Comorbidities of alopecia areata: a population-based cohort study.

BACKGROUND: Previous studies have associated alopecia areata (AA) with a number of comorbidities. However, the timing between AA and the development of such comorbidities remains poorly understood. AIM: To examine the temporal relationship between AA diagnosis and comorbidity development in Denmark. METHODS: A Danish nationwide register-based cohort study was performed on all individuals diagnosed with AA between 2007 and 2016 (n = 1843), and each patient was matched for age and sex with 10 healthy controls (HCs). Time between AA and comorbidity development was assessed, and incidence rate ratios (IRRs) were calculated to assess risk of comorbidity following initial AA diagnosis. RESULTS: Use of antidepressant and anxiolytic drugs were mostly started prior to AA diagnosis, and these drugs were used more frequently before than after diagnosis with AA. Additional frequent comorbidities included thyroid disease, hyperlipidaemia, type 2 diabetes and asthma. Most comorbidities occurred prior to AA diagnosis; however, among those that occurred after AA diagnosis, antidepressants (IRR = 1.26, 95% CI 1.01-1.56), anxiolytics (IRR = 1.55, 95% CI 1.17-2.05), atopic dermatitis (AD; IRR = 9.41, 95% CI 4.00-22.16), asthma (IRR = 2.17, 95% CI 1.46-3.21), vitiligo (IRR = 30.35, 95% CI 6.13-150.39), Crohn disease (CD; IRR = 3.04; 95% CI 1.22-7.56) and thyroid disease (IRR = 2.38; 95% CI 1.72-3.29) occurred more frequently among patients with AA compared with controls. CONCLUSION: A diagnosis of AA was significantly associated with risk of several comorbidities, most notably vitiligo, AD and CD. Nonetheless, the majority of patients appeared to have developed these comorbidities prior to AA diagnosis, suggesting that a thorough medical history screening by dermatologists at the initial visit may be appropriate.

Efficacy and safety of ixekizumab in a phase III, randomized, double-blind, placebo-controlled study in paediatric patients with moderate-to-severe plaque psoriasis (IXORA-PEDS).

BACKGROUND: Plaque psoriasis affects children and adults, but treatment options for paediatric psoriasis are limited. OBJECTIVES: To evaluate the efficacy and safety of ixekizumab (IXE), a high-affinity monoclonal antibody that selectively targets interleukin-17A, for moderate-to-severe paediatric psoriasis. METHODS: In a randomized, double-blind, placebo-controlled, phase III study (IXORA-PEDS), patients aged 6 to < 18 years with moderate-to-severe plaque psoriasis were randomized 2 : 1 to weight-based dosing of IXE every 4 weeks (IXE Q4W, n = 115) or placebo (n = 56) through week 12, followed by open-label IXE Q4W. Coprimary endpoints were the proportions of patients at week 12 achieving ≥ 75% improvement in Psoriasis Area and Severity Index (PASI 75) and those achieving a static Physician's Global Assessment score of 0 or 1 (sPGA 0,1). RESULTS: IXE was superior (P < 0·001) to placebo for both coprimary endpoints of PASI 75 (IXE Q4W, 89%; placebo, 25%) and sPGA (0,1) (IXE Q4W, 81%; placebo, 11%). IXE was also superior for all gated secondary endpoints, including PASI 75 and sPGA (0,1) at week 4, improvement in itch, and complete skin clearance. IXE Q4W provided significant (P < 0·001) improvements vs. placebo in quality of life and clearance of scalp and genital psoriasis. Responses at week 12 were sustained or further improved through week 48. Through week 12, 45% (placebo) and 56% (IXE) of patients reported treatment-emergent adverse events. One serious adverse event was reported (IXE), one patient discontinued due to an adverse event (placebo) and no deaths were reported. CONCLUSIONS: IXE was superior to placebo in the treatment of moderate-to-severe paediatric psoriasis, and the safety profile was generally consistent with that observed in adults. What is already known about this topic? Paediatric psoriasis affects approximately 1% of children and can negatively impact health-related quality of life. Treatment options for paediatric psoriasis are typically limited to off-label treatments and approved systemic biologics. Ixekizumab, a high-affinity monoclonal antibody that selectively targets interleukin-17A, is approved for moderate-to-severe plaque psoriasis in adults and was recently approved by the US Food and Drug Administration for moderate-to-severe paediatric psoriasis. What does this study add? Ixekizumab resulted in rapid and statistically significant improvements over placebo in skin involvement, itch and health-related quality of life, which persisted through 48 weeks of treatment in paediatric patients with moderate-to-severe plaque psoriasis. The safety profile of ixekizumab was generally consistent with that seen in adults. Ixekizumab may be an additional potential therapeutic option and an additional class of biologic therapy (interleukin-17A antagonist) for the treatment of moderate-to-severe paediatric psoriasis. Plain language summary available online.

Efficacy and safety of mirikizumab (LY3074828) in the treatment of moderate-to-severe plaque psoriasis: results from a randomized phase II study.

BACKGROUND: Inhibiting interleukin (IL)-23 in patients with psoriasis has demonstrated high levels of skin clearance. OBJECTIVES: To investigate, in a phase II (AMAF; NCT02899988), multicentre, double-blind trial, the efficacy and safety of three doses of mirikizumab (LY3074828), a p19-directed IL-23 antibody, vs. placebo in patients with moderate-to-severe plaque psoriasis. METHODS: Adult patients were randomized 1 : 1 : 1 : 1 to receive placebo (n = 52), mirikizumab 30 mg (n = 51), mirikizumab 100 mg (n = 51) or mirikizumab 300 mg (n = 51) subcutaneously at weeks 0 and 8. The primary objective was to evaluate the superiority of mirikizumab over placebo in achieving a 90% improvement in the Psoriasis Area and Severity Index (PASI 90) response at week 16. Comparisons were done using logistic regression analysis with treatment, geographical region and previous biological therapy in the model. Missing data were imputed as nonresponses. RESULTS: Ninety-seven per cent of patients completed the first 16 weeks of the study. The primary end point was met for all mirikizumab dose groups vs. placebo, with PASI 90 response rates at week 16 of 0%, 29% (P = 0·009), 59% (P < 0·001) and 67% (P < 0·001) for patients receiving placebo, and mirikizumab 30 mg, 100 mg and 300 mg, respectively. There were two (1%) serious adverse events in mirikizumab-treated patients vs. one (2%) in a placebo-group patient. CONCLUSIONS: At week 16, 67% of patients treated with mirikizumab 300 mg at 8-week intervals achieved PASI 90. The percentage of patients reporting at least one treatment-emergent adverse event was similar among patients treated with placebo or mirikizumab.

Psychometric properties of the Itch Numeric Rating Scale in patients with moderate-to-severe plaque psoriasis.

BACKGROUND: Itching is a profoundly distressing symptom for many patients with psoriasis, but it has not been rigorously studied using validated tools for this condition. OBJECTIVES: This study investigated the psychometric properties of the Itch Numeric Rating Scale (Itch NRS), a single-item patient-reported outcome (PRO) measuring the worst itching severity due to psoriasis in the past 24 h. METHODS: Using disease-specific clinician-rated and PRO data from one phase II and three phase III randomized clinical studies of subjects with moderate-to-severe plaque psoriasis, the Itch NRS was evaluated for test-retest reliability, construct validity and responsiveness. A responder definition was explored using anchor- and distribution-based methods. RESULTS: Test-retest reliability analyses supported the reproducibility of the measure (intraclass correlation coefficient range 0·71-0·74). To support the construct validity of the Itch NRS, large cross-sectional correlations with the Dermatology Life Quality Index (DLQI) Symptoms and Feelings domain (r ≥ 0·60 at baseline and r ≥ 0·80 at week 12) supported a priori hypotheses, while large correlations (r ≥ 0·71) between changes in Itch NRS scores and changes in DLQI Symptoms and Feelings domain scores from baseline to week 12 established responsiveness. A 4-point change was optimal for demonstrating a level of clinically meaningful improvement in itch severity after 12 weeks of treatment, which corresponds with marked clinical improvements in plaque psoriasis. CONCLUSIONS: The Itch NRS demonstrated sufficient reliability, validity and responsiveness, and appropriate interpretation standards for evaluating change over time in itch severity among patients with moderate-to-severe plaque psoriasis when validated using clinical trial data for this condition.

Understanding the Relationship Between Pruritus Severity and Work Productivity in Patients With Moderate-to-Severe Psoriasis: Sleep Problems Are a Mediating Factor.

BACKGROUND: Psoriasis is a debilitating skin disease associated with substantial pruritus, work impairment, and sleep disturbance. OBJECTIVE: This study evaluated associations between pruritus and work productivity, and the role of sleep problems as a possible mediator of the relationship between the two. METHODS AND MATERIALS: Data from a pruritus visual analog scale (Itch VAS), the Medical Outcomes Study Sleep Scale (MOS-SS), and the Work Productivity and Activity Impairment Questionnaire (WPAI) were collected in a phase 2 clinical trial in patients with psoriasis treated with ixekizumab or placebo. Mediating effects of sleep were tested in multiple regressions with pruritus severity (independent variable) and work productivity (dependent variable). Sobel tests evaluated the significance of sleep's effect. RESULTS: Several MOS-SS domains were significantly associated with the WPAI presenteeism, work productivity, and activity impairment scores, and decreased the effect of pruritus. Sobel tests indicated that the Sleep Problems Index I had a significant effect (P<.05) in mediating the relationship between pruritus and presenteeism, work productivity, and activity impairment. CONCLUSION: Sleep may mediate the role of pruritus on work productivity, but both factors appear to have independent negative effects on work.

Prevalence and incidence rates of cardiovascular, autoimmune, and other diseases in patients with psoriatic or psoriatic arthritis: a retrospective study using Clinical Practice Research Datalink.

BACKGROUND: Previous studies have demonstrated that patients with psoriasis have higher rates of comorbidities compared to the general population. Despite the clinical and economic burden of psoriatic disease, there have been few large-scale observational studies focused on this condition. OBJECTIVE: To assess rates of cardiovascular, autoimmune, infectious and other conditions in patients with psoriasis or psoriatic arthritis (PSA). METHODS: The data for this retrospective study were obtained from the Clinical Practice Research Datalink (CRPD). Cohorts of patients with psoriasis (n = 27,672; mild, n = 22,174, severe, n = 5498) and PSA (n = 1952) were generated based on the diagnosis made by general practitioner or specialist recorded in CPRD between 2006 and 2010. Frequencies of comorbidities at baseline and incidence rate ratios (IRR) of medical conditions occurring during follow-up were calculated and compared between groups. Cox proportional hazard models were employed to compare hazard ratios (HR) of comorbidities across the same subpopulations previously described. RESULTS: Significant differences in the unadjusted risk of cardiovascular disease, hyperlipidaemia, diabetes, skin cancer and autoimmune diseases were observed between patients with differing severity of psoriasis or between PSA and psoriasis patients. The adjusted HR analyses confirmed patients with severe psoriasis had significantly higher rates of several conditions including diabetes (1.23; 95% CI: 1.01-1.51) and rheumatoid arthritis (2.88; 95% CI: 2.25-3.67) compared to patients with mild psoriasis. Patients with PSA had significantly higher adjusted rates of hypertension (1.30; 95% CI: 1.01-1.68), rheumatoid arthritis (6.93; 95% CI: 5.45-8.80) and ankylosing spondylitis (6.98; 95% CI: 2.37-20.58) compared to those with severe psoriasis. CONCLUSION: Patients with mild psoriasis are less affected by comorbid conditions than those with severe psoriasis, and patients with psoriasis are less affected by comorbidities than those with PSA. Given the differences observed across severities of psoriasis and between psoriasis and PSA, each patient subgroup should be taken into consideration in clinical practice and future research.

Itching is a significant problem and a mediator between disease severity and quality of life for patients with psoriasis: results from a randomized controlled trial.

BACKGROUND: In patients with moderate-to-severe psoriasis, health-related quality of life (HRQOL) has been shown to improve in parallel with improvement in disease severity. OBJECTIVES: To evaluate the role of pruritus (itch) in mediating the relationship between improvements in disease severity and HRQOL. METHODS: Data from a phase 2 clinical trial, in which 142 patients with moderate-to-severe plaque psoriasis received ixekizumab or placebo, were used for this posthoc analysis. Relationships between improvement in Psoriasis Area and Severity Index (PASI), Itch Visual Analogue Scale (VAS) and Dermatology Life Quality Index (DLQI), as well as in individual DLQI domains (symptoms and feelings, treatment, work and school, daily activities, leisure, and personal relationships) from baseline to week 16 were determined. Multiple hierarchical linear regressions and Sobel tests were conducted to evaluate the results. RESULTS: Improvement in PASI was highly correlated with pruritus improvement and improvements in DLQI total and domain scores at week 16 (P < 0·01). Multiple hierarchical linear regression analyses showed a statistically significant (P < 0·01) association between improvement in pruritus and improvement in DLQI total score and each of the six DLQI domain scores after adjusting for improvement in PASI. Sobel tests indicated that pruritus had a significant mediation effect (P < 0·05) on the association of PASI improvement with improvement in DLQI total score and all domains except the personal relationships score. CONCLUSIONS: Pruritus appears to be an important mediator of the association between improvements in disease severity and HRQOL in patients with moderate-to-severe psoriasis.

Early clinical response as a predictor of subsequent response to ixekizumab treatment: results from a phase II study of patients with moderate-to-severe plaque psoriasis.

BACKGROUND: Early identification of responsiveness to biologic treatments in psoriasis has significant clinical and economic implications. OBJECTIVES: To evaluate whether early clinical improvements in Psoriasis Area and Severity Index (PASI) scores could predict subsequent clinical responses in patients treated with ixekizumab, an anti-interleukin-17 monoclonal antibody. METHODS: This post hoc analysis was derived from a phase II study in patients with moderate-to-severe plaque psoriasis (n = 114) who received multiple doses of ixekizumab 10, 25, 75 or 150 mg subcutaneously over 20 weeks. PASI score improvements from baseline to weeks 2, 4 and 6 were evaluated to determine the optimal threshold for predicting subsequent PASI responses at week 12. RESULTS: Early clinical improvement in disease symptoms at weeks 4 and 6 was predictive of ≥ 75% improvement in PASI score (PASI 75) at week 12 with ≥ 90% predictability. A 40-50% improvement in PASI (PASI 40 to PASI 50) from baseline to weeks 4 and 6 was the optimum range for predicting PASI 75 response at week 12. For all doses combined, achieving PASI 40 at week 4 or week 6 was associated with high negative predictive values (NPVs) (80% and 95%, respectively) and positive predictive values (PPVs) (89% and 84%, respectively). For all doses combined, achieving PASI 50 at week 4 or week 6 was associated with NPVs of 71% and 89% and PPVs of 94% and 89%, respectively. Sensitivity analysis with the high-dose group (75 and 150 mg) results confirmed these findings. CONCLUSIONS: Early clinical responses (and nonresponse) may help predict later clinical responses in patients treated with ixekizumab.