The term pustular psoriasis indicates a group of severe skin disorders characterized by eruptions of neutrophil-filled pustules. The disease, which often manifests with concurrent psoriasis vulgaris, ...can have an acute systemic (generalized pustular psoriasis GPP) or chronic localized (palmoplantar pustulosis PPP and acrodermatitis continua of Hallopeau ACH) presentation. Although mutations have been uncovered in IL36RN and AP1S3, the rarity of the disease has hindered the study of genotype-phenotype correlations.
We sought to characterize the clinical and genetic features of pustular psoriasis through the analysis of an extended patient cohort.
We ascertained a data set of unprecedented size, including 863 unrelated patients (251 with GPP, 560 with PPP, 28 with ACH, and 24 with multiple diagnoses). We undertook mutation screening in 473 cases.
Psoriasis vulgaris concurrence was lowest in PPP (15.8% vs 54.4% in GPP and 46.2% in ACH, P < .0005 for both), whereas the mean age of onset was earliest in GPP (31.0 vs 43.7 years in PPP and 51.8 years in ACH, P < .0001 for both). The percentage of female patients was greater in PPP (77.0%) than in GPP (62.5%; P = 5.8 × 10−5). The same applied to the prevalence of smokers (79.8% vs 28.3%, P < 10−15). Although AP1S3 alleles had similar frequency (0.03-0.05) across disease subtypes, IL36RN mutations were less common in patients with PPP (0.03) than in those with GPP (0.19) and ACH (0.16; P = 1.9 × 10−14 and .002, respectively). Importantly, IL36RN disease alleles had a dose-dependent effect on age of onset in all forms of pustular psoriasis (P = .003).
The analysis of an unparalleled resource revealed key clinical and genetic differences between patients with PPP and those with GPP.
Display omitted
Acne vulgaris is a highly heritable common, chronic inflammatory disease of the skin for which five genetic risk loci have so far been identified. Here, we perform a genome-wide association study of ...3823 cases and 16,144 controls followed by meta-analysis with summary statistics from a previous study, with a total sample size of 26,722. We identify 20 independent association signals at 15 risk loci, 12 of which have not been previously implicated in the disease. Likely causal variants disrupt the coding region of WNT10A and a P63 transcription factor binding site in SEMA4B. Risk alleles at the 1q25 locus are associated with increased expression of LAMC2, in which biallelic loss-of-function mutations cause the blistering skin disease epidermolysis bullosa. These findings indicate that variation affecting the structure and maintenance of the skin, in particular the pilosebaceous unit, is a critical aspect of the genetic predisposition to severe acne.
Systematic reviews suggest that narrowband ultraviolet B light combined with treatments such as topical corticosteroids may be more effective than monotherapy for vitiligo.
To explore the clinical ...effectiveness and cost-effectiveness of topical corticosteroid monotherapy compared with (1) hand-held narrowband ultraviolet B light monotherapy and (2) hand-held narrowband ultraviolet B light/topical corticosteroid combination treatment for localised vitiligo.
Pragmatic, three-arm, randomised controlled trial with 9 months of treatment and a 12-month follow-up.
Sixteen UK hospitals - participants were recruited from primary and secondary care and the community.
Adults and children (aged ≥ 5 years) with active non-segmental vitiligo affecting ≤ 10% of their body area.
Topical corticosteroids mometasone furoate 0.1% (Elocon
, Merck Sharp & Dohme Corp., Merck & Co., Inc., Whitehouse Station, NJ, USA) plus dummy narrowband ultraviolet B light; narrowband ultraviolet B light (narrowband ultraviolet B light plus placebo topical corticosteroids); or combination (topical corticosteroids plus narrowband ultraviolet B light). Topical corticosteroids were applied once daily on alternate weeks and narrowband ultraviolet B light was administered every other day in escalating doses, with a dose adjustment for erythema. All treatments were home based.
The primary outcome was self-assessed treatment success for a chosen target patch after 9 months of treatment ('a lot less noticeable' or 'no longer noticeable' on the Vitiligo Noticeability Scale). Secondary outcomes included blinded assessment of primary outcome and percentage repigmentation, onset and maintenance of treatment response, quality of life, side effects, treatment burden and cost-effectiveness (cost per additional successful treatment).
In total, 517 participants were randomised (adults,
= 398; and children,
= 119; 52% male; 57% paler skin types I-III, 43% darker skin types IV-VI). At the end of 9 months of treatment, 370 (72%) participants provided primary outcome data. The median percentage of narrowband ultraviolet B light treatment-days (actual/allocated) was 81% for topical corticosteroids, 77% for narrowband ultraviolet B light and 74% for combination groups; and for ointment was 79% for topical corticosteroids, 83% for narrowband ultraviolet B light and 77% for combination. Target patch location was head and neck (31%), hands and feet (32%), and rest of the body (37%). Target patch treatment 'success' was 20 out of 119 (17%) for topical corticosteroids, 27 out of 123 (22%) for narrowband ultraviolet B light and 34 out of 128 (27%) for combination. Combination treatment was superior to topical corticosteroids (adjusted risk difference 10.9%, 95% confidence interval 1.0% to 20.9%;
= 0.032; number needed to treat = 10). Narrowband ultraviolet B light was not superior to topical corticosteroids (adjusted risk difference 5.2%, 95% confidence interval -4.4% to 14.9%;
= 0.290; number needed to treat = 19). The secondary outcomes supported the primary analysis. Quality of life did not differ between the groups. Participants who adhered to the interventions for > 75% of the expected treatment protocol were more likely to achieve treatment success. Over 40% of participants had lost treatment response after 1 year with no treatment. Grade 3 or 4 erythema was experienced by 62 participants (12%) (three of whom were using the dummy) and transient skin thinning by 13 participants (2.5%) (two of whom were using the placebo). We observed no serious adverse treatment effects. For combination treatment compared with topical corticosteroids, the unadjusted incremental cost-effectiveness ratio was £2328.56 (adjusted £1932) per additional successful treatment (from an NHS perspective).
Relatively high loss to follow-up limits the interpretation of the trial findings, especially during the post-intervention follow-up phase.
Hand-held narrowband ultraviolet B light plus topical corticosteroid combination treatment is superior to topical corticosteroids alone for treatment of localised vitiligo. Combination treatment was relatively safe and well tolerated, but was effective in around one-quarter of participants only. Whether or not combination treatment is cost-effective depends on how much decision-makers are willing to pay for the benefits observed.
Development and testing of new vitiligo treatments with a greater treatment response and longer-lasting effects are needed.
Current Controlled Trials ISRCTN17160087.
This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in
; Vol. 24, No. 64. See the NIHR Journals Library website for further project information.
Variation in response to biologic therapy for inflammatory diseases, such as psoriasis, is partly driven by variation in drug exposure. Real‐world psoriasis data were used to develop a ...pharmacokinetic/pharmacodynamic (PK/PD) model for the first‐line therapeutic antibody ustekinumab. The impact of differing dosing strategies on response was explored. Data were collected from a UK prospective multicenter observational cohort (491 patients on ustekinumab monotherapy, drug levels, and anti‐drug antibody measurements on 797 serum samples, 1,590 measurements of Psoriasis Area Severity Index (PASI)). Ustekinumab PKs were described with a linear one‐compartment model. A maximum effect (Emax) model inhibited progression of psoriatic skin lesions in the turnover PD mechanism describing PASI evolution while on treatment. A mixture model on half‐maximal effective concentration identified a potential nonresponder group, with simulations suggesting that, in future, the model could be incorporated into a Bayesian therapeutic drug monitoring “dashboard” to individualize dosing and improve treatment outcomes.
Abstract
Narrowband UVB (NBUVB) is a recommended second-line treatment for moderate-to-severe atopic eczema unresponsive to adequate topical therapy, and is known to induce good short-term ...improvement of eczema severity (Reynolds NJ, Franklin V, Gray JC et al. NBUVB and broad-band ultraviolet A phototherapy in adult atopic eczema: a randomised controlled trial. Lancet 2001; 357:2012–16). However, it is unclear how adult patients fare with their eczema severity long after completion of a course of NBUVB. We aimed to investigate the severity of atopic eczema in adults, 1 year following the completion of NBUVB, using validated clinical activity measures. We hypothesized that, after 1 year, eczema severity would remain better than at baseline (prior to having NBUVB). We undertook a multicentre prospective observational study of adults with atopic eczema (as per Hanifin and Rajka criteria) prescribed NBUVB as part of their standard clinical care. Participants had moderate-to-severe disease, with a minimum objective SCORAD of 15 and minimum Investigator’s Global Assessment (IGA) of 3, and were resistant to at least one conventional treatment (e.g. potent topical steroid). Eczema severity was assessed by selected investigators using SCORAD and IGA. Assessments were made at baseline, at the end of NBUVB and at 4, 8 and 12 months after completion of NBUVB. We aimed to recruit 80 patients at the outset to provide us with about 25–30 patients for analysis at the 1 year post-NBUVB follow-up. Eighty patients (47 men, 33 women) with a mean age of 37 years (range 18–83) were recruited, with a baseline mean (SD) SCORAD of 39.2 (12.5). Forty-nine patients could not attend to complete NBUVB or the follow-up visits thereafter. Three patients had to stop NBUVB as their eczema flared. Mean baseline SCORAD of the 28 patients who completed the study was 41.3 (14.7), with the mean IGA being 3 (range 3–4; reflecting moderate to severe disease, respectively). Compared with baseline, mean SCORAD was significantly lower at the end of NBUVB 19.1 (13); P < 0.001 and at 4 months post-NBUVB 21.9 (11.9); P < 0.001. Furthermore, compared with baseline, there was a sustained ongoing reduction of mean SCORAD at 8 months 22.6 (13.1); P < 0.001 and 12 months post-NBUVB 21.1 (14.8); P < 0.001. Mean SCORAD at 1 year was not statistically significantly different to that on completion of NBUVB (P > 0.5). Change in IGA matched similar sustained improvement trends with SCORAD. These findings indicate that NBUVB may provide a long-lasting effect for patients who complete a course, helping to diminish their eczema severity to a more manageable level. These data can further inform consultations with patients, when outlining the approach of NBUVB for their care.
Biologic therapies can be highly effective for the treatment of severe psoriasis, but response for individual patients can vary according to drug. Predictive biomarkers to guide treatment selection ...could improve patient outcomes and treatment cost-effectiveness.
We sought to test whether HLA-C*06:02, the primary genetic susceptibility allele for psoriasis, predisposes patients to respond differently to the 2 most commonly prescribed biologics for psoriasis: adalimumab (anti–TNF-α) and ustekinumab (anti–IL-12/23).
This study uses a national psoriasis registry that includes longitudinal treatment and response observations and detailed clinical data. HLA alleles were imputed from genome-wide genotype data for 1326 patients for whom 90% reduction in Psoriasis Area and Severity Index score (PASI90) response status was observed after 3, 6, or 12 months of treatment. We developed regression models of PASI90 response, examining the interaction between HLA-C*06:02 and drug type (adalimumab or ustekinumab) while accounting for potentially confounding clinical variables.
HLA-C*06:02–negative patients were significantly more likely to respond to adalimumab than ustekinumab at all time points (most strongly at 6 months: odds ratio OR, 2.95; P = 5.85 × 10−7), and the difference was greater in HLA-C*06:02–negative patients with psoriatic arthritis (OR, 5.98; P = 6.89 × 10−5). Biologic-naive patients who were HLA-C*06:02 positive and psoriatic arthritis negative demonstrated significantly poorer response to adalimumab at 12 months (OR, 0.31; P = 3.42 × 10−4). Results from HLA-wide analyses were consistent with HLA-C*06:02 itself being the primary effect allele. We found no evidence for genetic interaction between HLA-C*06:02 and ERAP1.
This large observational study suggests that reference to HLA-C*06:02 status could offer substantial clinical benefit when selecting treatments for severe psoriasis.
The identification of disease alleles underlying human autoinflammatory diseases can provide important insights into the mechanisms that maintain neutrophil homeostasis. Here, we focused our ...attention on generalized pustular psoriasis (GPP), a potentially life-threatening disorder presenting with cutaneous and systemic neutrophilia. Following the whole-exome sequencing of 19 unrelated affected individuals, we identified a subject harboring a homozygous splice-site mutation (c.2031−2A>C) in MPO. This encodes myeloperoxidase, an essential component of neutrophil azurophil granules. MPO screening in conditions phenotypically related to GPP uncovered further disease alleles in one subject with acral pustular psoriasis (c.2031−2A>C;c.2031−2A>C) and in two individuals with acute generalized exanthematous pustulosis (c.1705C>T;c.2031−2A>C and c.1552_1565del;c.1552_1565del). A subsequent analysis of UK Biobank data demonstrated that the c.2031−2A>C and c.1705C>T (p.Arg569Trp) disease alleles were also associated with increased neutrophil abundance in the general population (p = 5.1 × 10−6 and p = 3.6 × 10−5, respectively). The same applied to three further deleterious variants that had been genotyped in the cohort, with two alleles (c.995C>T p.Ala332Val and c.752T>C p.Met251Thr) yielding p values < 10−10. Finally, treatment of healthy neutrophils with an MPO inhibitor (4-Aminobenzoic acid hydrazide) increased cell viability and delayed apoptosis, highlighting a mechanism whereby MPO mutations affect granulocyte numbers. These findings identify MPO as a genetic determinant of pustular skin disease and neutrophil abundance. Given the recent interest in the development of MPO antagonists for the treatment of neurodegenerative disease, our results also suggest that the pro-inflammatory effects of these agents should be closely monitored.
Abstract Background The main conventional systemic atopic dermatitis (AD) treatments are methotrexate (MTX) and ciclosporin (CyA). Dupilumab was the first novel systemic agent to enter routine ...clinical practice. There are no head-to-head randomised controlled trials or real-world studies comparing these agents directly. Network meta-analyses provide indirect comparative efficacy and safety data and have shown strong evidence for dupilumab and CyA. Objectives The aim of this study was to compare the real-world clinical effectiveness and safety of CyA, dupilumab and MTX in AD. Methods We compared the effectiveness and safety of these systemic agents in a prospective observational cohort study of adult and paediatric patients recruited into the UK-Irish Atopic eczema Systemic TherApy Register (A-STAR). Treatment effectiveness measures included Eczema Area and Severity Index (EASI), Patient-Oriented Eczema Measure (POEM), Peak Pruritus Numerical Rating Scale (PP-NRS), Dermatology Life Quality Index (DLQI) and children’s DLQI (cDLQI). Minimum duration of treatment was 28 days and follow-up was 12 months. Adjusted Cox-regression was used to compare the hazards of achieving EASI-50, EASI-75 and EASI-90 over time, and linear mixed-effects models were used to estimate changes in efficacy scores. Treatment safety was assessed by examining adverse events (AEs) at follow-up visits. Results 488 patients (n=311 adults and n=177 children/adolescents) on dupilumab (n=282), methotrexate (n=149), or CyA (n=57) were included. CyA and MTX were primarily used first line, while dupilumab was mainly a second line systemic as per UK National Institute of Clinical and Care Excellence (NICE) recommendations. EASI-50, EASI-75 and EASI-90 were achieved more rapidly in the dupilumab and CyA groups compared to MTX. After adjustment for previous severity, the reduction in EASI, POEM, PP-NRS and DLQI was greater for patients treated with dupilumab compared to MTX. In severe patients the reduction in EASI, POEM, and PP-NRS was even greater with CyA. The incidence of AEs was similar across groups (734, 654 and 594 per 10,000 person-month on CyA, dupilumab and MTX respectively). Conclusions This real-world comparison of CyA, dupilumab and MTX in AD suggests that dupilumab is consistently more effective than MTX and that CyA is most effective in very severe disease within one follow-up year.
Palmoplantar pustulosis (PPP) is an inflammatory skin disorder that mostly affects smokers and manifests with painful pustular eruptions on the palms and soles. Although the disease can present with ...concurrent plaque psoriasis, TNF and IL-17/IL-23 inhibitors show limited efficacy. There is therefore a pressing need to uncover PPP disease drivers and therapeutic targets.
We sought to identify genetic determinants of PPP and investigate whether cigarette smoking contributes to disease pathogenesis.
We performed a genome-wide association meta-analysis of 3 North-European cohorts (n = 1,456 PPP cases and 402,050 controls). We then used the scGWAS program to investigate the cell-type specificity of the association signals. We also undertook genetic correlation analyses to examine the similarities between PPP and other immune-mediated diseases. Finally, we applied Mendelian randomization to analyze the causal relationship between cigarette smoking and PPP.
We found that PPP is not associated with the main genetic determinants of plaque psoriasis. Conversely, we identified genome-wide significant associations with the FCGR3A/FCGR3B and CCHCR1 loci. We also observed 13 suggestive (P < 5 × 10−6) susceptibility regions, including the IL4/IL13 interval. Accordingly, we demonstrated a significant genetic correlation between PPP and TH2-mediated diseases such as atopic dermatitis and ulcerative colitis. We also found that genes mapping to PPP-associated intervals were preferentially expressed in dendritic cells and often implicated in T-cell activation pathways. Finally, we undertook a Mendelian randomization analysis, which supported a causal role of cigarette smoking in PPP.
The first genome-wide association study of PPP points to a pathogenic role for deregulated TH2 responses and cigarette smoking.
The identification of robust endotypes—disease subgroups of clinical relevance—is fundamental to stratified medicine. We hypothesized that HLA-C∗06:02 status, the major genetic determinant of ...psoriasis, defines a psoriasis endotype of clinical relevance. Using two United Kingdom–based cross-sectional datasets—an observational severe-psoriasis study (Biomarkers of Systemic Treatment Outcomes in Psoriasis; n = 3,767) and a large population-based bioresource (UK Biobank, including n = 5,519 individuals with psoriasis)—we compared demographic, environmental, and clinical variables of interest in HLA-C∗06:02–positive (one or two copies of the HLA-C∗06:02 allele) with those in HLA-C∗06:02‒negative (no copies) individuals of European ancestry. We used multivariable regression analyses to account for mediation effects established a priori. We confirm previous observations that HLA-C∗06:02–positive status is associated with earlier age of psoriasis onset and extend findings to reveal an association with disease expressivity in females (Biomarkers of Systemic Treatment Outcomes in Psoriasis: P = 2.7 × 10–14, UK Biobank: P = 1.0 × 10–8). We also show HLA-C∗06:02–negative status to be associated with characteristic clinical features (large plaque disease, OR for HLA-C∗06:02 = 0.73, P = 7.4 × 10–4; nail involvement, OR = 0.70, P = 2.4 × 10–6); higher central adiposity (Biomarkers of Systemic Treatment Outcomes in Psoriasis: waist circumference difference of 2.0 cm, P = 8.4 × 10–4; UK Biobank: waist circumference difference of 1.4 cm, P = 1.5 × 10–4), especially in women; and a higher prevalence of other cardiometabolic comorbidities. These findings extend the clinical phenotype delineated by HLA-C∗06:02 and highlight its potential as an important biomarker to consider in future multimarker stratified medicine approaches.
PDF
