs and intensity of eight subjective symptoms as measured by visual analogue scale (VAS). RESULTS:138 adult subjects (63.8% female, mean age 38 years) underwent DBPCFC. Challenge meals and defined evaluation criteria showed good applicability in all centres involved. 45.7% presented with objective signs and 65.2% with subjective symptoms at soy challenge. Placebo challenge meals elicited non-cardiovascular objective signs in 11.6%. In 82 (59.4%) subjects DBPCFC was judged as positive. 70.7% of DPBCFC+ showed objective signs and 85.4% subjective symptoms at soy challenge. Subjective symptoms to soy challenge meal in DBPCFC+ subjects started at significantly lower dose levels than objective signs (p < 0.001). Median cumulative eliciting doses for first objective signs in DBPCFC+ subjects were 4.7 g [0.7-24.7] and 0.7 g [0.2-4.7] total soy protein for first subjective symptoms (p = 0.01). CONCLUSIONS:We present the hitherto largest group of adults with Bet v 1 and Gly m 4 sensitization being investigated by DBPCFC. In this type of food allergy evaluation of DBPCFC outcome should not only include monitoring of objective signs but also scoring of subjective symptoms. Our data may contribute to standardize DBPCFC in pollen-related food allergy in multicentre settings. TRIAL REGISTRATION:EudraCT: 2009-011737-27.

Project description:Few studies with a limited number of patients have provided indications that cashew-allergic patients may experience severe allergic reactions to minimal amounts of cashew nut. The objectives of this multicentre study were to assess the clinical relevance of cashew nut sensitisation, to study the clinical reaction patterns in double-blind placebo-controlled food challenge tests and to establish the amount of cashew nuts that can elicit an allergic reaction.A total of 179 children were included (median age 9.0 years; range 2-17 years) with cashew nut sensitisation and a clinical history of reactions to cashew nuts or unknown exposure. Sensitised children who could tolerate cashew nuts were excluded. The study included three clinical visits and a telephone consultation. During the first visit, the medical history was evaluated, physical examinations were conducted, blood samples were drawn and skin prick tests were performed. The children underwent a double-blind placebo-controlled food challenge test with cashew nut during the second and third visits. The study showed that 137 (76.5%) of the sensitised children suspected of allergy to cashew nut had a positive double-blind placebo-controlled food challenge test, with 46% (63) manifesting subjective symptoms to the lowest dose of 1 mg cashew nut protein and 11% (15) developing objective symptoms to the lowest dose. Children most frequently had gastro-intestinal symptoms, followed by oral allergy and skin symptoms. A total of 36% (49/137) of the children experienced an anaphylactic reaction and 6% (8/137) of the children were treated with epinephrine.This prospective study demonstrated a strikingly high percentage of clinical reactions to cashew nut in this third line population. Severe allergic reactions, including anaphylaxis requiring epinephrine, were observed. These reactions were to minimal amounts of cashew nut, demonstrated the high potency of this allergens.www.ncbi.nlm.nih.gov/pubmed NTR3572.

Project description:INTRODUCTION:Palmoplantar psoriasis (PP) and palmoplantar pustulosis (PPP) are diseases affecting the hands and/or feet that can cause marked physical discomfort and functional disability. The tumor necrosis factor-alpha antagonists adalimumab, etanercept, and infliximab, the interleukin (IL)-17A inhibitors ixekizumab and secukinumab, and the IL-23 or IL-12/IL-23 inhibitors guselkumab and ustekinumab have been well studied for the treatment of moderate to severe plaque psoriasis. Less is known about the efficacy and safety of these agents for the treatment of PP (hyperkeratotic and pustular forms) and PPP. The aim of this review was to investigate the efficacy of biologic therapy for the treatment of hyperkeratotic PP, pustular PP, and PPP. METHODS:A systematic search of the medical electronic databases (Medline, Embase, and Cochrane Library) was conducted to identify studies or case reports which both used biologic therapy for the treatment of hyperkeratotic PP, pustular PP, and PPP and reported treatment outcomes. RESULTS:The systematic search identified 579 published articles, of which 44 were included in the analysis. Seven of the articles involved randomized placebo-controlled trials, two were open label trials, and the remaining were cohort studies, case series, or case reports. In the randomized controlled trials on the treatment of hyperkeratotic PP, adalimumab, guselkumab, infliximab, ixekizumab, and secukinumab each demonstrated superiority to placebo at 16, 16, 14, 12, and 12 or 16 weeks, respectively (p < 0.05). For the treatment of pustular PP, ustekinumab 45 mg was not superior to placebo at 12 and 16 weeks, respectively (p > 0.05), although an open label study demonstrated that four of five patients on a therapeutic regimen of ustekinumab 90 mg achieved clinical clearance at 16 weeks. For the treatment of PPP, etanercept and ustekinumab 45 mg were not superior to placebo at 12 and 16 weeks, respectively (p > 0.05). A combined analysis of studies for hyperkeratotic PP demonstrated that 94.7%, 90.0%, 82.5%, 89.1%, and 86.7% of patients experienced an improvement of at least 50% upon treatment with adalimumab, guselkumab, ixekizumab, secukinumab, and ustekinumab, respectively. In a combined analysis of case reports examining PPP, infliximab showed the greatest efficacy at 100.0% clinical improvement of patients from case reports, followed by ustekinumab at 58.8% clinical improvement. Few serious adverse events were reported, but several were reported in patients treated with infliximab or secukinumab. CONCLUSION:Biologic therapy is effective and well-tolerated for the treatment of hyperkeratotic PP, but less data are available on the treatment of pustular PP or PPP. Adalimumab, guselkumab, ixekizumab, secukinumab, and ustekinumab all showed > 80% efficacy for the treatment of hyperkeratotic PP, while infliximab and ustekinumab showed moderate efficacy for the treatment of pustular PP, and infliximab was the most efficacious treatment for PPP.

Project description:ImportanceNail involvement is common in synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome, which has a strong association with quality of life in patients with SAPHO. Tofacitinib is an oral Janus kinase inhibitor that has been previously shown to be effective for nail psoriasis.ObjectiveTo assess the efficacy and safety of tofacitinib for the treatment of nail involvement in SAPHO syndrome.InterventionsParticipants received tofacitinib, 5 mg, twice daily, for 12 weeks.Design, setting, and participantsThis open-label, single-arm, prospective pilot study included 13 patients with SAPHO syndrome accompanied by nail lesions and active palmoplantar pustulosis who were recruited from Peking Union Medical College Hospital from September 2019 to December 2019. Follow-up was completed in March 2020. Analysis began March 2020.Main outcomes and measuresThe primary end point was the percentage of the change from baseline in Nail Psoriasis Severity Index scores at week 12. Secondary end points included the percentage of the change from baseline in Palmoplantar Psoriasis Area and Severity Index scores, change from baseline in Visual Analogue Scale scores in global osteoarticular pain, Dermatology Life Quality Index scores, and inflammatory markers. Adverse events were recorded throughout the study.ResultsThirteen female Asian patients (means [SD] age, 39.7 [12.3] years) were included, all of whom completed the study. At week 12, significant improvements were observed in Nail Psoriasis Severity Index scores (median, -67% [interquartile range (IQR), -56% to -77%]; P < .001) and Palmoplantar Psoriasis Area and Severity Index scores (median, -71% [IQR, -58% to -78%]; P < .001). Significant improvement was also noted in Dermatology Life Quality Index scores (median, -12 [IQR, -8.5 to -15]; P < .001) at week 12. A significant decrease in Visual Analogue Scale scores in global osteoarticular pain was observed at week 8 (median, -4 [IQR, 0 to -5]; P = .02) but was not significant at week 12. Inflammatory marker levels were decreased, as indicated by erythrocyte sedimentation rate (median, -8 mm/h [IQR, -4 mm/h to -11 mm/h]; P < .001) and high-sensitivity C-reactive protein levels (median, -1.6 [IQR, -0.3 to -4.1]; P = .01). No severe adverse events were observed.Conclusions and relevanceIn this pilot study, tofacitinib yielded significant remission of nail lesions and palmoplantar psoriasis accompanied by an improvement in quality of life in patients with SAPHO syndrome. Additional follow-up studies to evaluate the long-term efficacy and safety of tofacitinib for nail involvement in SAPHO syndrome are warranted.Trial registrationChinese Clinical Trial Registry number: ChiCTR1900025941.

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Anakinra for palmoplantar pustulosis: results from a randomized, double-blind, multicentre, two-staged, adaptive placebo-controlled trial (APRICOT).

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