Population pharmacokinetics and pharmacodynamics of efmarodocokin alfa (IL-22Fc).

Efmarodocokin alfa (IL-22Fc) is a fusion protein of human IL-22 linked to the crystallizable fragment (Fc) of human IgG4. It has been tested in multiple indications including inflammatory bowel disease (IBD). The purposes of the present analyses were to describe the population pharmacokinetics (PK) of efmarodocokin alfa and perform pharmacodynamic (PD) analysis on the longitudinal changes of the PD biomarker REG3A after efmarodocokin alfa treatment as well as identify covariates that affect efmarodocokin alfa PK and REG3A PD. The data used for this analysis included 182 subjects treated with efmarodocokin alfa in two clinical studies. The population PK and PD analyses were conducted sequentially. Efmarodocokin alfa concentration-time data were analyzed using a nonlinear mixed-effects modeling approach, and an indirect response model was adopted to describe the REG3A PD data with efmarodocokin alfa serum concentration linked to the increase in REG3A. The analysis software used were NONMEM and R. A 3-compartment model with linear elimination best described the PK of efmarodocokin alfa. The estimated population-typical value for clearance (CL) was 1.12 L/day, and volume of central compartment was 6.15 L. Efmarodocokin alfa CL increased with higher baseline body weight, C-reactive protein, and CL was 27.6% higher in IBD patients compared to healthy subjects. The indirect response PD model adequately described the longitudinal changes of REG3A after efmarodocokin alfa treatment. A popPK and PD model for efmarodocokin alfa and REG3A was developed and covariates affecting the PK and PD were identified.

Population-Based Pharmacodynamic Modeling of Omalizumab in Pediatric Patients with Moderate to Severe Persistent Inadequately Controlled Allergic Asthma.

Omalizumab is the first approved anti-immunoglobulin E (IgE) agent for the treatment of moderate to severe persistent inadequately controlled allergic asthma in adults and adolescents (≥ 12 years old). In 2016, it was approved in pediatric patients (6-11 years old). The objective of this study was to quantitatively characterize the relationship between serum free IgE and pulmonary function (as measured by forced expiratory volume in 1 s [FEV1]) in pediatrics using a population-based pharmacodynamic model. Data collected during the steroid-stable period (first 24 weeks) of an omalizumab trial with pediatric asthma patients (Study IA05) were used to build the pediatric IgE-FEV1 model. The previously developed population IgE-FEV1 model in adults/adolescents was adapted to characterize the FEV1 and IgE relationship in pediatrics with different magnitude and onset of response. The pediatric IgE-FEV1 model adequately characterized the IgE-FEV1 relationship in pediatrics, particularly at the extremes of the observed body weights (i.e., ≤ 30 kg) and IgE values at screening (i.e., > 700 IU/mL). The estimated sigmoidal free IgE-FEV1 curves were similar in shape and maximum effect, but the estimated free IgE concentration leading to 50% maximum effect (IC50) in pediatric patients (39.4, 95% confidence interval [CI] 24.3-63.9 ng/mL) was higher than estimated in adults (19.8, 95% CI 15.1-24.5 ng/mL). The model further confirmed that the current omalizumab dosing rationale based on the mean target free IgE level of 25 ng/ml was appropriate. The pediatric model can be used to predict population FEV1 response for omalizumab when combined with an omalizumab pharmacokinetic-IgE model.

First-in-human phase 1 trial evaluating safety, pharmacokinetics, and pharmacodynamics of NLRP3 inflammasome inhibitor, GDC-2394, in healthy volunteers.

Inappropriate and chronic activation of the cytosolic NOD-, LRR-, and pyrin domain-containing 3 (NLRP3) inflammasome, a key component of innate immunity, likely underlies several inflammatory diseases, including coronary artery disease. This first-in-human phase I trial evaluated safety, pharmacokinetics (PKs), and pharmacodynamics (PDs) of oral, single (150-1800 mg) and multiple (300 or 900 mg twice daily for 7 days) ascending doses (SADs and MADs) of GDC-2394, a small-molecule inhibitor of NLRP3, versus placebo in healthy volunteers. The study also assessed the food effect on GDC-2394 and its CYP3A4 induction potential in food-effect (FE) and drug-drug interaction (DDI) stages, respectively. Although GDC-2394 was adequately tolerated in the SAD, MAD, and FE cohorts, two participants in the DDI stage experienced grade 4 drug-induced liver injury (DILI) deemed related to treatment, but unrelated to a PK drug interaction, leading to halting of the trial. Both participants experiencing severe DILI recovered within 3 months. Oral GDC-2394 was rapidly absorbed; exposure increased in an approximately dose-proportional manner with low-to-moderate intersubject variability. The mean terminal half-life ranged from 4.1 to 8.6 h. Minimal accumulation was observed with multiple dosing. A high-fat meal led to delays in time to maximum concentration and minor decreases in total exposure and maximum plasma concentration. GDC-2394 had minimal CYP3A4 induction potential with the sensitive CYP3A4 substrate, midazolam. Exploratory ex vivo whole-blood stimulation assays showed rapid, reversible, and near-complete inhibition of the selected PD biomarkers, IL-1ß and IL-18, across all tested doses. Despite favorable PK and target engagement PD, the GDC-2394 safety profile precludes its further development.

PK/PD modeling to characterize placebo and treatment effect of omalizumab for chronic spontaneous urticaria.

The pharmacokinetic (PK) characteristics of omalizumab and its pharmacodynamic (PD) effect in patients has yet to be fully characterized in chronic spontaneous urticaria, which could elucidate its pathogenesis and treatment response. This study has two objectives; (1) characterize the population PK of omalizumab and its PD effect on IgE, and (2) develop a drug effect model of omalizumab in urticaria (via change in weekly itch severity score). The target-mediated population of PK/PD model incorporating omalizumab-IgE binding and turnover adequately described PK and PD of omalizumab. The effect compartment model and linear drug effect and additive placebo response adequately described placebo and treatment effects of omalizumab. Several baseline covariates were identified for PK/PD and drug effect models. The developed model has the potential to aid in understanding variability in PK/PD as well as response to omalizumab treatment.

A mechanistic PK/PD model to enable dose selection of the potent anti-tryptase antibody (MTPS9579A) in patients with moderate-to-severe asthma.

Tryptase, a protease implicated in asthma pathology, is secreted from mast cells upon activation during an inflammatory allergic response. MTPS9579A is a novel monoclonal antibody that inhibits tryptase activity by irreversibly dissociating the active tetramer into inactive monomers. This study assessed the relationship between MTPS9579A concentrations in healthy subjects and tryptase levels in serum and nasal mucosal lining fluid from healthy subjects and patients with moderate-to-severe asthma. These data were used to develop a mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model that quantitatively inter-relates MTPS9579A exposure and inhibition of active tryptase in the airway of patients with asthma. From initial estimates of airway tryptase levels and drug partitioning, the PK/PD model predicted almost complete neutralization of active tryptase in the airway of patients with asthma with MTPS9579A doses of 900 mg and greater, administered intravenously (i.v.) once every 4 weeks (q4w). Suppression of active tryptase during an asthma exacerbation event was also evaluated using the model by simulating the administration of MTPS9579A during a 100-fold increase in tryptase secretion in the local tissue. The PK/PD model predicted that 1800 mg MTPS9579A i.v. q4w results in 95.7% suppression of active tryptase at the steady-state trough concentration. Understanding how the exposure-response relationship of MTPS9579A in healthy subjects translates to patients with asthma is critical for future clinical studies assessing tryptase inhibition in the airway of patients with moderate-to-severe asthma.

A nontraditional presentation and treatment for emphysematous cystitis.

Emphysematous cystitis (EC) is a bladder pathology typically resulting from gas-producing bacterial infections. Risk factors include female gender, age greater than 60, diabetes mellitus, glycosuria, and urinary stasis. If not addressed promptly, it can progress to critical conditions. Management depends on severity, ranging from conservative to surgical interventions. We present a unique case of EC in a patient who lacked the most common risk factors, and who experienced a spontaneous intraperitoneal bladder rupture. Additionally, we treated this presentation against what historically is suggested. Lastly, this is the first published incidence of a patient with both Parkinson's Disease and EC.

Population Pharmacokinetics of Tenecteplase in Patients With Acute Myocardial Infarction and Application to Patients With Acute Ischemic Stroke.

The pharmacokinetics (PK) of tenecteplase in patients with acute ischemic stroke has not been extensively studied. This study aimed to describe PK characteristics of tenecteplase in patients with acute myocardial infarction (AMI) using a population PK approach and to assess applicability of the findings to patients with acute ischemic stroke by means of external validation. A population PK model was developed using nonlinear mixed-effects modeling based on the phase II TIMI 10B study in patients with AMI (785 PK observations from 103 patients). The statistical and clinical impact of selected covariates on PK parameters were evaluated by a stepwise covariate modeling procedure and simulations, respectively. The performance of the final model was evaluated for patients with acute ischemic stroke using summary statistics of tenecteplase concentrations of 75 patients from investigator-initiated study N1811s. Tenecteplase PK was well described by a 2-compartment linear model, incorporating allometric scaling of clearance and volume parameters and weight-normalized creatinine clearance on clearance. Simulations showed that the identified covariates (weight and creatinine clearance) were of limited influence on exposure at the intended dosing regimen for patients with acute ischemic stroke. The model overpredicted mean tenecteplase plasma concentrations from N1811s by 39%, but 72% of the distribution from N1811s was within the 90% prediction interval of the model predictions. The PK characteristics of tenecteplase in patients with AMI were well described by the final model. Simulations from the model indicated that no specific dose recommendations based on covariates are warranted for patients with AMI.

Effects of inhaled JAK inhibitor GDC-4379 on exhaled nitric oxide and peripheral biomarkers of inflammation.

BACKGROUND: Janus Kinases (JAKs) mediate activity of many asthma-relevant cytokines. GDC-0214, an inhaled small molecule JAK1 inhibitor, has previously been shown to reduce fractional exhaled nitric oxide (FeNO) in patients with mild asthma, but required an excessive number of inhalations. AIM: To assess whether GDC-4379, a new inhaled JAK inhibitor, reduces FeNO and peripheral biomarkers of inflammation. METHODS: This study assessed the activity of GDC-4379 in a double-blind, randomized, placebo-controlled, Phase 1 study in patients with mild asthma. Participants included adults (18-65y) with a diagnosis of asthma for ≥6 months, forced expiratory volume in 1 s (FEV1)> 70% predicted, FeNO >40 ppb, using as-needed short-acting beta-agonist medication only. Four sequential, 14-day, ascending-dose cohorts (10 mg QD, 30 mg QD, 40 mg BID, and 80 mg QD) of 12 participants each were randomized 2:1 to GDC-4379 or placebo. The primary activity outcome was percent change from baseline (CFB) in FeNO to Day 14 compared to the pooled placebo group. Safety, tolerability, pharmacokinetics, and pharmacodynamic biomarkers, including blood eosinophils, serum CCL17, and serum CCL18, were also assessed. RESULTS: Of 48 enrolled participants, the mean age was 25 years and 54% were female. Median (range) FeNO at baseline was 79 (41-222) ppb. GDC-4379 treatment led to dose-dependent reductions in FeNO. Compared to placebo, mean (95% CI) percent CFB in FeNO to Day 14 was: -6 (-43, 32) at 10 mg QD, -26 (-53, 2) at 30 mg QD, -55 (-78, -32) at 40 mg BID and -52 (-72, -32) at 80 mg QD. Dose-dependent reductions in blood eosinophils and serum CCL17 were also observed. Higher plasma drug concentrations corresponded with greater FeNO reductions. No serious AEs occurred. The majority of AEs were mild to moderate. The most common AEs were headache and oropharyngeal pain. Minor changes in neutrophils were noted at 80 mg QD, but were not considered clinically meaningful. CONCLUSIONS: In patients with mild asthma, 14-day treatment with GDC-4379 reduced FeNO levels and peripheral biomarkers of inflammation. Treatment was well tolerated without any major safety concerns. AUSTRALIAN NEW ZEALAND CLINICAL TRIALS REGISTRY: ACTRN12619000227190.

Phase I and scintigraphy studies to evaluate safety, tolerability, pharmacokinetics, and lung deposition of inhaled GDC-0214 in healthy volunteers.

Several inflammatory cytokines that promote inflammation and pathogenesis in asthma signal through the Janus kinase 1 (JAK1) pathway. This phase I, randomized, placebo-controlled trial assessed the pharmacokinetics and safety of single and multiple ascending doses up to 15 mg twice daily for 14 days of a JAK1 inhibitor, GDC-0214, in healthy volunteers (HVs; n = 66). Doses were administered with a dry powder, capsule-based inhaler. An accompanying open-label gamma scintigraphy study in HVs examined the lung deposition of a single dose of inhaled Technetium-99m (99m Tc)-radiolabeled GDC-0214. GDC-0214 plasma concentrations were linear and approximately dose-proportional after both single and multiple doses. Peak plasma concentrations occurred at 15-30 min after dosing. The mean apparent elimination half-life ranged from 32 to 56 h across all single and multiple dose cohorts. After single and multiple doses, all adverse events were mild or moderate, and none led to treatment withdrawal. There was no clear evidence of systemic toxicity due to JAK1 inhibition, and systemic exposure was low, with plasma concentrations at least 15-fold less than the plasma protein binding-corrected IC50 of JAK1 at the highest dose. Scintigraphy showed that approximately 50% of the emitted dose of radiolabeled GDC-0214 was deposited in the lungs and was distributed well to the peripheral airways. 99m Tc-radiolabeled GDC-0214 (1 mg) exhibited a mean plasma Cmax similar to that observed in phase I at the same dose level. Overall, inhaled GDC-0214 exhibited pharmacokinetic properties favorable for inhaled administration.

Pharmacokinetics and exposure-efficacy relationships of omalizumab in patients with nasal polyps.

The anti-immunoglobulin E (IgE) antibody, omalizumab (Xolair), is approved in the United States for the treatment of allergic asthma and chronic spontaneous urticaria, and has recently been studied for the treatment of nasal polyposis following completion of the two replicate phase 3 studies (POLYP 1 and POLYP 2). The dosing of omalizumab used in the phase 3 studies is based on a combination of patients' pre-treatment IgE level and body weight, similar to the approach used in allergic asthma. The objectives of the current analyses were to evaluate whether the pharmacokinetics (PK) of omalizumab and its pharmacodynamic (PD) effect on free and total IgE level in chronic rhinosinusitis with nasal polyps (CRSwNP) are consistent with those in allergic asthma via population PK/PD modeling and simulation, and to graphically explore exposure-response relationships and free IgE-response relationships in CRSwNP. Omalizumab PK and PD effect of total and free IgE in CRSwNP are generally consistent with those in asthma. Observed post-treatment free IgE suppressions were generally within the target range of the baseline IgE- and body weight-based omalizumab dosing table, with 74.2% and 93.0% of patients achieving a serum free IgE level below 25 ng/mL and 50 ng/mL, respectively at Week 24. Exposure-response analyses indicated that there was no clear correlation between omalizumab or free IgE concentration and key efficacy endpoints within the POLYP studies. Overall, these results indicate that the body weight and IgE-based dosing regimen of omalizumab was appropriate for use in CRSwNP patients.

Inhaled JAK inhibitor GDC-0214 reduces exhaled nitric oxide in patients with mild asthma: A randomized, controlled, proof-of-activity trial.

BACKGROUND: The Janus kinase (JAK) pathway mediates the activity of many asthma-relevant cytokines, including IL-4 and IL-13. GDC-0214 is a potent, inhaled, small-molecule JAK inhibitor being developed for the treatment of asthma. OBJECTIVE: We sought to determine whether GDC-0214 reduces fractional exhaled nitric oxide (Feno), a JAK1-dependent biomarker of airway inflammation, in patients with mild asthma. METHODS: We conducted a double-blind, randomized, placebo-controlled, phase 1 proof-of-activity study in adults with mild asthma and Feno higher than 40 parts per billion (ppb). Subjects were randomized 2:1 (GDC-0214:placebo) into 4 sequential ascending-dose cohorts (1 mg once daily [QD], 4 mg QD, 15 mg QD, or 15 mg twice daily). All subjects received 4 days of blinded placebo, then 10 days of either active drug or placebo. The primary outcome was placebo-corrected percent reduction in Feno from baseline to day 14. Baseline was defined as the average Feno during the blinded placebo period. Pharmacokinetics, safety, and tolerability were also assessed. RESULTS: Thirty-six subjects (mean age, 28 years; 54% females) were enrolled. Mean Feno at baseline across all subjects was 93 ± 43 ppb. At day 14, placebo-corrected difference in Feno was -23% (95% CI, -37.3 to -9) for 15 mg QD and -42% (95% CI, -57 to -27.4) for 15 mg twice daily. Higher plasma exposure was associated with greater Feno reduction. No dose-limiting adverse events, serious adverse events, or treatment discontinuations occurred. There were no major imbalances in adverse events or laboratory findings, or evidence of systemic JAK inhibition. CONCLUSIONS: GDC-0214, an inhaled JAK inhibitor, caused dose-dependent reductions in Feno in mild asthma and was well tolerated without evidence of systemic toxicity.

Collapsing FSGS with Concurrent Class 2 and 3 Lupus Nephritis: A Case Report and Review of the Literature.

Lupus nephritis (LN) and the collapsing variant of focal segmental glomerulosclerosis (cFSGS) are separate histologic diagnoses that are generally thought to have separate etiologies. We describe the presentation of a 20-year-old African American female with advanced renal failure (creatinine 7.16 mg/dL), nephrotic-range proteinuria, and a 30-pound weight loss. Renal biopsy demonstrated class 2 and 3 LN as well as cFSGS. A review of the current literature demonstrates that the dual diagnosis of LN and cFSGS may not be as rare as previously understood. Whether the presence of one of these pathophysiologic processes predisposes a patient to the development of the other, or whether genetic variation increases the risk for development of both conditions, remains unclear. Currently there is no standard therapy to manage these patients, and overall renal prognosis is poor.

Efficacy and safety of omalizumab in nasal polyposis: 2 randomized phase 3 trials.

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by IgE hyperproduction and eosinophilic inflammation. The anti-IgE antibody, omalizumab, has demonstrated efficacy in patients with CRSwNP and comorbid asthma previously. OBJECTIVE: Our aim was to determine omalizumab safety and efficacy in CRSwNP in phase 3 trials (POLYP 1 and POLYP 2). METHODS: Adults with CRSwNP with inadequate response to intranasal corticosteroids were randomized (1:1) to omalizumab or placebo and intranasal mometasone for 24 weeks. Coprimary end points included change from baseline to week 24 in Nasal Polyp Score (NPS) and Nasal Congestion Score. Secondary end points included change from baseline to week 24 in Sino-Nasal Outcome Test-22 (SNOT-22) score, University of Pennsylvania Smell Identification Test, sense of smell, postnasal drip, runny nose, and adverse events. RESULTS: Patients in POLYP 1 (n = 138) and POLYP 2 (n = 127) exhibited severe CRSwNP and substantial quality of life impairment evidenced by a mean NPS higher than 6 and SNOT-22 score of approximately 60. Both studies met both the coprimary end points. SNOT-22 score, University of Pennsylvania Smell Identification Test score, sense of smell, postnasal drip, and runny nose were also significantly improved for omalizumab versus placebo. In POLYP 1 and POLYP 2, the mean changes from baseline at week 24 for omalizumab versus placebo were as follows: NPS, -1.08 versus 0.06 (P < .0001) and -0.90 versus -0.31 (P = .0140); Nasal Congestion Score, -0.89 versus -0.35 (P = .0004) and -0.70 versus -0.20 (P = .0017); and SNOT-22 score, -24.7 versus -8.6 (P < .0001) and -21.6 versus -6.6 (P < .0001). Adverse events were similar between groups. CONCLUSION: Omalizumab significantly improved endoscopic, clinical, and patient-reported outcomes in severe CRSwNP with inadequate response to intranasal corticosteroids, and it was well tolerated.

The Prevalence of Y-chromosome Microdeletions in Oligozoospermic Men: A Systematic Review and Meta-analysis of European and North American Studies.

CONTEXT: European and North American guidelines recommend Y-chromosome microdeletion (YCM) screening in azoospermic and oligozoospermic men with sperm concentrations of <5 million sperm/ml; however, numerous studies have suggested that YCMs are rare when sperm concentrations are >1 million sperm/ml. OBJECTIVE: We systematically reviewed and meta-analyzed European and North American studies to determine the prevalence of a complete YCM in oligozoospermic men with sperm concentrations of >0-1, >1-5, and >5-20 million sperm/ml, and to determine whether 1 or 5 million sperm/ml is the most appropriate sperm concentration threshold for YCM screening. EVIDENCE ACQUISITION: A systematic review of MEDLINE, EMBASE, Cochrane Library, and ClinicalTrials.gov was performed for studies assessing the prevalence of a complete YCM in oligozoospermic men in European and North American studies. EVIDENCE SYNTHESIS: Thirty-seven studies were identified during a systematic review (n = 12 492 oligozoospermic men). All complete YCMs in oligozoospermic men were AZFc microdeletions. Eighteen studies contained data conducive to meta-analysis (n = 10 866 men). Comparing the pooled estimated prevalence by sperm concentration, complete YCMs were significantly more common in men with sperm concentrations of >0-1 million sperm/ml (5.0% [95% confidence interval {CI}: 3.6-6.8%]) versus >1-5 million sperm/ml (0.8% [95% CI: 0.5-1.3%], p < 0.001). YCMs were similar in men with sperm concentrations of >1-5 and >5-20 million sperm/ml (0.8% [95% CI: 0.5-1.3%] vs 0.5% [95% CI: 0.2-0.9%], p = 0.14). CONCLUSIONS: In Europe and North America, the majority of YCMs occur in men with sperm concentrations of ≤1 million sperm/ml, with <1% identified in men with >1 million sperm/ml. Male infertility guidelines for North America and Europe should reconsider the sperm concentration screening thresholds to recommend testing for YCMs only for men with sperm concentrations of <1 million sperm/ml. PATIENT SUMMARY: Complete Y-chromosome microdeletions (YCMs) are rare in men with >1 million sperm/ml. Routine screening for YCMs should occur only if sperm concentration is ≤1 million sperm/ml.

A phase I, randomized, observer-blinded, single and multiple ascending-dose study to investigate the safety, pharmacokinetics, and immunogenicity of BITS7201A, a bispecific antibody targeting IL-13 and IL-17, in healthy volunteers.

BACKGROUND: Inhibition of interleukin (IL)-13, a Type 2 inflammatory mediator in asthma, improves lung function and reduces exacerbations; however, more effective therapies are needed. A subset of asthma patients also exhibits elevated IL-17, which is associated with greater disease severity, neutrophilic inflammation, and steroid resistance. BITS7201A is a novel, humanized bispecific antibody that binds and neutralizes both IL-13 and IL-17. METHODS: Safety, pharmacokinetics, and immunogenicity of BITS7201A were evaluated in a phase 1 study. Part A was a single ascending-dose design with 5 cohorts: 30-, 90-, and 300-mg subcutaneous (SC), and 300- and 750-mg intravenous (IV). Part B was a multiple ascending-dose design with 3 cohorts: 150-, 300-, and 600-mg SC every 4 weeks × 3 doses. Both parts enrolled approximately 8 healthy volunteers into each cohort (6 active: 2 placebo). Part B included an additional cohort of patients with mild asthma (600-mg SC). RESULTS: Forty-one subjects (31 active, 10 placebo) and 26 subjects (20 active, 6 placebo) were enrolled into Parts A and B, respectively. The cohort with mild asthma patients was terminated after enrollment of a single patient. No deaths, serious adverse events, or dose-limiting adverse events occurred. In Part A, 12 active (39%) and 5 placebo subjects (50%), and in Part B, 6 active (30%) and 3 placebo subjects (50%) experienced at least 1 treatment-emergent adverse event (TEAE). The most common AEs were fatigue (n = 3) and influenza-like illness (n = 2). One injection-site reaction was reported. Two subjects with elevated blood eosinophil counts at baseline had transient elevations in blood eosinophils (≥Grade 2, > 1500 cells/µL). In Parts A and B, 16 of 30 (53%) and 16 of 17 (94%) active subjects, respectively, tested positive for anti-drug antibodies (ADAs). No anaphylaxis or hypersensitivity events occurred. BITS7201A exhibited single- and multiple-dose pharmacokinetic characteristics consistent with an IgG monoclonal antibody; exposure generally increased dose-proportionally. Postdose elevations of the serum pharmacodynamic biomarkers, IL-17AA and IL-17FF, occurred, confirming target engagement. CONCLUSIONS: BITS7201A was well tolerated, but was associated with a high incidence of ADA formation. TRIAL REGISTRATION: ClinicalTrials.gov , NCT02748642; registered April 6, 2016 (retrospectively registered).

Inflammatory linear verrucous epidermal nevus responsive to 308-nm excimer laser treatment.

Inflammatory linear verrucous epidermal nevus (ILVEN) is a rare cutaneous disease that presents as linear psoriasiform plaques with associated prominent pruritus. The lesions commonly pre-sent on the legs with onset during childhood. Inflammatory linear verrucous epidermal nevus typically is refractory to treatment. Therapies range from topical treatments to lasers and surgical options. It is clinically and histopathologically similar to psoriasis, suggesting it may respond to established psoriasis treatments such as the excimer laser. We report the case of an otherwise healthy 20-year-old woman with dry, pruritic, red lesions on the right leg that had been present since infancy. Biopsy revealed psoriasiform hyperplasia with a verruciform surface. Multiple topical treatments including ablative CO2 laser therapy showed no remarkable improvement. The patient was then treated with a UV 308-nm excimer laser and showed noticeable clinical improvement. Because of its clinical and histopathological similarities to psoriasis, we hypothesized that the excimer laser may be useful in the treatment of these lesions.

Best practice in the diagnosis and treatment of varicocele in children and adolescents.

A varicocele is an abnormal dilation of the pampiniform plexus of veins in the scrotum which begins at puberty in approximately 15% of males. Although common in the general population and often asymptomatic, varicoceles are associated with gonadal dysfunction including testicular atrophy, infertility, and hypogonadism in a subset of men diagnosed later in life. Because of the high prevalence and uncertain pathogenesis, definitive management guidelines for varicoceles diagnosed in the pediatric and adolescent population remain poorly defined. The varicocele is the most common etiology of male factor infertility, and treatment in the pediatric and adolescent population may improve semen quality and improve fecundity in adulthood. Evaluation of the pediatric and adolescent varicocele should include history, physical exam, and measurement of testicular volume with orchidometer or ultrasound. Testicular volume differentials and peak retrograde flow on Doppler ultrasonography are important factors in risk stratification of the pediatric varicocele population. Semen analysis and reproductive endocrine assessment should also be considered as part of the workup for adolescent patients. A variety of treatment approaches exist for varicocele, and while the microsurgical subinguinal approach is the gold standard for the adult population, it has yet to be confirmed as superior for the adolescent population. Referral to an andrologist for the adolescent patient with varicocele should be considered in equivocal cases. While active treatment of varicocele in the pediatric and adolescent population is controversial, it is clear that some untreated patients will suffer symptoms later in life, while overtreatment remains a concern for this large, vulnerable population. Therefore, surveillance strategies and improved accuracy in diagnosis of clinically important pediatric varicoceles prompting treatment are needed in the future.

Eosinophilic pustular folliculitis with underlying mantle cell lymphoma.

Eosinophilic pustular folliculitis (EPF) is a noninfectious condition characterized by folliculocentric papules, pustules, and plaques on the head, trunk, and extremities. Three subtypes of EPF have been described. Histopathology predominantly shows abundant eosinophils concentrated at the follicle, and treatment typically consists of topical corticosteroids or oral indomethacin. We present an unusual case of EPF in a 52-year-old man that preceded the diagnosis of mantle cell lymphoma.

Efficacy and safety of lebrikizumab (an anti-IL-13 monoclonal antibody) in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical corticosteroids: A randomized, placebo-controlled phase II trial (TREBLE).

BACKGROUND: Interleukin (IL)-13 plays a key role in type 2 inflammation and is an emerging pathogenic mediator in atopic dermatitis (AD). OBJECTIVE: We investigated the efficacy and safety of lebrikizumab, an IL-13 monoclonal antibody, as an add-on to topical corticosteroid (TCS) treatment. METHODS: A randomized, placebo-controlled, double-blind, phase 2 study. Adults with moderate-to-severe AD were required to use TCS twice daily and then randomized (1:1:1:1) to lebrikizumab 125 mg single dose, lebrikizumab 250 mg single dose, lebrikizumab 125 mg every 4 weeks for 12 weeks, or placebo every 4 weeks for 12 weeks, after a 2-week TCS run-in. The primary endpoint was percentage of patients achieving Eczema Area and Severity Index (EASI)-50 at week 12. RESULTS: In total, 209 patients received the study drug. At week 12, significantly more patients achieved EASI-50 with lebrikizumab 125 mg every 4 weeks (82.4%; P = .026) than placebo every 4 weeks (62.3%); patients receiving a single dose of lebrikizumab showed no statistically significant improvements in EASI-50 compared with placebo. Adverse events were similar between groups (66.7% all lebrikizumab vs 66.0% placebo) and mostly mild or moderate. LIMITATIONS: Protocol-mandated twice daily TCS treatment limits our understanding of the efficacy of lebrikizumab as a monotherapy. The short study duration did not enable long-term efficacy or safety evaluations. CONCLUSION: When combined with TCS, lebrikizumab 125 mg taken every 4 weeks led to a significant improvement and was well tolerated in patients with moderate-to-severe AD.