Cytochrome P450 inhibitor/inducer treatment patterns among patients in the United States with advanced ovarian cancer who were prescribed or were eligible for poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitors in the first-line maintenance setting.

Poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitors (PARPi) are metabolized either via carboxylesterase (niraparib) or cytochrome P450 (CYP) enzymes (olaparib and rucaparib). Patients with advanced epithelial ovarian cancer (aOC) who receive concomitant medication metabolized by the CYP system may be at risk of drug-drug interactions impacting PARPi efficacy and tolerability. This study investigated CYP inhibitor/inducer treatment patterns in the first-line maintenance (1Lm) setting for patients with aOC. This retrospective cohort study used de-identified databases of US patients with aOC. Eligible patients were aged ≥18 years, diagnosed with aOC between January 2015-March 2021, and received CYP inhibitors/inducers during 1Lm PARPi initiation or the eligibility window (90 days before to 120 days after first-line platinum-based therapy ended [index]). Patients were either prescribed 1Lm PARPi monotherapy (PARPi cohort) or were not prescribed any 1Lm therapy within 120 days post-index (PARPi-eligible cohort). Strong/moderate CYP inhibitors/inducers were defined as area under the plasma concentration-time curve ratio (AUCR) ≥2 or clearance ratio (CL) ≤0.5 (inhibitors), and AUCR ≤0.5 or CL ratio ≥2 (inducers). Of 1411 patients (median age 63), 158 were prescribed PARPis and 1253 were PARPi-eligible. Among the PARPi cohort, 46.2%, 48.7%, and 5.1% were prescribed niraparib, olaparib, and rucaparib, respectively. For patients prescribed olaparib or rucaparib, 42.4% also received strong and/or moderate CYP inhibitors/inducers. This real-world study indicated a considerable proportion of patients received strong and/or moderate CYP inhibitors/inducers and were prescribed PARPis metabolized by the CYP system. Understanding potential impacts of concomitant CYP inhibitors/inducers on PARPi efficacy and safety is warranted.

Unmet Medical Needs in the Treatment and Management of Generalized Pustular Psoriasis Flares: Evidence from a Survey of Corrona Registry Dermatologists.

INTRODUCTION: Generalized pustular psoriasis (GPP) is a rare, severe, and potentially life-threatening systemic and chronic autoinflammatory disease characterized by sterile, neutrophilic pustules. The standard of care for GPP varies by region, with limited information and experience of flares and their treatment. Our aim was to establish current unmet needs in GPP by better understanding the natural history of GPP, examining how dermatologists diagnose GPP and GPP flares, and establishing the range and adequacy of GPP treatment options currently prescribed by dermatologists. METHODS: Eligible dermatologists (N = 29) completed a 28-question structured survey, covering ten themes, ranging from GPP diagnostic criteria to GPP symptoms and treatment. RESULTS: All dermatologists stated that pustules were necessary to diagnose a GPP flare. The most frequently reported triggering factors for GPP were steroid withdrawal (64%), infection (58%), and stress (50%). Most dermatologists indicated that available treatment options for GPP flares were adequate "most" (79%) or "all" (14%) of the time. Despite this reported adequacy, 38% of dermatologists reported that it was at least "somewhat common" for a flare to require hospitalization. Furthermore, 72% of dermatologists indicated that treatments were too slow to control flares, and 66% indicated that treatments did not adequately prevent new flares at least "sometimes". CONCLUSION: This survey suggests that there are key features of GPP flares, and could initiate discussion around forming consensus guidelines for diagnosis and management. While the results suggest that moderately effective therapies may exist, the need for GPP-specific treatments remains.

The clinical, humanistic, and economic burden of palmoplantar pustulosis: a structured review.

Introduction: Palmoplantar pustulosis (PPP) is a chronic, relapsing and refractory disease characterized by sterile pustules appearing on the palms and/or soles, accompanied by erythema, blistering, scales and/or keratinization. The overall burden of PPP in terms of its clinical impact, effect on patients and families, and economic consequences has not previously been investigated in a structured manner.Areas covered: A structured search focused on identification of studies in PPP using specific search terms in PubMed and EMBASE® from 2005 onwards, with additional back-referencing and pragmatic searches. Outcomes of interest included clinical burden, humanistic burden, and economic burden.Expert opinion: In cross-sectional studies, approximately 75% of all PPP patients suffer from active disease, with risk of relapse remaining constant over time. Patients' health-related quality of life is significantly impaired, as expected for a disease affecting hands and feet. Tools have been described that assess the clinical as well as patient-reported burden of PPP; their performance in larger cohorts and/or clinical trials remains to be investigated. The key data limitations identified include inconsistent definitions for characterizing remission/relapse, and limited humanistic and economic burden data; future studies are required to address these evidence gaps.

The clinical, humanistic, and economic burden of generalized pustular psoriasis: a structured review.

Introduction: Generalized pustular psoriasis (GPP) is characterized by widespread erythema and edema, superficial sterile coalescing pustules, and lakes of pus. Although the impact of GPP is thought to be substantial, emerging literature on its clinical, humanistic, and economic burden has not previously been described in a structured way.Areas covered: A structured search focused on the identification of studies in GPP using specific search terms in PubMed and EMBASE® from 2005 onwards, with additional back-referencing and pragmatic searches. Outcomes of interest included clinical, humanistic, and economic burden.Expert opinion: Despite its significant clinical, humanistic, and economic burden, GPP is poorly classified and inadequately studied. A recent European (ERASPEN) consensus classifies GPP into relapsing and persistent disease and classifies patients on the presence or absence of psoriasis vulgaris. Classification of GPP lesions involving >30% body surface area or use of hospitalization as a surrogate may be a way to identify significant flares. Given the frequency of flares, the impaired quality of life during the post-flare period, and safety/tolerability issues, it is clear that current treatment options are not sufficient. Long-term studies utilizing the European consensus statement with subclassifiers are required to supplement our current understanding of the burden of GPP.

Levetiracetam Pregnancy Registry: Final results and a review of the impact of registry methodology and definitions on the prevalence of major congenital malformations.

BACKGROUND: To evaluate pregnancy outcomes among women participating in the antiepileptic drug (AED) Levetiracetam Registry (LEV-Registry), and to review the impact of using two other registries' outcome definitions on the number of major congenital malformations (MCMs). METHODS: This US-based prospective study (ClinicalTrials.gov NCT00345475) was overseen by an independent Expert Panel. Women exposed to levetiracetam at any time during pregnancy enrolled, directly, or via their healthcare provider. The primary outcome was prevalence of MCMs, defined according to a modified version of the Metropolitan Atlanta Congenital Defects Program criteria. RESULTS: Of 491 women enrolled, 465 (94.7%) had a documented outcome. Most (92.3%) received levetiracetam for epilepsy; 323 (69.4%) as monotherapy and 142 (30.5%) as polytherapy. With three twin pregnancies, there were 468 outcomes-444 livebirths, 3 stillbirths, 19 miscarriages, and 2 terminations. Based on the MCM definition used by LEV-Registry, 46 infants among 444 livebirths had MCMs resulting in 10.4% (95% CI 7.7, 13.6) for overall prevalence, 9.4% (95% CI 6.4, 13.2) with monotherapy, and 12.6% (95% CI 7.5, 19.4) with polytherapy. When MCM reports were reviewed independently by staff at EURAP (International Registry of AEDs) and North American AED Pregnancy Registry according to their respective criteria, only 22 and 7 infants of the 46, respectively, were classified as having MCMs. CONCLUSION: The LEV-Registry Expert Panel did not find evidence suggestive of teratogenic association with prenatal exposure to levetiracetam. The substantial differences in which physical findings were considered MCMs highlight the major impact of pregnancy registry methodology on MCM prevalence estimates.

Peroxisome proliferator-activated receptor-alpha (PPARA) genetic polymorphisms and breast cancer risk: a Long Island ancillary study.

Peroxisome proliferator-activated receptor-alpha (PPARA) has been shown to increase fatty acid oxidation and decrease cytokine levels and has been implicated in insulin production. Genetic variants of PPARA have been associated with cardiovascular disease, obesity and type II diabetes mellitus. Although no research to date has investigated the possible link between PPARA and breast cancer, the function of this gene suggests that it could play a role in breast cancer development. Six PPARA polymorphisms were evaluated in association with incident breast cancer in a population-based case-control study (n = 1073 cases and n = 1112 controls) using unconditional logistic and multilevel regression and haplotype-based analyses. The odds of breast cancer were doubled among women with PPARA polymorphism rs4253760 (odds ratio = 1.97 for rare versus common homozygote alleles; 95% confidence interval: 1.14, 3.43). This association remained constant with the inclusion of all interrogated polymorphisms studied in hierarchical models. No additive interactions with body mass index or weight gain were present, but there was some evidence of interaction between PPARA variants and aspirin use, defined as use at least once per week for 6 months or longer. Fourteen haplotypes were imputed with frequencies >1% among postmenopausal women, but no statistically significant differences in haplotype frequencies between cases and controls were evident. Our results are the first to evaluate the relationship between PPARA and breast cancer incidence and suggest that replication in an independent cohort is warranted.