Influence of autozygosity on common disease risk across the phenotypic spectrum.

Autozygosity is associated with rare Mendelian disorders and clinically relevant quantitative traits. We investigated associations between the fraction of the genome in runs of homozygosity (FROH) and common diseases in Genes & Health (n = 23,978 British South Asians), UK Biobank (n = 397,184), and 23andMe. We show that restricting analysis to offspring of first cousins is an effective way of reducing confounding due to social/environmental correlates of FROH. Within this group in G&H+UK Biobank, we found experiment-wide significant associations between FROH and twelve common diseases. We replicated associations with type 2 diabetes (T2D) and post-traumatic stress disorder via within-sibling analysis in 23andMe (median n = 480,282). We estimated that autozygosity due to consanguinity accounts for 5%-18% of T2D cases among British Pakistanis. Our work highlights the possibility of widespread non-additive genetic effects on common diseases and has important implications for global populations with high rates of consanguinity.

A genome-wide meta-analysis of palmoplantar pustulosis implicates TH2 responses and cigarette smoking in disease pathogenesis.

BACKGROUND: 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. OBJECTIVES: We sought to identify genetic determinants of PPP and investigate whether cigarette smoking contributes to disease pathogenesis. METHODS: 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. RESULTS: 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. CONCLUSIONS: The first genome-wide association study of PPP points to a pathogenic role for deregulated TH2 responses and cigarette smoking.

The treatment of latent tuberculosis infection in migrants in primary care versus secondary care.

BACKGROUND: Control of latent tuberculosis infection (LTBI) is a priority in the World Health Organization strategy to eliminate tuberculosis (TB). Many high-income low TB incidence countries have prioritised LTBI screening and treatment in recent migrants. We tested whether a novel model of care, based entirely within primary care, was effective and safe as compared to secondary care. METHODS: This was a pragmatic cluster-randomised, parallel group, superiority trial conducted in 34 general practices in London, UK, comparing LTBI treatment in recent migrants in primary care to secondary care. The primary outcome was treatment completion, defined as taking at least 90% of antibiotic doses. Secondary outcomes included treatment acceptance, adherence, adverse effects, patient satisfaction, TB-incidence and a cost-effectiveness analysis. The trial is registered at ClinicalTrials.gov (NCT03069807). Analyses were performed on an intention-to-treat basis. RESULTS: Between September 2016 and May 2019, 362 recent migrants with LTBI were offered treatment and 276 accepted. Treatment completion was similar in primary and secondary care (82·6% versus 86·0%, aOR:0·64, 95%CI:0·31-1·29). There was no difference in drug induced liver injury (DILI) between primary and secondary care (0·7% versus 2·3%, aOR:0·29, 95%CI:0·03-2·84). Treatment acceptance was lower in primary care (65·2% (146/224) versus 94.2% (130/138), aOR:0·10, 95%CI:0·03-0·31). The estimated cost per patient completing treatment was lower in primary care, with an incremental saving of £315. 27(£313.47-£317.07). CONCLUSIONS: The treatment of LTBI in recent migrants within primary care does not result in higher rates of treatment completion but is safe and costs less when compared to secondary care.

Prevalence, incidence, mortality, and healthcare resource use for generalised pustular psoriasis, palmoplantar pustulosis, and plaque psoriasis in England: a population-based cohort study.

BACKGROUND: Generalised pustular psoriasis (GPP) and palmoplantar pustulosis (PPP) are chronic, inflammatory skin conditions. Accumulating evidence shows that GPP and PPP have different characteristics compared with plaque psoriasis and are distinct clinical entities. OBJECTIVES: To assess the epidemiology, comorbidities, mortality and healthcare use for patients with GPP and PPP compared with those with plaque psoriasis in England. METHODS: A cohort study involving analyses of longitudinal electronic health record data in the Clinical Practice Research Datalink Aurum database and linked hospital and mortality data between 2008 and 2019. The primary study outcome was the incidence and prevalence rates for GPP, PPP and plaque psoriasis in England. Secondary outcomes included survival rates and healthcare resource use (HCRU) by disease type. RESULTS: We identified 373 patients with GPP, 1,828 with PPP and 224,223 with plaque psoriasis. The mean age was 55.9 years (standard deviation [SD]: 18.6) for patients with GPP, 51.5 years (SD: 16.4) for those with PPP, and 48.5 years (SD: 19.1) for those with plaque psoriasis; 62.5% and 65.9% of patients with GPP and PPP, respectively, were women, compared with 49.4% of those with plaque psoriasis. About half of the patients were overweight or obese at baseline (GPP, 48.6%; PPP, 56.0%; and plaque psoriasis, 45.9%). The incidence rates for GPP, PPP and plaque psoriasis were 0.25 (95% CI: 0.21-0.28), 2.01 (95% CI: 1.92-2.11) and 103.2 (95% CI: 102.5-103.9) per 100,000 person-years, respectively. From 2008 to 2019, the prevalence rates per 100,000 persons ranged from 1.61 to 3.0 for GPP, 1.1 to 18.7 for PPP and 1771.0 to 1903.8 for plaque psoriasis. Survival rates were lower for patients with GPP, particularly those who were over 55 years old and those with a history of ≥1 comorbidity in each cohort. HCRU was lower in the plaque psoriasis cohort and highest in the GPP cohort, particularly among those who had ≥1 GPP flare. CONCLUSIONS: Our results provide further evidence that GPP is a distinct disease with different epidemiology, lower survival and higher HCRU than plaque psoriasis in England.

EGFR/MEK inhibitor therapy induces a distinct inflammatory hair follicle response that includes a collapse of immune privilege.

AIMS: Inhibitors of epidermal growth factor receptor (EGFRi) or mitogen-activated protein kinase (MEKi) induce a folliculitis in 75-90% of patients, whose pathobiology remains insufficiently understood. OBJECTIVES: (1) Characterize changes in the skin immune status and global transcriptional profile of EGFRi-treated patients (2) Probe whether EGFRi affects the hair follicle's (HF) immune privilege (IP) (3) Identify early pro-inflammatory signals induced by EGFRi/MEKi in human scalp HFs ex vivo. METHODS: Scalp biopsies were taken from long-term EGFRi-treated patients exhibiting folliculitis (Chronic-EGFRi, n=9) vs normal scalp skin (n=9) and patients prior to commencing EGFRi therapy and after two weeks of EGFRi therapy (Acute-EGFRi, n=5). Healthy organ-cultured scalp HFs were exposed to EGFRi (Erlotinib) or MEKi (Cobimetinib) (n=5 patients, each). Samples were assessed by quantatitive immunohistomorphometry, RNAseq and in situ hybridization. RESULTS: The Chronic-EGFRi cohort showed CD8+ T cell infiltration of the bulge alongside a partial collapse of the HF's IP, evidenced by upregulated MHC class I, ß2-microglobulin and MHC class II and decreased TGF-ß1 protein expression. Healthy HFs treated with EGFRi/MEKi ex vivo also showed partial HF IP collapse and increased transcription of HLA-A, HLA-DR, ß2-microglobulin transcripts. RNAseq anlysis showed increased transcription of chemokines (CXCL1, CXCL13, CCL18, CCL3, CCL7) and IL-26 in Chronic-EGFRi biopsies, as well as increased interlukin IL-33 and decreased IL-37 expesssion in both Acute-EGFRi biopsies and organ-cultured HFs. CONCLUSION: These data show that EGFRi/MEKi compromise the physiological IP of human scalp HFs and suggest that future clinical management of EGFRi/MEKi-induced folliculitis requires HF IP protection and inhibition of IL-33.

The impact of irritant challenge on the skin barrier and myeloid resident immune cells in post-menopausal women is modulated by hormone replacement therapy.

BACKGROUND: Sex hormone changes during menopausal transition contribute to declining skin health. However, how menopause and its treatment by hormone replacement therapy (HRT) impact the skin barrier and immune system is unclear. Therefore, we examined how menopause and HRT affect skin barrier and immune cell composition in post-menopausal women following irritant challenge. METHODS: Two cohorts of post-menopausal women were recruited to the study, one untreated (HRT-; n = 10; mean age 56.5 yrs [range 48-63 yrs]) and the other receiving HRT (n = 8; mean age 54 yrs [range 48-63 yrs]). Skin irritation was induced by applying 1.25% topical Sodium Lauryl Sulfate (SLS) to occluded buttock skin for 48 hours. Clinical assessment was conducted after 24 hours, followed by biopsy of both SLS-challenged and unchallenged skin for analysis of skin barrier proteins and immune cell distribution using immunofluorescence. RESULTS: Clinically, there were no significant differences in skin irritant responses between those taking or not taking HRT (including increased skin redness and blood flow). In response to SLS challenge a significant increase in trans-epidermal water loss (p<0.05), filaggrin deposition and keratin-10-positive cell layers (p<0.01) was observed in individuals receiving HRT compared to the HRT- group. Following SLS challenge in individuals taking HRT, a significant (p<0.01) reduction of CD207+ cells in the epidermis was observed, accompanied by an increase of CD207+ cells in the dermis, indicative of migrating Langerhans' cells (LCs). Significantly fewer migrating LCs were observed in those not receiving HRT (p<0.01). Furthermore, the number of dermal dendritic cells (DCs), macrophages, and CD11c+CD206- and CD68+CD206- subsets were found to be significantly (p<0.05) higher in those taking HRT following SLS challenge. CONCLUSION: Individuals receiving HRT displayed enhanced skin barrier response to SLS challenge with thicker filaggrin and increased keratin-10-positive epidermal cell layers. Following challenge, HRT users exhibited elevated counts of LCs, inflammatory DCs, and macrophages in the dermis. These may render skin both, more prone to inflammation and more capable of resolving it, while also promoting skin repair.

Quality of life following perioperative optimization with nutritional supplements in patients undergoing gastrointestinal surgery for cancer: A randomized, placebo-controlled feasibility clinical trial.

BACKGROUND: Up to two thirds of patients presenting for abdominal cancer surgery are malnourished pre-operatively. Perioperative nutritional supplementation has been proposed to improve surgical outcomes, though its effect on quality of life (QoL) is not yet understood. METHODS: A randomized controlled feasibility trial for perioperative nutrition among patients undergoing major abdominal cancer surgery was conducted. Participants in the intervention group received supplements for 30 days before surgery. Participants completed two QoL questionnaires (EORTC-QLQ-C-30 and FACT-G) at baseline, then 4 and 12 weeks postoperatively. Participants were compared between and within groups at baseline, Weeks 4, and 12 using t tests. Minimal clinically important differences (MCIDs) were considered as a 10-point worsening from baseline. RESULTS: Sixty-six participants were available for analysis in this study, including 33 in the intervention and 30 in the control arms. Baseline demographics were balanced between groups except for different rates of pancreas cancer (36% intervention vs. 9% control) and colorectal cancer (19% intervention vs. 34% control). At baseline, participants in the intervention group had lower overall QoL (59% vs. 77%, p = 0.01), role functioning (72% vs 88%, p = 0.045), and cognitive functioning (79% vs 90%, p = 0.047). Following surgery, role and physical functioning worsened in the control group, without significant differences between groups. Role functioning was persistently worsened at 12 weeks in the control group. The rates of MCIDs were similar between both intervention and control groups. DISCUSSION: Perioperative nutrition was associated with preservation of QoL in the postoperative period following major abdominal cancer surgery compared to placebo. SUMMARY: Among patients undergoing surgery for cancer, the majority present at high risk for malnutrition. In this placebo-controlled randomized trial among patients undergoing major abdominal surgery for cancer, preoperative nutrition supplementation was associated with the preservation of QoL in the postoperative period.

Comparing cefazolin/ metronidazole, piperacillin-tazobactam, or c efoxitin as surgical antibiotic prophylaxis in patients undergoing pancreaticoduodenectomy: A retrospective cohort study.

BACKGROUND: Preoperative antibiotic options for pancreaticoduodenectomy (PD) include cefoxitin (CX), piperacillin-tazobactam (PT), or combined cefazolin and metronidazole (CM). Recent studies suggest the superiority of PT over CX, but evidence for CM is unclear. OBJECTIVE: To explore the impact of preoperative antibiotic selection (CM vs. PT and CX vs. PT) on the development of surgical site infections (SSI). METHODS: Consecutive adult patients at one institution who underwent PD from November 2017 to December 2021 and received either CM, PT, or CX preoperatively, were included. The primary outcome was SSI. Secondary outcomes included postoperative infections and clinically significant postoperative pancreatic fistula (POPF). Logistic regression models were used. RESULTS: Among 127 patients included in the study, PT, CM, and CX were administered in 46 (36.2%), 44 (34.6%), and 37 (29.4%) patients, respectively. There were 32 (27.1%) SSI, 20 (36.1%) infections, and 21 (22.9%) POPF events. PT use was associated with reduced risk of SSI compared to CX (OR: 0.32, 95% CI: 0.11-0.89, p = 0.03), but there was no difference as compared to CM (OR: 0.75, 95% CI: 0.27-2.13, p = 0.59). There were no differences in secondary outcomes. CONCLUSION: PT reduced SSI rates compared to CX but was no different to CM among patients undergoing PD at our center.

Implementing well-being in the management of psoriasis: An expert recommendation.

Psoriasis causes detriment in a person's physical, mental and social health which impairs their quality of life (QoL). However, the current psoriasis management may not adequately address all relevant health domains. Since the goal of healthcare is to restore or maintain health, health outcomes should include all areas of the patient's overall health. Life satisfaction, QoL and patient well-being are essential to a comprehensive approach to the disease. With the inclusion of more people-centred policies, care of patients with psoriasis should evolve towards a holistic and integrated assessment of the disease impact, including subjective measures of well-being in order to encompass all aspects of health. The main objective of this expert review is to give the concept of well-being a place as an entity within the holistic therapeutic approach for patients with psoriasis. Identifying and defining common goals beyond the skin with the patient and testing them throughout the course of treatment will benefit and enhance treatment success. We propose a series of recommendations for application in clinical practice, providing tangible clinical guidance for implementing well-being in the management of psoriasis. Among the recommendations are the need to initially listen to the patient, to know their level of empowerment or what they want to achieve, their preferences in decision making, the evaluation of not only the physical but also the emotional impact of the disease (well-being), the definition of the aspects that can generate a cumulative deterioration of the disease throughout life, and a continuous assessment of the patient's preferences with the opinion of the expert clinician and the integration of the knowledge of external clinical evidence.

Risk of serious infection and infection mortality in patients with psoriasis: A nationwide cohort study using the Taiwan National Health Insurance claims database.

BACKGROUND: The risks of serious infections that lead to hospitalization and mortality in patients with psoriasis in Asia have not been comprehensively studied. OBJECTIVES: We examined the incidence of serious infection and infection mortality in patients with psoriasis. METHODS: This population-based retrospective cohort study used the Taiwan National Health Insurance claims database from 2000 to 2017. Adult patients with psoriasis were identified by a relevant International Classification of Diseases (ICD) code and matched to six comparators without psoriasis on age and sex. Psoriasis patients were categorized as having moderate-to-severe disease once exposed to systemic therapies, phototherapy or biologic therapies. The incidence of serious infection and infection mortality were identified by ICD codes from inpatient hospitalization and death registration. Cox proportional hazard models were used to compare the risk, and the results were adjusted for covariates and presented as adjusted hazard ratios (aHR) and 95% confidence interval (95% CI). RESULTS: Overall, 185,434 psoriasis patients and 1,112,581 comparators were included. A higher rate of serious infection (aHR: 1.21, 95% CI: 1.19-1.22) was found in patients with psoriasis compared to matched comparators without psoriasis, and the risk was enhanced when patients had moderate-to-severe psoriasis (aHR: 1.30, 95% CI: 1.27-1.34). Specifically, there was an increased risk of serious infection due to respiratory infections (aHR: 1.11, 95% CI: 1.09-1.13), skin/soft-tissue infections (aHR: 1.57, 95% CI: 1.52-1.62), sepsis (aHR: 1.23, 95% CI: 1.19-1.27), urinary tract infections (aHR: 1.11, 95% CI: 1.08-1.14), hepatitis B (aHR: 1.18, 95% CI: 1.06-1.30) and hepatitis C (aHR: 1.49, 95% CI: 1.32-1.69). Furthermore, psoriasis patients were associated with a higher risk of infection-related mortality (aHR: 1.15, 95% CI: 1.11-1.18) compared to matched comparators. CONCLUSION: Patients with psoriasis had a higher risk of serious infection and infection mortality, which was enhanced by moderate-to-severe psoriasis. Practitioners should be aware of the increased risk in patients with psoriasis, but it should not be a barrier to offering effective treatment.

Benefits Over Five Years of Ixekizumab Treatment in Patients With Psoriasis Involving Challenging Body Areas.

BACKGROUND: Psoriasis involving challenging body areas, such as the scalp, face, palmoplantar surfaces, or nails, can be challenging to treat and negatively affects patient outcomes. OBJECTIVE: To assess clear responses and cumulative clinical benefits over 5 years of ixekizumab treatment of moderate-to-severe plaque psoriasis in patients with and without baseline involvement of challenging body areas. METHODS: This post hoc analysis included patients treated with ixekizumab in the UNCOVER-3 trial. We assessed PASI100 responses through the week (W) 264 and cumulative clinical benefits at W264 (calculated as least-squares mean of the percentage of maximum area under the curve for PASI100 and PASI% improvement and expressed as cumulative clearance days). Statistical differences were calculated via ANCOVA. RESULTS: A total of 385 patients were analyzed: 349 with scalp involvement, 152 with facial involvement, 96 with palmoplantar involvement, and 229 with nail involvement. Proportions of patients achieving PASI100 were numerically similar between patients with and without scalp and nail involvement. More patients without facial and palmoplantar involvement achieved PASI100 at W60 (only palmoplantar), W108, W156, W204, and W264 (only palmoplantar). At W264, cumulative clinical benefits for PASI100 and PASI% improvement were high and similar in both patient groups, with and without challenging body areas. A significant difference (P=0.006) was only observed for PASI% improvement between patients with and without nail involvement. CONCLUSION: For most efficacy measures, patients treated with ixekizumab over 5 years achieved similar clear responses and cumulative clinical benefits regardless of baseline involvement of challenging body areas. J Drugs Dermatol. 2024;23(8):619-625.  doi:10.36849/JDD.8160.

Integrated proteomics and genomics analysis of paradoxical eczema in psoriasis patients treated with biologics.

BACKGROUND: Few studies have explored the immunology and genetic risk of paradoxical eczema occurring as an adverse event of biologic therapy in patients with psoriasis. OBJECTIVES: We sought to describe the systemic inflammatory signature of paradoxical eczema using proteomics and explore whether this is genetically mediated. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Treatment and Outcomes of Congenital Ovarian Cysts A Study by the Canadian Consortium for Research in Pediatric Surgery (CanCORPS).

OBJECTIVE: We conducted a multicenter study to assess treatments and outcomes in a national cohort of infants with congenital ovarian cysts. SUMMARY BACKGROUND DATA: Wide variability exists in the treatment of congenital ovarian cysts. The effects of various treatment strategies on outcomes, specifically ovarian preservation, are not known. METHODS: Female infants diagnosed with congenital intra-abdominal cysts between 2013 and 2017 at 10 Canadian pediatric surgical centers were retrospectively evaluated. Sonographic characteristics, median time to cyst resolution, incidence of ovarian preservation, and predictors of surgery were evaluated. Subgroup analyses were performed in patients with complex cysts and cysts ≥40 mm in diameter. RESULTS: The study population included 189 neonates. Median gestational age at diagnosis and median maximal prenatal cyst diameter were 33 weeks and 40 mm, respectively. Cysts resolved spontaneously in 117 patients (62%), 14 (7%) prenatally, and the remainder at a median age of 124 days. Intervention occurred in 61 patients (32%), including prenatal aspiration (2, 3%), ovary sparing resection (14, 23%), or oophorectomy (45, 74%). Surgery occurred at a median age of 7.4weeks. Independent predictors of surgery included postnatal cyst diameter ≥40 mm [odds ratio (OR) 6.19, 95% confidence interval (CI) 1.66-35.9] and sonographic complex cyst character (OR 63.6, 95% CI 10.9-1232). There was no significant difference in the odds of ovarian preservation (OR 3.06, 95% CI 0.86 -13.2) between patients who underwent early surgery (n = 22) and those initially observed for at least 3 months (n = 131). CONCLUSIONS: Most congenital ovarian cysts are asymptomatic and spontaneously resolve. Early surgical intervention does not increase ovarian preservation.

Rebound in asthma exacerbations following relaxation of COVID-19 restrictions: a longitudinal population-based study (COVIDENCE UK).

BACKGROUND: The imposition of restrictions on social mixing early in the COVID-19 pandemic was followed by a reduction in asthma exacerbations in multiple settings internationally. Temporal trends in social mixing, incident acute respiratory infections (ARI) and asthma exacerbations following relaxation of COVID-19 restrictions have not yet been described. METHODS: We conducted a population-based longitudinal study in 2312 UK adults with asthma between November 2020 and April 2022. Details of face covering use, social mixing, incident ARI and severe asthma exacerbations were collected via monthly online questionnaires. Temporal changes in these parameters were visualised using Poisson generalised additive models. Multilevel logistic regression was used to test for associations between incident ARI and risk of asthma exacerbations, adjusting for potential confounders. RESULTS: Relaxation of COVID-19 restrictions from April 2021 coincided with reduced face covering use (p<0.001), increased frequency of indoor visits to public places and other households (p<0.001) and rising incidence of COVID-19 (p<0.001), non-COVID-19 ARI (p<0.001) and severe asthma exacerbations (p=0.007). Incident non-COVID-19 ARI associated independently with increased risk of asthma exacerbation (adjusted OR 5.75, 95% CI 4.75 to 6.97) as did incident COVID-19, both prior to emergence of the omicron variant of SARS-CoV-2 (5.89, 3.45 to 10.04) and subsequently (5.69, 3.89 to 8.31). CONCLUSIONS: Relaxation of COVID-19 restrictions coincided with decreased face covering use, increased social mixing and a rebound in ARI and asthma exacerbations. Associations between incident ARI and risk of severe asthma exacerbation were similar for non-COVID-19 ARI and COVID-19, both before and after emergence of the SARS-CoV-2 omicron variant. STUDY REGISTRATION NUMBER: NCT04330599.

Characteristics associated with poor COVID-19 outcomes in people with psoriasis, psoriatic arthritis and axial spondyloarthritis: data from the COVID-19 PsoProtect and Global Rheumatology Alliance physician-reported registries.

OBJECTIVES: To investigate factors associated with severe COVID-19 in people with psoriasis (PsO), psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA). METHODS: Demographic data, clinical characteristics and COVID-19 outcome severity of adults with PsO, PsA and axSpA were obtained from two international physician-reported registries. A three-point ordinal COVID-19 severity scale was defined: no hospitalisation, hospitalisation (and no death) and death. ORs were estimated using multivariable ordinal logistic regression. RESULTS: Of 5045 cases, 18.3% had PsO, 45.5% PsA and 36.3% axSpA. Most (83.6%) were not hospitalised, 14.6% were hospitalised and 1.8% died. Older age was non-linearly associated with COVID-19 severity. Male sex (OR 1.54, 95% CI 1.30 to 1.83), cardiovascular, respiratory, renal, metabolic and cancer comorbidities (ORs 1.25-2.89), moderate/high disease activity and/or glucocorticoid use (ORs 1.39-2.23, vs remission/low disease activity and no glucocorticoids) were associated with increased odds of severe COVID-19. Later pandemic time periods (ORs 0.42-0.52, vs until 15 June 2020), PsO (OR 0.49, 95% CI 0.37 to 0.65, vs PsA) and baseline exposure to TNFi, IL17i and IL-23i/IL-12+23i (OR 0.57, 95% CI 0.44 to 0.73; OR 0.62, 95% CI 0.45 to 0.87; OR 0.67, 95% CI 0.45 to 0.98; respectively; vs no disease-modifying antirheumatic drug) were associated with reduced odds of severe COVID-19. CONCLUSION: Older age, male sex, comorbidity burden, higher disease activity and glucocorticoid intake were associated with more severe COVID-19. Later pandemic time periods, PsO and exposure to TNFi, IL17i and IL-23i/IL-12+23i were associated with less severe COVID-19. These findings will enable risk stratification and inform management decisions for patients with PsO, PsA and axSpA during COVID-19 waves or similar future respiratory pandemics.

Acrodermatitis continua of Hallopeau and generalised pustular psoriasis: Should they be the same or different entities?

Pustular psoriasis is characterised by eruptions of neutrophilic sterile pustules. The European Rare and Severe Psoriasis Expert Network consensus defines pustular psoriasis into three subtypes; generalised pustular psoriasis (GPP), palmoplantar pustulosis and acrodermatitis continua of Hallopeau (ACH). Mixed forms are categorised according to their predominant features. However, the Japanese Dermatological Association includes ACH under the diagnosis of GPP. This article aims to review the similarities and differences between ACH and GPP. Based on our review, interleukin (IL)-36RN mutations, the most frequent genetic findings in pustular psoriasis are found most commonly in GPP, followed by ACH. Genotypes of IL-36RN mutations among GPP patients and ACH patients are different between European and Asian ethnicities. IL-36 signalling pathway is the main mechanism. Metabolic diseases are common comorbidities and joint involvement can occur in 20.5%-36.4% of both conditions. Associated plaque psoriasis is more common in GPP than in ACH. Generally, ACH, even the generalised type, does not have systemic inflammation whereas GPP can occur with or without systemic inflammation. ACH can occur before, simultaneously, or after the development of GPP. However, response to treatment for GPP and ACH even in the same patients appear to be different. ACH seemed to be more recalcitrant to treatment than GPP but severe flare of GPP can lead to morbidity and mortality. Although GPP and ACH share genotypes and pathogenesis, we believe that ACH should be classified separately from GPP, and not under diagnosis of GPP. Future research is warranted to satisfactorily distinguish the two conditions.

Uptake of tumour necrosis factor-alpha inhibitor biosimilars for psoriasis: a drug utilization study from the British Association of Dermatologists Biologic and Immunomodulators Register (BADBIR).

BACKGROUND: Tumour necrosis factor-alpha inhibitors (TNFi) have revolutionized the treatment of moderate-to-severe psoriasis. Following patent expiry of the originator biologics, TNFi biosimilars became available, presenting the opportunity for significant reductions in drug costs. OBJECTIVES: To describe the uptake of TNFi biosimilars for psoriasis treatment in the UK and Ireland. METHODS: This observational cohort study utilizes data from the British Association of Dermatologists Biologic and Immunomodulators Register (BADBIR), a national pharmacovigilance study register for patients with psoriasis on systemic treatments. We analysed biosimilar uptake trends over time in nine geographical regions of England along with Wales, Scotland, Northern Ireland and the Republic of Ireland. We assessed the incidence of switching to biosimilars in an originator-user cohort (switchers). Patients on originators infliximab, etanercept and adalimumab at the time originator patents expired, entered the cohort on 1 February 2015, August 2015 and October 2018, respectively, and were followed up until 31 October 2021. Trends in biosimilar initiations were assessed in an adalimumab-naïve cohort who started adalimumab between 1 October 2018 and 31 July 2019 (starters). We assessed the associations between patient factors and originator-to-biosimilar switching and biosimilar initiation using a multivariable Cox regression model and a multivariable logistic regression model, respectively. RESULTS: Included in the originator-user cohort were 4202 patients (209 on infliximab, 742 on etanercept and 3251 on adalimumab). For infliximab, etanercept and adalimumab, respectively, the cumulative incidence of originator-to-biosimilar switching increased with time to 14.8%, 23.6% and 66.6% after 3 years. Across geographical regions, 3-year switching rates varied from 0% to 43.7% for infliximab; from 0% to 40.4% for etanercept; and from 12.5% to 84.3% for adalimumab. Out of the 528 patients included in the adalimumab-naïve cohort, 67.8% started on biosimilars. Originator-to-biosimilar switching and biosimilar initiation were more common in men and in patients who had lower Psoriasis Area and Severity Index at cohort entry. CONCLUSIONS: The uptake of biosimilars increased over time and varied considerably across the UK and Ireland; adalimumab had the highest biosimilar uptake rate compared with that of other TNFi drugs.

Imsidolimab, an anti-interleukin-36 receptor monoclonal antibody, for the treatment of generalized pustular psoriasis: results from the phase II GALLOP trial.

BACKGROUND: Generalized pustular psoriasis (GPP) is a systemic inflammatory disease that can be severe, debilitating and life threatening. Uncontrolled activation of interleukin (IL)-36 proinflammatory activity may underlie the pathogenesis of GPP. Currently, GPP-specific treatment options are limited. OBJECTIVES: To evaluate the efficacy and safety of the anti-IL-36 receptor antibody imsidolimab in patients with GPP. METHODS: In an open-label, single-arm, multiple-dose study, patients with GPP were treated with imsidolimab to assess clinical efficacy, tolerability and safety. Patients received an intravenous dose of imsidolimab 750 mg on day 1, followed by three subcutaneous doses of imsidolimab 100 mg administered on days 29, 57 and 85. The primary efficacy endpoint was the proportion of patients who achieved a clinical response at weeks 4 and 16 following treatment with imsidolimab, as measured by the Clinical Global Impression scale. RESULTS: Eight patients were enrolled and six completed the study. Responses were observed as early as day 3, most rapidly for pustulation relative to other manifestations of GPP, with continued and consistent improvement across multiple efficacy assessments at day 8, day 29 and through day 113. Most treatment-emergent adverse events (TEAEs) were mild to moderate in severity. No patient discontinued the study owing to a nonserious TEAE. Two patients experienced serious adverse events (SAEs); no deaths were reported. CONCLUSIONS: Imsidolimab demonstrated a rapid and sustained resolution of symptoms and pustular eruptions in patients with GPP. It was generally well tolerated, with an acceptable safety profile, and is advancing to phase III trials. These data support the targeting of IL-36 signalling with a specific antibody - imsidolimab - as a therapeutic option for this severely debilitating condition.

Incidence and prevalence of generalized pustular psoriasis in multiethnic Johor Bahru, Malaysia: a population-based cohort study using routinely captured electronic health records in the Teleprimary Care (TPC®) clinical information system from 2010 to 2020.

BACKGROUND: There is limited understanding of the epidemiology of generalized pustular psoriasis (GPP) internationally, with no population-based estimates of GPP in South East Asia. OBJECTIVES: To determine the incidence and prevalence of GPP in the Malaysian population and characterize its flares and trigger factors. METHODS: We conducted a population-based cohort study using the Teleprimary Care database between January 2010 and December 2020. We identified 230 dermatologist-confirmed GPP cases using International Classification of Diseases, 10th revision, diagnostic codes. Annual prevalence and incidence rates were stratified by age, sex and ethnicity. We compared data regarding flares and trigger factors for patients with GPP who had associated psoriasis vulgaris (PV) with those who did not have associated PV. RESULTS: The prevalence of GPP was 198 per million (267 women, 127 men) and incidence was 27.2 per million person-years [95% confidence interval (CI) 22.8-31.6]; 35.3 (28.4-42.2) per million person-years for women and 18.3 (13.1-23.5) per million person-years for men. Rates were higher in Chinese individuals [prevalence 271 per million; incidence 41.6 per million person-years (28.9-54.3)] than in the Malay population [prevalence 186; incidence 24.6 (19.4-29.7)] or the Indian ethnic group [prevalence 179; incidence 25.0 (13.8-36.3)]. Annual prevalence was consistently higher in women than in men and highest among the Chinese population, followed by the Indian and Malay populations. Overall, 67% of patients with GPP had associated PV. The prevalence and incidence of GPP without PV were lower than GPP with PV at 66 vs. 132 per million and 19.3 (95% CI 15.6-23.0) vs. 8.0 (95% CI 5.6-10.3) per million person-years, respectively. The mean age at GPP onset was 42.7 years (SD 18.4). A bimodal trend in the age of GPP onset was observed, with first and second peaks at age 20-29 years and age 50-59 years, respectively. Disease onset was significantly earlier in patients with GPP without PV than in those with PV [mean age 37.5 years (SD 20.7) vs. 44.9 years (SD 17.0), P = 0.026]. Flares occurred more frequently in patients without PV than in those with PV [mean number of flares per patient per year was 1.35 (SD 0.77) vs. 1.25 (SD 0.58), P = 0.039]. Common triggers of flares in patients with GPP who did not have PV were infections, pregnancy, menstruation and stress, whereas withdrawal of therapy, particularly systemic corticosteroids, was a more frequent trigger in patients with GPP who also had PV. CONCLUSIONS: Our findings contribute to the global mapping of GPP, which will help inform the management of this rare condition.

Access to psoriasis treatment in Brazil and Chile: A cross-sectional multicentre Global Healthcare Study on Psoriasis.

BACKGROUND: Sufficient data on access to systemic treatment for patients with psoriasis living in Latin America (LA) including Brazil and Chile are lacking. Understanding the availability and limiting factors of access to treatments can help to improve patient care and decrease long-term healthcare costs. OBJECTIVES: In association with the Global Psoriasis Atlas, this cross-sectional survey study analysed the availability and insurance reimbursement of systemic treatments for adult patients with psoriasis in Brazil and Chile. METHODS: A multicentre, cross-sectional Global Healthcare Study on Psoriasis was performed in Brazil and Chile in 2020. For each eligible adult patient with psoriasis, doctors and nurses completed a 48-item questionnaire about clinical aspects of psoriasis including the Psoriasis Area Severity Index (PASI), body surface area (BSA) score and the Dermatology Life Quality Index (DLQI), as well as the availability of systemic treatments and insurance reimbursement status. Between-country differences were compared with Wilcoxon rank sum tests for continuous variables, and a χ2-test or Fisher's exact test, where appropriate, for categorical variables. The median and interquartile range (IQR) was calculated for non-normal distributed data. RESULTS: A total of 1424 patients with psoriasis from 43 centres [27 centres in Brazil (n = 826) and 16 in Chile (n = 598)], were included with a mean (SD) age of 49.1 (16.3) and 49.2 (15.1) years, respectively. Unstratified analyses revealed that patients with psoriasis in Chile had more severe disease than those in Brazil [PASI 11.6 vs. 8.4 (P < 0.001) and BSA 14.7 vs. 12.0 (P = 0.003), respectively]. For patients with moderate-to-severe psoriasis, defined as PASI and/or BSA ≥ 10, systemic nonbiologic drugs were available (81.2% in Brazil and 65.3% in Chile, P ≤ 0.001), but only 37.0% of patients in Brazil and 27.3% in Chile received biologics (P = 0.01). Lack of availability and/or lack of insurance reimbursement for biologic drugs for patients with moderate-to-severe psoriasis was reported for 22.2% (50 of 225) in Brazil and 67.9% (148 of 218) in Chile (P < 0.001). Patients with no access to biologic therapies due to lack of availability/insurance reimbursement had a median PASI of 9.15 (IQR 3.00-14.25) in Brazil and 12.0 (IQR 5.00-19.00) in Chile (P = 0.007), as well as a median BSA of 7.0 (IQR 3.00-15.00) and 12.0 (IQR 5.00-22.50) (P = 0.002), and median DLQI of 11.0 (6.00-15.00) and 21.0 (6.50-25.00) (P = 0.007), respectively. CONCLUSIONS: Chilean patients had significantly more severe psoriasis compared with Brazilian patients in our study. While nonbiologic treatments for moderate-to-severe psoriasis were available in both LA countries, there is a high need for improvement in access to more effective psoriasis treatments including biologics. Our results highlight a significant gap between treatment recommendations in international psoriasis guidelines and real-world situations in Brazil and Chile.