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

BACKGROUND: 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. OBJECTIVES: To determine whether anakinra (an IL-1 receptor antagonist) delivers therapeutic benefit in PPP. METHODS: 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. RESULTS: 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. CONCLUSIONS: No evidence for the superiority of anakinra was found. IL-1 blockade is not a useful intervention for the treatment of PPP.

Comparing the efficacy and tolerability of biologic therapies in psoriasis: an updated network meta-analysis.

BACKGROUND: The rapid expansion of psoriasis biologics has led to an urgent need to understand their relative efficacy and tolerability to inform treatment decisions better and, specifically, to inform guideline development. OBJECTIVES: To update a 2017 meta-analysis on the comparative efficacy and tolerability of biologic treatments for psoriasis. METHODS: We searched the MEDLINE, PubMed, Embase and Cochrane databases for randomized controlled trials (RCTs), published up to 7 September 2018, of 11 licensed, NICE-approved biologics targeting tumour necrosis factor (adalimumab, etanercept, infliximab, certolizumab pegol), interleukin (IL)-12/IL-23p40 (ustekinumab), IL-17A (secukinumab, ixekizumab), IL-17RA (brodalumab) and IL-23p19 (guselkumab, tildrakizumab, risankizumab). A frequentist network meta-analysis ascertained direct or indirect evidence comparing biologics with one another, methotrexate or placebo. This was combined with hierarchical cluster analyses to consider efficacy (≥ 90% improvement in Psoriasis Area and Severity Index (PASI 90) or Physician's Global Assessment 0 or 1; PASI 75; Dermatology Life Quality Index improvement) and tolerability (drug withdrawal due to adverse events) outcomes at 10-16 weeks, followed by assessments of study quality, heterogeneity and inconsistency. RESULTS: We identified 62 RCTs presenting data on direct comparisons (31 899 participants). All biologics were efficacious compared with placebo or methotrexate at 10-16 weeks. Hierarchical cluster analyses revealed that adalimumab, brodalumab, certolizumab pegol, guselkumab, risankizumab, secukinumab, tildrakizumab and ustekinumab were comparable with respect to high short-term efficacy and tolerability. Infliximab and ixekizumab clustered together, with high short-term efficacy but relatively lower tolerability than the other agents, although the number of drug withdrawal events across the network was low, so these findings should be treated with caution. CONCLUSIONS: Using our methodology we found that most biologics cluster together with respect to short-term efficacy and tolerability, and we did not identify any single agent as 'best'. These data need to be interpreted in the context of longer-term efficacy, effectiveness data, safety, posology and drug acquisition costs when making treatment decisions.

Identification of loci associated with late-onset psoriasis using dense genotyping of immune-related regions.

BACKGROUND: Chronic plaque psoriasis can be subdivided into two groups according to the age of onset: type 1 (early onset, before 40 years) and type 2 (late onset, at or beyond 40 years). So far, 36 genetic loci have been associated with early-onset psoriasis in genome-wide association studies of white populations, while few studies have investigated genetic susceptibility to late-onset psoriasis. OBJECTIVES: To characterize the genetics underpinning late-onset psoriasis. METHODS: We genotyped 543 cases of late-onset psoriasis and 4373 healthy controls using the Immunochip array, a dense genotyping chip containing single-nucleotide polymorphisms previously associated with autoimmune diseases. Imputation using SNP2HLA and stepwise logistic regression analysis was performed for markers spanning the human leucocyte antigen gene region. RESULTS: Two loci (HLA-C and IL12B) previously associated with early-onset psoriasis showed significant association at a genome-wide threshold in the current study (P < 5 × 10(-8)). Six more loci (TRAF3IP2, IL23R, RNF114, IFIH1, IL23A and HLA-A) showed study-wide significant association (P < 2·3 × 10(-5); calculated using Genetic type 1 error calculator). Additionally, we identified an association at IL1R1 on chromosome 2q13, which is not associated with early-onset disease. CONCLUSIONS: This is the largest study to date of genetic loci in late-onset psoriasis, and demonstrates the overlap that exists with early-onset psoriasis. It also suggests that some loci are associated exclusively with late-onset psoriasis.

A case of tumour necrosis factor-α inhibitor- and rituximab-induced plantar pustular psoriasis that completely resolved with tocilizumab.

Rituximab, a chimeric B-cell-depleting monoclonal antibody, is a well-established therapy for rheumatoid arthritis. It is emerging that classical psoriatic lesions and plantar pustular psoriasis (PPP) are cutaneous side-effects of this drug. Antitumour necrosis factor (anti-TNF) therapies have multiple documented side-effects including PPP and psoriasis. We report a patient who has rheumatoid arthritis, who failed on anti-TNF therapies and then was commenced on rituximab. Subsequently she developed localized PPP. Due to deterioration of her joint disease she was switched to the interleukin-6 blocker tocilizumab, and the PPP resolved.

Practical experience of ustekinumab in the treatment of psoriasis: experience from a multicentre, retrospective case cohort study across the U.K. and Ireland.

BACKGROUND: There are limited data on the use of ustekinumab outside of clinical trials. OBJECTIVES: To assess the efficacy and safety of ustekinumab in patients with severe psoriasis attending 10 dermatology centres in the U.K. and Ireland. METHODS: A retrospective case-note review of 129 patients with psoriasis treated with ustekinumab. RESULTS: Baseline Psoriasis Area and Severity Index (PASI) was 22·9±10·1 (mean±SD). After 16weeks of treatment with ustekinumab PASI 75 (75% reduction in PASI) was observed in 63·0% (n=80/127) of patients, although four patients required concomitant therapy at the 16-week time point. Previous biologic use did show a small, non-significant trend towards treatment failure. A PASI 75 response was seen in 29·4% (n=5/17) of individuals weighing 90-100kg and treated with the standard 45mg ustekinumab dose compared with PASI 75 of 70·3%, 71·4%, 75·0% and 55·6% for weight groups <80, 80-90, 100-110 and >110kg, respectively (P=0·024). Ustekinumab therapy was well tolerated; serious adverse events were observed in 2·3% (n=3/129) of patients. CONCLUSIONS: Ustekinumab is a novel biologic agent for psoriasis. When used in everyday clinical practice it demonstrates high levels of short-term therapeutic efficacy with an acceptable short-term safety profile.

Clinical applicability of T-cell interferon-a release assay for tumour necrosis factor-a inhibitor therapy in severe psoriasis.

Many studies have found that screening and treatment of latent tuberculosis (TB) before starting treatment with tumour necrosis factor (TNF)-a inhibitors reduces associated TB infections. The new T-cell interferon-a release assay (TIGRA), is more specific and sensitive for detection of latent TB compared with the tuberculin skin test (TST). We report results of TIGRA in our first 63 patients commencing TNF-a inhibitors for severe psoriasis. Of the 63 patients, 5 (7.9%) had a positive TIGRA result and were started on treatment for latent TB. We found that the only risk factor for TB associated with a positive TIGRA was a history of travel to countries with high TB incidence. To our knowledge, this is the first study to identify the background risk (7.9%) of latent TB in an endemic UK population. This result emphasizes the importance of TIGRA testing to reduce the risk of TB in patients treated with TNF-a inhibitor.

Ultraviolet-B-induced erythema is mediated by nitric oxide and prostaglandin E2 in combination.

Ultraviolet-B-induced erythema (one, two, or four times the minimal erythema dose) was reduced but not abolished by application of 1% indomethacin gel immediately after irradiation of human skin. Continuous synthesis of prostaglandins is reflected by similar levels of indomethacin-mediated inhibition of erythema at any time within 48 h after irradiation. Repeated applications of indomethacin did not increase the inhibition. Twenty-four hours after irradiation with four minimal erythema doses, mean prostaglandin E2 levels in suction blisters were 27.2 ng per ml (SEM 11) compared with 8.6 ng per ml in unirradiated skin (n = 25; p < 0.01). Prosta glandin E2 levels in dermal tissues, sampled by microdialysis (depth 0.6 +/- 0.1 mm), were 310 pg per ml (SEM 123) and 237 pg per ml (SEM 88) in irradiated and unirradiated skin, respectively (n = 7, n.s.). Nitric oxide also made a significant contribution to ultraviolet-B-induced erythema. Ultraviolet erythema was inhibited by L-NAME in a dose-related fashion with 2 mM L-NAME causing total abolition of the response. L-NAME was effective at all time points up to 48 h suggesting that NO was produced continuously. NO was undetectable in suction blister fluid but in dermal microdialysate NO was present at 44.3 ng per ml (SEM 6.2) following ultraviolet B compared with 26.0 ng per ml (SEM 8.0) in unirradiated skin (p < 0.05), approximately 1000 times the molar concentration of prostaglandin E2. These findings confirm prostaglandin E2 and NO to be mediators of ultraviolet-induced erythema. They also show that there is prolonged synthesis of both mediators within the erythemal response and that synthesis of NO is induced by lower doses of ultraviolet B compared with that of prostaglandin E2.

UVR-induced oxidative stress in human skin in vivo: effects of oral vitamin C supplementation.

Previous studies of cultured skin cells and murine skin in vivo have indicated that UVR-induced damage involves the generation of reactive oxygen species and depletion of endogenous antioxidant systems. In order to explore the relevance of this to UVR-induced damage to human skin, we have undertaken a detailed examination of the time-course of changes in markers of oxidative stress in human skin following exposure to physiological amounts of UVR in vivo. In addition, we have examined the skin bioavailability of a common nutritional antioxidant, vitamin C, and have assessed the effects of supplementation on markers of oxidative stress. Our hypothesis was that acute exposure of human skin to UVR in vivo would lead to oxidation of cellular biomolecules that could be prevented by prior vitamin C treatment. A UVR-challenge of 120 mJ/cm2 of broadband UVB (peak 310 nm, range 270-400 nm) was applied to buttock skin of 8 healthy volunteers. This caused a rapid and significant rise in activity of skin catalase at 1 h and an increase in the oxidized/total glutathione ratio at 6 h post-UVR. AP-1 DNA binding also peaked at 1-6 h post-UVR, then declined rapidly to baseline levels. No significant changes were seen in skin malonaldehyde content. Oral vitamin C supplements (500 mg/day) were taken by 12 volunteers for 8 weeks resulting in significant rises in plasma and skin vitamin C content. Supplementation had no effect on the UVR-induced erythemal response. The skin malonaldehyde content was reduced by vitamin C supplementation, but surprisingly, reductions in the skin content of total glutathione and protein thiols were also seen. We speculate that this apparently paradoxical effect could be due to regulation of total reductant capacity by skin cells, such that vitamin C may have been replacing other reductants in these cells. No evidence was obtained for an effect of the supplementary vitamin C on the mild oxidative stress seen in human skin following UVR exposure.

Treatment of recalcitrant plantar warts with imiquimod.

Myrmecia are viral warts that result from the coalescence of plantar or palmar warts into large plaques. Treatment of these warts involves physical or chemical destruction of the verrucae, potent keratolytics or immunotherapy. Imiquimod 5% cream is a novel topical immunomodulator that has been used successfully in the treatment of genital and common warts. We report its successful use in a 35-year-old immunocompetent man who had had resistant plantar warts for 15 years.

Giant bathing trunk naevus with lymphadenopathy and unusual pathology.

Giant congenital melanocytic naevi remain a challenge to clinicians and histopathologists with respect to observation for malignant change and interpretation of histology findings, respectively. We report a 5-year-old boy with a giant bathing trunk naevus who, after multiple previous skin biopsies, developed lymphadenopathy. Biopsy from the lymph nodes demonstrated collections of naevomelanocytes within the lymph node. Interpretation of these findings and subsequent management is discussed.