A comparison of psoriasis severity in pediatric patients treated with methotrexate vs biologic agents

This cohort study compares the use of methotrexate vs biologic agents in children with moderate to severe psoriasis. Question What is the association between use of methotrexate vs biologics and psoriasis severity and drug survival (rate and duration of adherence to a specific drug regimen) in pediatric patients with moderate to severe psoriasis? Findings In this cohort study including 234 pediatric patients with moderate to severe psoriasis, those receiving biologics were more likely than those treated with methotrexate to achieve a Physician Global Assessment status of clear/almost clear and 75% or more improvement of the Psoriasis Area and Severity Index rating at 6 months. In addition, biologics were associated with better drug survival rates at 1, 3, and 5 years, with comparable discontinuation rates owing to lack of response. Meaning In pediatric patients with psoriasis, treatment with biologics may be associated with a significantly greater reduction in psoriasis severity than methotrexate; nevertheless, with 35.6% of the patients achieving clear/almost clear and 40.0% reaching 75% or more improvement on the Psoriasis Area and Severity Index, methotrexate remains an effective treatment for pediatric psoriasis. Importance Few studies have compared the use of methotrexate and biologics, the most commonly used systemic medications for treatment of moderate to severe psoriasis in children. Objective To assess the real-world, 6-month reduction in psoriasis severity and long-term drug survival (rate and duration of adherence to a specific drug) of methotrexate vs biologics in plaque psoriasis in children. Design, Setting, and Participants A retrospective medical records review was conducted at 20 European and North American centers. Treatment response was based on site-reported Psoriasis Area and Severity Index (PASI) and/or Physician Global Assessment (PGA) scores at baseline and within the first 6 months of treatment. Participants included all 234 consecutively seen children with moderate to severe psoriasis who received at least 3 months of methotrexate or biologics from December 1, 1990, to September 16, 2014, with sufficient data for analysis. Data analysis was performed from December 14, 2015, to September 1, 2016. Main Outcomes and Measures PASI, with a range from 0 to 72 (highest score indicating severe psoriasis), and/or PGA, with a scale of 0 (clear), 1 (minimal), 2 (mild), 3 (moderate), 4 (severe), and 5 (very severe). Results Of 234 pediatric patients (103 boys [44.0%]; 131 girls [56.0%]) treated with methotrexate and/or biologics, 163 patients (69.7%) exclusively received methotrexate, 47 patients (20.1%) exclusively received biologics, and 24 children (10.2%) received methotrexate and biologics sequentially. Of the latter cohort, 23 children were treated initially with methotrexate. Mean (SD) age at initiation was 11.6 (3.7) years for methotrexate and 13.3 (2.9) years for biologics (73.2% for etanercept) (P = .002). Among patients evaluated by a scoring method at 6-month follow-up, 75% or greater improvement in PASI (PASI75) was achieved in 12 of 30 patients (40.0%) receiving methotrexate and 20 of 28 patients (71.4%) receiving biologics, and PGA was clear/almost clear (PGA 0/1) in 41 of 115 patients (35.6%) receiving methotrexate and 18 of 37 patients (48.6%) receiving biologics. Achieving PASI75 and/or PGA 0/1 between baseline and 6 months was more likely with biologics than methotrexate (PASI75: odds ratio [OR], 4.56; 95% CI, 2.02-10.27; P < .001; and PGA 0/1: OR, 2.00; 95% CI, 0.98-4.00; P = .06). Decreased mean PASI and PGA scores were associated with biologics more than with methotrexate (PASI effect, -3.13; 95% CI, -4.33 to -1.94; P < .001; and PGA effect, -0.31; 95% CI, -0.56 to -0.06; P = .02). After 1, 3, and 5 years of use, overall drug survival rates for methotrexate were 77.5%, 50.3%, and 35.9%, and for biologics, the rates were 83.4%, 64.3%, and 57.1%, respectively. Biologics were associated with a better confounder-corrected drug survival than methotrexate (hazard ratio [HR], 2.23; 95% CI, 1.21-4.10; P = .01). Discontinuation owing to lack of response was comparable (HR, 1.64; 95% CI, 0.80-3.36; P = .18). Conclusions and Relevance Methotrexate and biologics appear to be associated with improvement in pediatric psoriasis, although biologics seem to be associated with greater reduction in psoriasis severity scores and higher drug survival rates than methotrexate in the real-world setting. Additional studies directly comparing these medications should be performed for confirmation

Psoriasiform eruptions during Kawasaki disease (KD): A distinct phenotype.

BackgroundA psoriasis-like eruption develops in a subset of patients with Kawasaki disease (KD).ObjectiveWe sought to systematically compare KD-associated psoriasiform eruptions with classic psoriasis and the outcomes of KD in children with and without this rash.MethodsThis was a retrospective study of 11 KD cases with a psoriasiform eruption matched 1:2 by age, gender, and ethnicity with psoriasis-only and KD-only controls. Genotyping was performed in 10 cases for a deletion of 2 late cornified envelope (LCE) genes, LCE3C_LCE3B-del, associated with increased risk for pediatric-onset psoriasis.ResultsSimilar to classic psoriasis, KD-associated eruptions were characterized clinically by well-demarcated, scaly pink plaques and histopathologically by intraepidermal neutrophils, suprabasilar keratin 16 expression, and increased Ki-67 expression. They showed less frequent diaper area involvement, more crust and serous exudate, and an enduring remission (91% vs 23% with confirmed resolution; P &lt; .001). Frequency of LCE3C_LCE3B-del and major KD outcomes were similar between cases and controls.LimitationsThe study was limited by the small number of cases, treatment variation, and availability of skin biopsy specimens.ConclusionsAlthough the overall clinical and histopathologic findings were similar to conventional psoriasis, this appears to be a distinct phenotype with significantly greater propensity for remission. No adverse effect on KD outcomes was noted

Combined Intravenous Sildenafil and L-Arginine Administration in a Porcine Animal Model: Hemodynamic Safety Profile and Effects on Coronary Blood Flow.

BackgroundEndothelial dysfunction in the nitric oxide-cyclic guanosine monophosphate pathway is a potential contributor to perioperative myocardial ischemia. The nitric oxide precursor, L-arginine, and the cyclic guanosine monophosphate degradation blocker, sildenafil, have vasodilatory effects under high dosage.ObjectiveThis study examined the hemodynamic safety and effect profiles of the combined administration of L-arginine and sildenafil using an in-vivo pig model.MethodsHemodynamic safety including mean arterial pressure, central venous pressure, heart rate, coronary vascular resistance, and systemic vascular resistance, as well as effect profiles including cardiac output and left anterior descending blood flow were measured in ten female swine after administrations of L-arginine, sildenafil, as well as combined L-arginine and sildenafil. Measurements were compared using repeated-measures analysis of variance and linear mixed models.ResultsThe combination of L-arginine and sildenafil produced a significant dose-dependent increase in left anterior descending flow and cardiac output. In contrast, mean arterial pressure, heart rate, central venous pressure, coronary vascular resistance, and systemic vascular resistance did not show any significant changes. No significant change in serum osmolality was observed after administrations of L-arginine.ConclusionsThe combined intravenous administration of sildenafil and L-arginine in a porcine animal model was safe, well tolerated, and had at least additive effects on left anterior descending artery blood flow. Simultaneous application of both drugs might have dose-sparing effects leading to desired coronary effects at lower and safer sildenafil and L-arginine plasma concentrations. Hyperosmolality was only a minor factor in L-arginine hemodynamic effects

Clinical manifestations of pediatric psoriasis: results of a multicenter study in the United States

The clinical features of pediatric psoriasis warrant further attention. A national study was conducted to determine the prevalence of scalp and nail involvement and a history of guttate psoriasis at onset according to age, sex, and disease severity. One hundred eighty-one children ages 5 to 17 years with plaque psoriasis were enrolled in a multicenter, cross-sectional study. Subjects and guardians were asked about a history of scalp and nail involvement and whether the initial presentation was guttate. Peak psoriasis severity was assessed and defined historically as mild psoriasis (MP) or severe psoriasis (SP) according to the Physician\u27s Global Assessment and body surface area measures. One hundred forty-three (79.0%) subjects reported a history of scalp involvement, and 71 (39.2%) described a history of nail involvement. Boys were less likely than girls to report a history of scalp involvement (odds ratio [OR] = 0.40, 95% confidence interval [CI] = 0.19-0.84) but more likely to have had nail involvement (OR = 3.01, 95% CI = 1.62-5.60). Scalp and nail involvement was not related to psoriasis severity. In contrast, subjects with SP (35.9%) more often reported a history of guttate lesions than did those with MP (21.8%) (p = .02). Antecedent streptococcal infection was more common in children with guttate than those with plaque psoriasis at onset (p = .02) but did not correlate with severity. Sex-related differences in scalp and nail involvement suggest koebnerization. Preceding streptococcal infection predicts guttate morphology but not severity, and initial guttate morphology is associated with eventual greater severity of disease. More aggressive monitoring and management should be considered for guttate psoriasis, given its later association with more severe disease

Relationship Among Treatment, Pruritus, Investigator's Static Global Assessment, and Quality of Life in Patients with Atopic Dermatitis

The Investigator's Static Global Assessment (ISGA) is a 5-point rating scale that is recommended by the US Food and Drug Administration for assessing the severity of atopic dermatitis (AD), and ISGA success is a widely used endpoint in AD clinical studies. In this study, we seek to interpret the relationship of ISGA with treatment, pruritus, and quality of life (QoL) by conducting post hoc analyses of pooled data from two phase 3 crisaborole studies. Patients aged ≥ 2 years with baseline ISGA of 2 (mild) or 3 (moderate) were randomly assigned 2:1 to receive crisaborole or vehicle for 28 days. Disease severity, pruritus severity, and QoL were assessed with the ISGA, Severity of Pruritus Scale (SPS), and Dermatology Life Quality Index (DLQI; patients aged ≥ 16 years), or Children's Dermatology Life Quality Index (CDLQI; patients aged 2-15 years), respectively. The effect of treatment on ISGA and the relationship between ISGA and QoL were analyzed using a longitudinal repeated-measures model. The interrelationship between treatment, disease severity, pruritus, and QoL was analyzed with a mediation model. Overall, 1522 patients (crisaborole, n = 1016; vehicle, n = 506) were included. Estimated longitudinal profiles indicated changes in ISGA by day 8 were large for crisaborole (effect size [ES]: - 0.68) and small for vehicle (ES: - 0.34). There was a direct relationship between ISGA and DLQI and CDLQI severity bands in the longitudinal repeated-measures model. For both QoL mediation models, treatment effects on QoL were mediated indirectly by reduction in pruritus (DLQI, 42.4%; CDLQI, 58.1%) and disease severity (DLQI, 12.2%; CDLQI, 33.1%). These post hoc analyses suggest that ISGA success is a clinically meaningful endpoint associated with reduction in the severity of pruritus and improvement in QoL

Safety, pharmacokinetics, and efficacy of ruxolitinib cream in children and adolescents with atopic dermatitis.

BACKGROUND: Therapies for children with atopic dermatitis (AD) have safety and tolerability concerns that may limit long-term use. Ruxolitinib cream, a Janus kinase (JAK) inhibitor, is effective and well tolerated in adolescents and adults with AD. OBJECTIVE: To analyze the safety and tolerability of ruxolitinib cream in pediatric patients. Pharmacokinetics and efficacy were also evaluated in this phase 1 study (NCT03257644). METHODS: Patients aged 2 to 17 years with AD (affected body surface area 8%-20%; Investigator\u27s Global Assessment score ≥2) were enrolled stepwise in 6 age-descending, strength-increasing cohorts to apply 0.5%, 0.75%, or 1.5% ruxolitinib cream twice daily for 28 days. Safety, pharmacokinetics, and efficacy were analyzed at baseline, week 2 (day 10), and week 4 (day 29). RESULTS: Among 71 patients, 44 (62.0%) had a baseline Investigator\u27s Global Assessment score of 3; median (range) body surface area affected at baseline was 12.2% (1.7%-20.4%). Ruxolitinib cream was well tolerated, with 4 patients (5.6%) experiencing treatment-related adverse events (all grades 1/2). No clinically meaningful changes in mean chemistry or hematology values were observed, and no consistent pattern of change in bone biomarkers was detected. Mean plasma ruxolitinib levels within each cohort (range, 23.1-97.9 nM) were well below the half-maximal inhibitory concentration for thrombopoietin phosphorylation of STAT3 (281 nM). All cohorts experienced improvements in exploratory efficacy end points. CONCLUSION: Ruxolitinib cream was well tolerated in pediatric patients with AD, with no effect on blood counts or bone biomarkers. Mean plasma concentration was low. Efficacy was consistent with data from previous studies in adolescents and adults. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03257644

Association of Pediatric Psoriasis Severity With Excess and Central Adiposity: An International Cross-Sectional Study

ObjectiveTo investigate the relationship of excess and central adiposity with pediatric psoriasis severity.Design, setting, and participantsMulticenter, cross-sectional study of 409 psoriatic children. Psoriasis was classified as mild (worst Physician's Global Assessment score ≤3 with body surface area ≤10%) or severe (worst Physician's Global Assessment score ≥3 with body surface area &gt;10%). Children were enrolled from 9 countries between June 19, 2009, and December 2, 2011.Main outcome measuresExcess adiposity (body mass index percentile) and central adiposity (waist circumference percentile and waist to height ratio).ResultsExcess adiposity (body mass index ≥85th percentile) occurred in 37.9% of psoriatic children (n=155) vs 20.5% of controls (n=42) but did not differ significantly by severity. The odds ratio (95% CI) of obesity (body mass index ≥95th percentile) overall in psoriatic children vs controls was 4.29 (1.96-9.39) and was higher with severe (4.92; 2.20-10.99) than with mild (3.60; 1.56-8.30) psoriasis, particularly in the United States (7.60; 2.47-23.34, and 4.72; 1.43-15.56, respectively). Waist circumference above the 90th percentile occurred in 9.3% of the control (n=19), 14.0% of the mild psoriasis (n=27), and 21.2% of the of severe psoriasis (n=43) participants internationally; this incidence was highest in the United States (12.0% [n=13], 20.8% [16], and 31.1% [32], respectively). Waist to height ratio was significantly higher in psoriatic (0.48) vs control (0.46) children but was unaffected by psoriasis severity. Children with severe psoriasis at its worst, but mild at enrollment, showed no significant difference in excess or central adiposity from children whose psoriasis remained severe.ConclusionsGlobally, children with psoriasis have excess adiposity and increased central adiposity regardless of psoriasis severity. The increased metabolic risks associated with excess and central adiposity warrant early monitoring and lifestyle modification.Trial registrationclinicaltrials.gov Identifier: NCT0087994