Treatment Patterns and Negative Health Outcomes in Palmoplantar Pustulosis Patients in Germany and the US.

INTRODUCTION: Limited information exists on the epidemiology, treatment, and burden of palmoplantar pustulosis (PPP) and defining the optimal course of treatment remains challenging without approved targeted treatments in most countries. Here, we describe the clinical and demographic characteristics, treatments received, and negative health outcomes experienced among patients with PPP in the United States (US) and Germany. METHODS: Retrospective cohort study between 2016 and 2021 using data from the US Merative™ MarketScan® Research Database and IQVIA™ German Disease Analyzer. Adult patients with PPP (ICD-10-CM L40.3) were followed from the date of their first qualifying PPP diagnosis and continued until the earlier of disenrollment or end date of database, during which treatment patterns and incidence rates of negative health outcomes were assessed. Treatment patterns included adherence, non-persistence, discontinuation, re-initiation, switching, and combination therapy. RESULTS: The prevalence of PPP was 0.005% and 0.065% in the MarketScan database and German Disease Analyzer, respectively, with 1629 and 3866 patients meeting the inclusion criteria. Most patients were female (71.3%, 67.8%), with mean (SD) age of 54.1 (11.7) and 56.9 (14.3) years, respectively. One year post index, most patients received topical treatment (77.4%, 65.3%), but non-persistence and discontinuation were high. Oral and biologic treatments displayed higher levels of adherence, particularly apremilast and tofacitinib among oral treatments and TNF inhibitors and IL-23 inhibitors among biologics. Rates of negative health outcomes were higher among patients not receiving treatment post-index compared with those receiving treatment post-index across both databases, regardless of prior treatment history. CONCLUSIONS: Establishing treatment guidelines remains an unmet need for patients with PPP and could improve quality of life by reducing the occurrence of negative health outcomes. The findings from this study may provide insight into the effectiveness of current treatment options for patients with PPP and can be leveraged to support the development of treatment guidelines.

Redefining Disease Severity with Special Area Involvement and Reflecting on Treatment Patterns in a Real-World Psoriasis Population.

BACKGROUND: The International Psoriasis Council (IPC) recommends an approach that considers body surface area (BSA), involvement in special areas, and treatment history for classifying patients as candidates for topical or systemic treatment. This study aimed to quantify the burden of psoriasis by describing BSA distribution, special area involvement, and treatments in a real-world population. METHODS: This retrospective cohort study included patients with psoriasis from the Optum® deidentified Electronic Health Records database with a BSA value (< 3%, 3-10%, and > 10%) recorded between 1 March 2014 and 1 September 2020. Treatments and special area involvement (face, scalp, palms/soles, nails, genitals) were identified within 90 days of the BSA value and stratified by BSA category. RESULTS: Among eligible patients (N = 5120), mean age was 51.4 years and 49.3% were women. The majority of patients (78.9%) were treated with any topical. Proportions of patients with BSA < 3%, 3-10%, and > 10% were 23.4%, 41.9%, and 34.6%, respectively; proportions with 0, 1, and 2+ special areas were 21.6%, 31.6%, and 45.7%, respectively; and 44.4%, 45.7%, and 45.9% of patients with BSA < 3%, 3-10%, and > 10%, respectively, had 2+ special areas. CONCLUSION: The IPC classification can likely identify many more patients who may benefit from systemic therapy than BSA alone.

Apremilast Adherence and Persistence in Patients with Psoriasis and Psoriatic Arthritis in the Telehealth Setting Versus the In-person Setting During the COVID-19 Pandemic.

INTRODUCTION: Limited access to healthcare during the COVID-19 pandemic prompted patients to seek care using telehealth. In this study, we assessed whether treatment patterns differed for patients with psoriasis (PsO) or psoriatic arthritis (PsA) initiating apremilast by either a telehealth or an in-person visit. METHODS: We estimated adherence and persistence among US patients in the Merative© MarketScan© Commercial and Supplemental Medicare Databases who newly initiated apremilast between April and June 2020, categorized by the type of visit (telehealth or in-person) when apremilast was first prescribed. Adherence was defined as the proportion of days covered (PDC), with PDC ≥ 0.80 considered to indicate high adherence. Persistence was defined as having apremilast available to take without a 60-day gap during follow-up. Factors associated with high adherence and persistence were estimated with logistic and Cox regression. RESULTS: Among apremilast initiators (n = 505), the mean age was 47.6 years, 57.8% were female, and the majority had PsO (79.6%). Telehealth index visits were more likely among patients residing in Northeast USA (odds ratio [OR] 3.31, 95% confidence interval [CI] 1.63-6.71) and Western USA (OR 2.52, 95% CI 1.07-5.93]), those with a prescribing rheumatologist (OR 2.27, 95% CI 1.10-4.68), and those with any baseline telehealth visit (OR 1.91, 85% CI 1.20-3.04). Those initiating apremilast with a telehealth visit (n = 141) had similar mean PDC to those initiating apremilast with an in-person visit (n = 364) (0.695 vs. 0.728; p = 0.272). At the end of the 6-month follow-up, 54.3% of the overall population had high adherence (PDC ≥ 0.80) and 65.1% were persistent. After adjusting for potential confounders, patients initiating apremilast via telehealth had similar full adherence (OR 0.80, 95% CI 0.52-1.21) and persistence as those initiating apremilast in-person. CONCLUSION: Patients with PsO and patients with PsA initiating apremilast via telehealth or in-person during the COVID-19 pandemic had similar medication adherence and persistence during the 6-month follow-up period. These data suggest that patients initiating apremilast can be as effectively managed with telehealth visits as with in-person visits.

Characteristics and outcomes of patients with psoriasis treated with apremilast in the real-world in Austria - results the APPRECIATE study.

Background: Apremilast, an oral phosphodiesterase 4 inhibitor, is approved in the European Union for the treatment of moderate-to-severe chronic plaque psoriasis in adult patients refractory or contraindicated to or intolerant of other systemic therapies. Objectives: The APPRECIATE study assessed apremilast use in real-world practice and its clinical value to physicians and patients. APPRECIATE was a multinational, observational, retrospective, cross-sectional study. Methods: Apremilast effectiveness at 6 (±1) months was assessed on the basis of psoriasis severity and health-related quality-of-life scores and treatment satisfaction using physician/patient-reported outcomes, respectively. We report the Austrian cohort of 72 patients. Results: At 6 (±1) months, three-quarters of patients remained on apremilast, while physicians and patients reported treatment benefits across all psoriasis symptoms and manifestations. Of patients, the majority were satisfied with their treatment and achieved treatment goals considered most relevant. Patients' and physicians' perceptions of treatment effectiveness were aligned, and health-related quality-of-life scores indicated an improvement in the majority of patients. Apremilast tolerability was consistent with the known safety profile. Conclusions: Among psoriasis patients receiving apremilast in Austria, improvement in clinical outcomes were observed and satisfaction with apremilast treatment among patients and physicians was high. Registration: ClinicalTrials.gov NCT02740218.

Safety of Apremilast in Patients with Psoriasis and Psoriatic Arthritis: Findings from the UK Clinical Practice Research Datalink.

INTRODUCTION: This real-world safety analysis was requested by the European Medicines Agency following approval of apremilast, an oral treatment for psoriasis or psoriatic arthritis. OBJECTIVE: We aimed to compare incidence rates of adverse events of special interest identified a priori, in patients receiving apremilast with those receiving other systemic treatments for psoriasis or psoriatic arthritis. METHODS: This 5-year cohort study was conducted in Clinical Practice Research Datalink GOLD between January 2015 and June 2020. Incidence rates of adverse events of special interest were estimated for four matched cohorts: apremilast-exposed and three matched non-apremilast cohorts (oral only, injectable only, and oral and injectable psoriasis or psoriatic arthritis treatments). RESULTS: The apremilast-exposed cohort included 341 patients and the three non-apremilast cohorts included 4981 patients. There were no incident cases of vasculitis, hematologic malignancy, non-melanoma skin malignancy, treated depression, treated anxiety, or suicidal behaviors in the apremilast-exposed cohort during the follow-up. Similar incidence rates of all-cause mortality, major adverse cardiac events, tachyarrhythmias, and solid malignancies were recorded in the apremilast and non-apremilast cohorts. The incidence rate (95% confidence interval) per 1000 person-years of opportunistic and serious infections in the apremilast-exposed cohort (64 [40-102])) was similar to incidence rates in the oral (50 [42-60]) and oral and injectable non-apremilast cohorts (57 [47-69]), while the incidence rates were lower in the injectable treatment-only cohort (20 [10-41]). Limitations include small numbers of apremilast-exposed patients and potential exposure misclassification partly owing to missing information on biologic and other specialty treatment use. CONCLUSIONS: No new apremilast safety signals were identified in this study. These results provide evidence that the long-term safety of apremilast in psoriasis and psoriatic arthritis in a real-world setting is comparable to that reported in clinical trials.

Real-World Experience of Patient-Relevant Benefits and Treatment Satisfaction with Apremilast in Patients with Psoriasis: An Analysis of the APPRECIATE Study.

INTRODUCTION: In the real-world APPRECIATE study (NCT02740218), most patients with psoriasis demonstrated notable improvements on disease severity measures and reported clinically meaningful treatment benefits with apremilast. OBJECTIVE: We aim to further describe patient-relevant needs and benefits and patient satisfaction with apremilast, including subgroup analyses based on patient characteristics. METHODS: APPRECIATE, a multinational, retrospective, cross-sectional study, enrolled patients with chronic plaque psoriasis who started apremilast according to the European label. Patient Benefit Index (PBI; range 0 (no patient-relevant benefit) to 4 (maximum patient-relevant benefit), global PBI score ≥ 1 indicating minimum patient-relevant benefit and ≥ 3 indicating high benefit) and nine-item Treatment Satisfaction Questionnaire for Medication (TSQM-9; range 0-100) were assessed 6 (± 1) months after apremilast initiation and summarized descriptively. Relationships between global PBI and TSQM-9 assessments were analyzed by Pearson correlations. RESULTS: Of 480 enrolled patients, 347 (72.3%) had remained on apremilast at 6 (± 1) months; 90.9% (300/330) achieved global PBI score ≥ 1. Mean (standard deviation) global PBI score was 2.8 (1.2). Higher achievement of global PBI score ≥ 3 was observed in patients with no prior treatments (61.1% (22/36)) or prior phototherapy (64.6% (42/65)) versus prior conventional systemic (54.4% (100/184)) or biologic (38.6% (17/44)) treatment. Strong correlations were observed between the global PBI score and the TSQM-9 global satisfaction and effectiveness subscale scores. CONCLUSION: Patients continuing apremilast for 6 (± 1) months in APPRECIATE reported patient-relevant treatment benefits. Findings suggest that receiving apremilast earlier versus later in treatment management is consistent with greater improvements in patient-relevant treatment outcomes.

Enhancing the reliability and throughput of neurosphere culture on hydrogel microwell arrays.

The neurosphere assay is the standard retrospective assay to test the self-renewal capability and multipotency of neural stem cells (NSCs) in vitro. However, it has recently become clear that not all neurospheres are derived from a NSC and that on conventional cell culture substrates, neurosphere motility may cause frequent neurosphere "merging" [Nat Methods 2006;3:801-806; Stem Cells 2007;25:871-874]. Combining biomimetic hydrogel matrix technology with microengineering, we developed a microwell array platform on which NSC fate and neurosphere formation can be unequivocally attributed to a single founding cell. Using time-lapse microscopy and retrospective immunostaining, the fate of several hundred single NSCs was quantified. Compared with conventional neurosphere culture methods on plastic dishes, we detected a more than 100% increase in single NSC viability on soft hydrogels. Effective confinement of single proliferating cells to microwells led to neurosphere formation of vastly different sizes, a high percentage of which showed stem cell phenotypes after one week in culture. The reliability and increased throughput of this platform should help to better elucidate the function of sphere-forming stem/progenitor cells independent of their proliferation dynamics. Disclosure of potential conflicts of interest is found at the end of this article.

Conventional protein kinase C isoforms mediate neuroprotection induced by phorbol ester and estrogen.

Rapid signal transduction pathways play a prominent role in mediating neuroprotective actions of estrogen in the CNS. We have previously shown that estrogen-induced neuroprotection of primary cerebrocortical neurons from beta-amyloid peptide (Abeta) toxicity depends on activation of protein kinase C (PKC). PKC activation with phorbol-12-myristate-13-acetate (PMA) also provides neuroprotection in this paradigm. Because the PKC family includes several isoforms that have opposing roles in regulating cell survival, we sought to identify which PKC isoforms contribute to neuroprotection induced by PMA and estrogen. We detected protein expression of multiple PKC isoforms in primary neuron cultures, including conventional (alpha, betaI, betaII), novel (delta, epsilon, theta) and atypical (zeta, iota/lambda) PKC. Using a panel of isoform-specific peptide inhibitors and activators, we find that novel and atypical PKC isoforms do not participate in the mechanism of either PMA or estrogen neuroprotection. In contrast, a selective peptide activator of conventional PKC isoforms provides dose-dependent neuroprotection against Abeta toxicity. In addition, peptide inhibitors of conventional, betaI, or betaII PKC isoforms significantly reduce protection afforded by PMA or 17beta-estradiol. Taken together, these data provide evidence that conventional PKC isoforms mediate phorbol ester and estrogen neuroprotection of cultured neurons challenged by Abeta toxicity.

Neuroprotective properties of selective estrogen receptor agonists in cultured neurons.

To investigate the role of the estrogen receptor (ER) in mediating neuroprotection, the neuroprotective profiles of selective ER agonists for ERalpha and ERbeta, propylpyrazole triol (PPT) and 2,3-bis(4-hydroxyphenyl) proprionitrile (DPN), respectively, were compared to that of 17beta-estradiol and 17alpha-estradiol in primary neuron cultures challenged by beta-amyloid toxicity. All compounds were found to be neuroprotective in an ER-dependent manner. However, protein kinase C (PKC) inhibition completely blocked the protective effects of 17beta-estradiol and 17alpha-estradiol and significantly attenuated PPT but not DPN neuroprotection. These data indicate that estrogen-mediated neuroprotection likely involves a variety of mechanisms and that protection due to PKC activation is more likely due to ERalpha compared to ERbeta.

The synthetic estrogen 4-estren-3 alpha,17 beta-diol (estren) induces estrogen-like neuroprotection.

Estrogen has demonstrated neuroprotective properties, which may underlie the observed preventive effect of estrogen-based hormone therapy (HT) against the development of neurodegenerative disorders such as Alzheimer's disease. Deleterious side effects of HT have increased efforts to develop safer compounds that selectively reproduce beneficial estrogen actions. Recently, 4-estren-3 alpha,17 beta-diol (estren) was identified as having estrogen agonist properties in bone, without significantly stimulating growth of reproductive tissues. Here, we examined whether estren parallels the neuroprotective actions of estrogen against beta-amyloid (A beta) in cultured cerebrocortical neurons. Estren increased neuronal viability to a similar extent to that observed with 17 beta-estradiol (E2) and 17 alpha-estradiol. As we previously reported for E2, estren rapidly increased PKC activity, and PKC inhibition prevented estren neuroprotection. In contrast, the estrogen receptor antagonist ICI 182,780 blocked E2, but not estren neuroprotection. Our results indicate that estren-induced activation of rapid cell signaling pathways protects cultured neurons from A beta toxicity.

Estrogen activates protein kinase C in neurons: role in neuroprotection.

It has been previously demonstrated that estrogen can protect neurons from a variety of insults, including beta-amyloid (Abeta). Recent studies have shown that estrogen can rapidly modulate intracellular signaling pathways involved in cell survival. In particular, estrogen activates protein kinase C (PKC) in a variety of cell types. This enzyme plays a key role in many cellular events, including regulation of apoptosis. In this study, we show that 17beta-estradiol (E2) rapidly increases PKC activity in primary cultures of rat cerebrocortical neurons. A 1 h pre-treatment with E2 or phorbol-12-myristate-13-acetate (PMA), a potent activator of PKC, protects neurons against Abeta toxicity. Protection afforded by both PMA and E2 is blocked by pharmacological inhibitors of PKC. Further, depletion of PKC levels resulting from prolonged PMA exposure prevents subsequent E2 or PMA protection. Our results indicate that E2 activates PKC in neurons, and that PKC activation is an important step in estrogen protection against Abeta. These data provide new understanding into the mechanism(s) underlying estrogen neuroprotection, an action with therapeutic relevance to Alzheimer's disease and other age-related neurodegenerative disorders.