This article presents the results of the UK extension of a previously conducted global Delphi panel on generalised pustular psoriasis (GPP). Five UK based dermatologists experienced in GPP management ...have expressed their level of agreement on 101 questionnaire statements addressing four aspects of GPP: clinical course and flare definition, diagnosis, treatment goals, and holistic management. Consensus was achieved for 89 of 101 statements (88%). Disagreement was detected on issues around the prognostic value of age, QoL assessment tools and the nature of comorbidities associated with GPP. Overall, the panelists corroborated the results of the global study and confirmed that the clinical algorithm derived from the global study is in accordance with the UK clinical practice.
Abstract
Achieving clear skin when treating psoriasis is the clinical priority for some clinicians, but it may not be the priority for all patients; wellbeing may be more important. To gain insights ...into the relative importance of clear skin for wellbeing, we retrospectively reviewed real-world data from four specialist dermatology departments in England and Scotland. We assessed the evolution in absolute Psoriasis Area and Severity Index (PASI) and Dermatology Life Quality Index (DLQI) scores in 122 adults treated with tildrakizumab for plaque psoriasis, to determine whether a reduction in PASI scores to < 3 or < 1 was needed to achieve a DLQI of 1 or 0. Mean age was 49 years (range 17–82). Median time since diagnosis was 18 years (range 4–67). Median time on treatment with tildrakizumab was 9 months (range 1–21). At baseline, the median PASI score was 12 (range 0–40) and median DLQI was 20 (range 0–30). The proportion of patients with PASI < 3 increased from 6% at baseline to 60% at final visit, and with PASI < 1 from 3% to 48%. The proportion of patients with PASI < 1 was greater for patients having > 52 weeks of data (61%) than for patients having > 28 weeks of data (52%). The median DLQI score at baseline was 20 (range 0–30) and that at final visit was 1 (range 0–22). The proportion of patients with a DLQI of 0 or 1 increased from 4% at baseline to 54% at final visit. The proportion of patients with a DLQI of 0 or 1 was no different for patients having > 52 weeks of data (52%) than for patients having > 28 weeks of data (56%). An improvement in the PASI score to < 1 or < 3 was accompanied by a reduction in DLQI to 1 or 0, but it was not a requirement. Tildrakizumab demonstrated substantial improvement in psoriasis signs and in patient quality of life comparable with other interleukin (IL)-23 inhibitors in UK clinical practice. The PASI score decreased and was maintained in line with the thinking that IL-23p19 antagonists such as tildrakizumab have good survival. An improvement in the PASI score to < 1 or < 3 may not be necessary for a patient to feel that their life is unaffected by their psoriasis. It may be prudent for clinicians to prioritize patient wellness and durability of treatment rather than aim for clear skin in every patient.
Funding sources: Almirall.
Drug survival of biologic therapies for psoriasis is a proxy for longer-term treatment effectiveness and safety. Patient factors that are associated with the survival of each biologic differently ...(effect modifiers) may inform the decision to choose between biologics.
To assess the drug survival associated with the effectiveness and safety of commonly used biologics for psoriasis in the UK and Ireland and identify effect modifiers for these biologics and their survival.
We conducted a prospective cohort study of patients with psoriasis using data from the British Association of Dermatologists Biologics and Immunomodulators Register (BADBIR) between November 2007 and August 2021.
Adalimumab, ustekinumab, secukinumab, guselkumab, ixekizumab.
We conducted a survival analysis and fitted separate flexible parametric models for drug survival as a proxy for effectiveness and safety.
A total of 16 122 treatment courses were included: 6607 (41.0%) in which treatment with adalimumab was initiated, 5405 (33.5%) with ustekinumab, 2677 (16.6%) with secukinumab, 730 (4.5%) with guselkumab, and 703 (4.4%) with ixekizumab. The crude survival functions at year 1 for measures of effectiveness for treatment with adalimumab was 0.81 (95% CI, 0.80-0.82), 0.89 for ustekinumab (95% CI, 0.88-0.89), 0.86 for secukinumab (95% CI, 0.85-0.87), 0.94 for guselkumab (95% CI, 0.92-0.96), and 0.86 for ixekizumab (95% CI, 0.83-0.89). The adjusted survival curves from the multivariable model for effectiveness showed that treatment with guselkumab had the higher survival (adjusted hazard ratio, 0.13; 95% CI, 0.03-0.56) and adalimumab had the lower survival (adjusted hazard ratio, 2.37; 95% CI, 2.03-2.76) compared with ustekinumab. Secukinumab and ixekizumab had similar survival curves over time. Psoriatic arthritis, previous biologic exposure, nail involvement, and ethnicity were effect modifiers for survival in association with treatment effectiveness. The crude survival functions at year 1 for safety were 0.91 for treatment with adalimumab (95% CI, 0.90-0.91), 0.94 for ustekinumab (95% CI, 0.94-0.95), 0.94 for secukinumab (95% CI, 0.92-0.94), 0.96 for guselkumab (95% CI, 0.94-0.98), and 0.92 for ixekizumab (95% CI, 0.89-0.94). Guselkumab, ustekinumab, and secukinumab had similar adjusted survival curves for safety, while adalimumab (adjusted hazard ratio, 1.66; 95% CI, 1.46-1.89) and ixekizumab (adjusted hazard ratio, 1.52; 95% CI, 1.13-2.03) had lower survival compared with ustekinumab.
The results of this cohort study suggest that guselkumab had the highest drug survival in BADBIR of the included biologics for treatment persistence that was associated with effectiveness, and guselkumab had highest drug survival for safety compared with other biologics except ustekinumab. Psoriatic arthritis, nail involvement, previous biologic exposure, and ethnicity were effect modifiers for biologics and their survival in association with treatment effectiveness. This information on longer-term treatment persistence, safety, and tolerability may help patients and their clinicians make an informed decision to initiate treatment with a biologic therapy.
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.
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.
Few studies have explored the immunology and genetic risk of paradoxical eczema occurring as an adverse event of biologic therapy in patients with psoriasis.
We sought to describe the systemic ...inflammatory signature of paradoxical eczema using proteomics and explore whether this is genetically mediated.
This study used the Olink Target 96 Inflammation panel on 256 serum samples from 71 patients with psoriasis and paradoxical eczema, and 75 controls with psoriasis to identify differentially expressed proteins and enriched gene sets. Case samples from 1 or more time points (T1 prebiologic, T2 postbiologic, and T3 postparadoxical eczema) were matched 1:1 with control samples. Genes contributing to enriched gene sets were selected, and functional single nucleotide polymorphisms used to create polygenic risk scores in a genotyped cohort of 88 paradoxical eczema cases and 3124 psoriasis controls.
STAMBP expression was lower in cases at T1 than in controls (log-fold change: −0.44; adjusted P = .022); no other proteins reached statistical significance at equivalent time points. Eleven gene sets including cytokine and chemokine pathways were enriched in cases at T2 and 10 at T3. Of the 39 proteins contributing to enriched gene sets, the majority are associated with the atopic dermatitis serum proteome. A polygenic risk score including 38 functional single nucleotide polymorphisms linked to enriched gene sets was associated with paradoxical eczema (adjusted P = .046).
The paradoxical eczema systemic inflammatory proteome trends toward atopic dermatitis at a gene-set level and is detectable before onset of the phenotype. This signature could be genetically determined.
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