GWAS meta-analysis of psoriasis identifies new susceptibility alleles impacting disease mechanisms and therapeutic targets.

Psoriasis is a common, debilitating immune-mediated skin disease. Genetic studies have identified biological mechanisms of psoriasis risk, including those targeted by effective therapies. However, the genetic liability to psoriasis is not fully explained by variation at robustly identified risk loci. To move towards a saturation map of psoriasis susceptibility we meta-analysed 18 GWAS comprising 36,466 cases and 458,078 controls and identified 109 distinct psoriasis susceptibility loci, including 45 that have not been previously reported. These include susceptibility variants at loci in which the therapeutic targets IL17RA and AHR are encoded, and deleterious coding variants supporting potential new drug targets (including in STAP2, CPVL and POU2F3). We conducted a transcriptome-wide association study to identify regulatory effects of psoriasis susceptibility variants and cross-referenced these against single cell expression profiles in psoriasis-affected skin, highlighting roles for the transcriptional regulation of haematopoietic cell development and epigenetic modulation of interferon signalling in psoriasis pathobiology.

A partitioned 88-loci psoriasis genetic risk score reveals HLA and non-HLA contributions to clinical phenotypes in a Newfoundland psoriasis cohort.

Psoriasis is an immune-mediated inflammatory skin disease typically characterized by erythematous and scaly plaques. It affects 3% of the Newfoundland population while only affecting 1.7% of the general Canadian population. Recent genome-wide association studies (GWAS) in psoriasis have identified more than 63 genetic susceptibility loci that individually have modest effects. Prior studies have shown that a genetic risk score (GRS) combining multiple loci can improve psoriasis disease prediction. However, these prior GRS studies have not fully explored the association of GRS with patient clinical characteristics. In this study, we calculated three types of GRS: one using all known GWAS SNPs (GRS-ALL), one using a subset of SNPs from the HLA region (GRS-HLA), and the last using non-HLA SNPs (GRS-noHLA). We examined the relationship between these GRS and a number of psoriasis features within a well characterized Newfoundland psoriasis cohort. We found that both GRS-ALL and GRS-HLA were significantly associated with early age of psoriasis onset, psoriasis severity, first presentation of psoriasis at the elbow or knee, and the total number of body locations affected, while only GRS-ALL was associated with a positive family history of psoriasis. GRS-noHLA was uniquely associated with genital psoriasis. These findings clarify the relationship of the HLA and non-HLA components of GRS with important clinical features of psoriasis.

Real World Studies of Psoriasis and Mental Illness in Newfoundland and Labrador.

BACKGROUND: Psoriasis is a chronic, immune-mediated inflammatory disease with an implied connection to psychiatric disorders. OBJECTIVE: This study aims to illustrate an association between psoriasis and psychiatric disorders using real world data gathered from the Newfoundland and Labrador population. METHODS: Data on 15,100 patients with psoriasis and 75,500 controls (1:5) was collected from the Newfoundland and Labrador Centre for Health Information's Electronic Health Records. The cases and controls were matched for age, sex, and geography. Indicators for psychiatric disorders include diagnosis of mental illnesses from physician's visits and hospitalization records (all coded for mental health using ICD-9 and ICD-10 codes). RESULTS: 9,991 (66.2%) cases were identified to have at least one visit with a diagnostic code for mental illness compared to 42,276 (56.0%), P < .0001 in the control group. The percentage of people coded for anxiety was 36.50% compared to 28.95%, P < .0001; depression was 37.04% compared to 30.19%, P < .0001; and adjustment disorder was 6.89% versus 5.48%, P < .0001, among those with and without psoriasis, respectively. The greatest risk for anxiety [OR 1.4 (1.20, 1.67)] and depression [OR 1.65 (1.36, 2.00)] among psoriasis patients was between the 0 to 20 age group. Women with psoriasis are more likely to have anxiety [OR 1.08 (1.03, 1.13)], depression [OR 1.04 (1.01, 1.09)] and adjustment disorder [OR 1.07 (0.98, 1.17)] compared to female controls. CONCLUSION: Our result shows that patients with psoriasis have an increased prevalence of mental illness. Using real world data to carry out further investigations will better elucidate this association and provide an increased understanding of the association between psoriasis and mental disorders.

International Dermatology Outcome Measures (IDEOM): Report from the 2021 Annual Meeting.

BACKGROUND: International Dermatology Outcome Measures (IDEOM) is a non-profit organization founded in 2013. It is composed of researchers and stakeholders who work to develop evidenced-based outcome measures to enhance research and treatment recommendations of dermatologic diseases. SUMMARY: The 2021 IDEOM Virtual Annual Meeting occurred from November 19-20, 2021. Contributions were made by leaders and stakeholders from the psoriasis, psoriatic arthritis, pediatric hidradenitis suppurativa, acne, vitiligo, actinic keratosis, alopecia areata, itch, and cutaneous lymphoma workgroups. The psoriasis, psoriatic arthritis, and actinic keratosis workgroups provided an overview of their respective instruments for treatment satisfaction and symptom measurement. The inaugural meetings of the itch, alopecia areata, and cutaneous lymphoma workgroups identified unmet needs of their respective diseases and future goals. The acne, vitiligo, and pediatric hidradenitis suppurativa workgroups discussed concerns of quality of life, instruments for symptom measurement, and screening tools. Additionally, a representative from the US Food and Drug Administration was in attendance and presented an update on topical drugs and generics. This report provides a summary of workgroup updates from the past year and future directions established during the meeting. KEY MESSAGES: This report summarizes progress made by each IDEOM workgroup at the 2021 IDEOM Virtual Annual Meeting. J Drugs Dermatol. 2022;21(8):867-874. doi:10.36849/JDD.6974.

Laying the foundation for Real-world evidence studies: a case study from Newfoundland and Labrador.

The Janssen and Newfoundland and Labrador Health Innovation Partnership (JANL-HIP) was established to carry out Real-World Evidence (RWE) projects to generate evidence about disease pathways, healthcare delivery, the effects of clinical interventions. Doing so will support and influence clinical decision-making in Newfoundland and Labrador (NL). This case study describes the foundational elements necessary for a real-world evidence generation project in NL and may provide learning for the effective execution of real-world studies in other jurisdictions. It uses an ongoing project in psoriatic disease in NL to illustrate the partnership and the benefits of RWE studies. Ultimately, the JANL-HIP RWE project aims to inform decisions that will drive improvements in health outcomes, system delivery, and policy mutually beneficial to health ecosystem stakeholders.

Moderate-to-severe plaque psoriasis patients treated with ixekizumab: early real-world outcomes and adverse events.

INTRODUCTION: Data on real-world experiences for patients treated with ixekizumab is currently limited. OBJECTIVES: Describe characteristics of ixekizumab-treated psoriasis patients and provide evidence of clinical outcomes using disease severity scores Body Surface Area (BSA) and Psoriasis Area and Severity Index (PASI) in the real world. METHODS: Chart review was performed for adult patients treated with ixekizumab at a single Canadian dermatology clinic (February 2017-August 2018). The cohort was stratified into responders (patients who remained on ixekizumab) and non-responders (patients who discontinued ixekizumab). Subgroup analyses were performed for responders to assess clinical improvement stratified by previous biologic exposure. RESULTS: Thirty-eight patients were included (mean observational time 32 weeks). At baseline, mean PASI and BSA were 10.8 and 11.6%, respectively. Mean changes in PASI and BSA were -7.8 and -6.7%, respectively, at week 4. PASI 100 was achieved in 70% of patients. Significant differences in mean change of BSA were seen between bio-naïve and bio-experienced patients. CONCLUSION: This analysis represents the first investigation of early clinical outcomes in a small cohort of Canadian patients treated with ixekizumab. Overall, complete and rapid skin clearance was observed. Future studies including more patients and longer follow-up time are crucial to confirm these findings.

The Incidence of Cutaneous Malignant Melanoma in Eastern Newfoundland and Labrador, Canada, from 2007 to 2015.

BACKGROUND: The incidence of cutaneous malignant melanoma continues to increase worldwide and in Canada. It is unclear whether the increase in incidence and clinical characteristic trends of cutaneous malignant melanoma are similar in the province of Newfoundland and Labrador. OBJECTIVE: The objective of this study is to examine the incidence and trends of cutaneous malignant melanoma in Eastern Newfoundland and Labrador. METHODS: Patients aged 18 years or older diagnosed with cutaneous malignant melanoma were identified from the Eastern Health Authority's Cancer Registry. The diagnosis was confirmed by a pathologist via histological subtype. Patients were excluded if the diagnosis was unspecified, a nonmelanoma skin cancer or if there was a recurrence in the same lesion location. In total 298 patients diagnosed with cutaneous malignant melanoma from 2007 to 2015 were included in the analysis. RESULTS: The total incidence increased from 4.1 to 15.6 cases/100,000 person-years, which represents a 283.0% increase from 2007 to 2015. The largest increases in incidence were seen in males and patients aged from 60 to 79 years. The most common lesion anatomical locations were the trunk in males and the lower extremity in females. The majority of cases had a Breslow thickness below 1.0 mm. CONCLUSION: The incidence of cutaneous malignant melanoma in Eastern Newfoundland and Labrador is increasing at a faster rate than in any other region in Canada. Health care providers should work to be aware of the clinical trends and risk factors associated with this disease to facilitate early detection and prevent morbidity.

Investigation of prevalence of biologic use and discontinuation rates in moderate-to-severe psoriasis patients in Newfoundland and Labrador using real-world data.

Real-world data for psoriasis includes registries, and meta-analyses could help guide biologic therapy choice. The objective was to determine the prevalence and reason for discontinuation of biologic or PD4 inhibitor therapy in patients with moderate-to-severe psoriasis in Newfoundland and Labrador, Canada from 2001 to 2017. A retrospective cohort study was conducted on data collected between 2001 and 2017, to determine the type of biologic therapy or PD4 inhibitor, length of treatment, prevalence of and reason for discontinuation. As multiple patients have been on more than one therapy (ie, an average of 1.8), the 459 patients included in the registry have had a total of 913 exposures to biologic or PD4 inhibitors. The treatment mean time was 37 months (SD 39.95). A total of 180 patients remained on their first biologic of which 75% were male. The average number of biologics per patient was 1.99. The reasons for discontinuation were primary failure (28.5%), adverse events (26.4%), secondary failure (24.3%), patient choice (4.4%), other/unknown in (6.6%), drug withdrawal from market (6.8%), and drug coverage issues (3%). The most common reasons for discontinuation of biologics or PD4 inhibitors include primary failure, adverse events, and secondary failures. Males were more likely to remain on their first biologic.

An Investigation of Comorbid Disease and Health Service Utilization Among Patients With Moderate to Severe Psoriasis in Newfoundland and Labrador.

Psoriasis is an inflammatory skin condition affecting 2% to 3% of the population and is associated with several comorbidities, including cardiovascular disease, depression, inflammatory bowel disease, metabolic syndrome, mood disorder, psoriatic arthritis, and weight gain. Psoriasis is treated with a number of topical and systemic therapies, including biologic drugs that directly target proinflammatory cytokines. This cross-sectional retrospective study investigated comorbid conditions reported in the Newfoundland and Labrador psoriasis population, outcomes associated with therapeutic treatment, and use of health care resources. Of the psoriasis comorbidities investigated, psoriatic arthritis was significantly associated with the use of biologic therapy while a failure to respond to biologics was associated with a higher incidence of cardiovascular disease. Patients responsive to biologic treatment had fewer hospital stays than patients treated with other therapies. Our results suggest that biologic therapies have a cardioprotective effect and reduce the number of hospital visits in patients whose symptoms are responsive to treatment.

Biologic Therapy Utilization in Patients With Moderate to Severe Psoriasis and Psoriatic Arthritis: An Observational Summary of Biologic Therapy Use in a Clinical Setting.

Plaque psoriasis affects approximately 2% to 3% of the global population, with psoriatic arthritis observed in approximately 20% to 30% of these individuals. Upon advances in research pathophysiology and treatment over the past decade, biologic therapies have been used more to treat moderate to severe psoriasis. In Canada, reimbursement bodies have defined prior authorization criteria to determine patient eligibility for funding of biologic treatments in moderate to severe plaque psoriasis. Generally, patients will have been treated with conventional therapies such as topical steroids, phototherapy, or systemic treatments such as methotrexate and cyclosporine before starting a biologic therapy. In difficult cases or severe flares in otherwise controlled disease, practitioners may augment the regimen with one or more conventional treatments. The objective of this observational report was to identify treatment pathways for psoriasis and psoriatic arthritis patients in Canada by examining initial biologic treatment and subsequent treatment optimization patterns for informed reimbursement discussions and decisions. A retrospective chart review was conducted at Newlab Clinical Research using medical records of patients who received at least 1 of 4 biologic agents approved at that time of the survey in Canada for the treatment of plaque psoriasis (adalimumab, etanercept, infliximab, ustekinumab). The study population consisted of patients who had moderate to severe plaque psoriasis, diagnosed by a dermatologist, for at least 6 months before the study index date and who attended Newlab Clinical Research between 2008 and 2013. All current and previous agents prescribed for the treatment of psoriasis were captured. A total of 248 patients with psoriasis treated with biologics were identified, of whom 27 (10.9%) were also diagnosed with psoriatic arthritis. Prior to initiating treatment with a biologic, most patients (72.1%) were treated with (or contraindicated to) methotrexate/cyclosporine. Treatment was supplemented with topical agents (70.6%) and/or followed by a course of ultraviolet light phototherapy (51.6%). Only 2.4% of patients were treated with a biologic first. Of 248 patients treated with biologics, almost half (47.6%) needed add-on therapy, whereas 16.5% of patients had an increase in dose or dosing interval. Furthermore, 14.1% of patients added a topical agent, 10.5% a topical steroid, or 6.5% a course of phototherapy while continuing biologic therapies. Finally, 30.4% of patients switched to another biologic treatment. Adalimumab was the most common agent used as a second-line agent (37.2%), and patients who started on adalimumab mainly switched to ustekinumab as a second-line agent (73.9%). Infliximab was the agent least often used as second-line therapy.

Psoriasis Patients Treated With Biologics and Methotrexate Have a Reduced Rate of Myocardial Infarction: A Collaborative Analysis Using International Cohorts.

Psoriasis is a chronic inflammatory skin condition characterised by the formation of red scaly plaques on the skin. It is an autoimmune disease cause by the dysregulation of cytokines controlling the inflammatory pathways, a mechanism likely contributing to various comorbidities observed in patients with psoriasis. Cardiovascular disease is one comorbidity observed more frequently in the psoriasis patient population. Biologic treatments specifically target the dysregulation of cytokines in the inflammation pathway and have shown to be an effective treatment for moderate to severe psoriasis where other systemic treatments have failed. More recently, biologics have been shown to reduce the incidence of myocardial infarction in patients with psoriasis compared to patients treated with topical agents. In the present study, 4 international psoriasis patient cohorts are combined and analyzed to examine the effect that biologic or methotrexate treatment has on reducing the incidence of myocardial infarction. Both methotrexate and biologic treatments were found to lower the incidence of myocardial infarction in moderate to severe psoriasis patient populations.

Do Biologics Protect Patients With Psoriasis From Myocardial Infarction? A Retrospective Cohort.

BACKGROUND: Psoriasis is a chronic immune-mediated inflammatory disorder that affects approximately 2% to 3% of the population, which translates to 17 million in North America and Europe and approximately 170 million people worldwide. Although psoriasis can occur at any age, most cases develop before age 40 years. Some larger studies have noted bimodal age at onset with the first peak occurring at approximately age 30 years and the second peak at around 55 to 60 years, but most patients have a younger age of onset (15-30 years). Psoriasis is associated with multiple comorbidities, decreased quality of life, and decreased longevity of life. Two recent systematic reviews and a meta-analysis concluded that psoriasis patients are at increased risk of major adverse cardiovascular events. Multiple studies confirm that many of the comorbidities found in patients with psoriasis are also important risk factors for cardiovascular disease, stroke, diabetes mellitus, hypertension, hyperlipidemia, obesity, and metabolic syndrome. METHODS: We conducted a retrospective cohort study using charts from a dermatology clinic combined with an administrative database of patients with moderate to severe psoriasis in Newfoundland and Labrador, Canada. We examined the role of clinical predictors (age of onset of psoriasis, age, sex, biologic use) in predicting incident myocardial infarction (MI). RESULTS: Logistic regression revealed that age of onset (odds ratio [OR], 8.85; P = .005), advancing age (OR, 1.07; P < .0001), and being male (OR, 3.64; P = .018) were significant risk factors for the development of MI. Neither biologic therapy nor duration of biologic therapy were statistically significant risk factors for the development of MI. Our study found that in patients with psoriasis treated with biologics, there was a nonsignificant trend in reduced MI by 78% (relative risk, 0.18; 95% confidence interval, 0.24-1.34; P = .056). CONCLUSION: Our study demonstrated a trend toward decreased MI in patients with moderate to severe psoriasis on biologics. Patients with an early age of onset of psoriasis (<25 years) were nearly 9 times more likely to have an MI. Clinicians should consider appropriate cardiovascular risk reduction strategies in patients with psoriasis.