Supplement Individual Article: A Reappraisal of Fixed-Combination Halobetasol Propionate and Tazarotene for the Treatment of Psoriasis: Biological Underpinnings, Therapeutic Mechanisms, and Economic Considerations.

Psoriasis is a complex inflammatory disease, which can be triggered by the interplay among keratinocytes, various immune cells, and even dermal vascular endothelial cells. Understanding of the key players and cytokine/chemokine messengers involved in the initiation and maintenance of psoriasis has significantly evolved and led to numerous systemic biologic therapies targeting those specific components. These therapies, despite their successes, do not ubiquitously affect all pathogenic cellular pathways. They also carry their risks and may be contraindicated in certain patient populations. Therefore, other therapeutics are still necessary. Tazarotene, a decades-old topical retinoid, has been successfully used for treating cutaneous psoriasis. Its retinoid effect via binding to retinoic acid receptors (RAR)/retinoic X receptors (RXR) alters cellular gene expression of numerous pathogenic cells and leads to a long-standing maintenance effect despite discontinuation - a phenomenon known as remittance. Concurrent use of tazarotene with topical corticosteroids results in reduced incidence of treatment-related adverse events. A fixed-combination lotion containing halobetasol propionate (HP) and tazarotene (HP 0.01%/TAZ 0.045%, Duobrii, Ortho Dermatologics) was developed implementing polymeric emulsion technology that demonstrates efficacy in psoriasis while mitigating adverse events associated with each component alone as monotherapy. In this paper, we review the pathogenesis of psoriasis and illuminate the effect of tazarotene and HP on key cellular pathways. In addition, we review the clinical efficacy of fixed-combination HP 0.01%/TAZ 0.045% lotion in psoriasis as well as its long-term treatment maintenance, applicability in skin of color, and beneficial economic impact for patients and healthcare stakeholders. As HP 0.01%/TAZ 0.045% lotion is safe and exhibits excellent efficacy, it should be within the therapeutic toolbox for every psoriasis patient.J Drugs Dermatol. 2023;22:1(Suppl 1):s3-10.

In vivo multiphoton imaging for non-invasive time course assessment of retinoids effects on human skin.

BACKGROUND: In vivo multiphoton imaging and automatic 3D image processing tools provide quantitative information on human skin constituents. These multiphoton-based tools allowed evidencing retinoids epidermal effects in the occlusive patch test protocol developed for antiaging products screening. This study aimed at investigating their relevance for non-invasive, time course assessment of retinoids cutaneous effects under real-life conditions for one year. MATERIALS AND METHODS: Thirty women, 55-65 y, applied either retinol (RO 0.3%) or retinoic acid (RA 0.025%) on one forearm dorsal side versus a control product on the other forearm once a day for 1 year. In vivo multiphoton imaging was performed every three months, and biopsies were taken after 1 year. Epidermal thickness and dermal-epidermal junction undulation were estimated in 3D with multiphoton and in 2D with histology, whereas global melanin density and its z-epidermal distribution were estimated using 3D multiphoton image processing tools. RESULTS: Main results after one year were as follows: a) epidermal thickening with RO (+30%); b) slight increase in dermal-epidermal junction undulation with RO; c) slight decrease in 3D melanin density with RA; d) limitation of the melanin ascent observed with seasonality and time within supra-basal layers with both retinoids, using multiphoton 3D-melanin z-epidermal profile. CONCLUSIONS: With a novel 3D descriptor of melanin z-epidermal distribution, in vivo multiphoton imaging allows demonstrating that daily usage of retinoids counteracts aging by acting not only on epidermal morphology, but also on melanin that is shown to accumulate in the supra-basal layers with time.

Prescription patterns and costs of acne/rosacea medications in Medicare patients vary by prescriber specialty.

BACKGROUND: Prescription patterns for acne/rosacea medications have not been described in the Medicare population, and comparisons across specialties are lacking. OBJECTIVE: To describe the medications used for treating acne/rosacea in the Medicare population and evaluate differences in costs between specialties. METHODS: A cross-sectional study was performed of the 2008 and 2010 Centers for Medicare and Medicaid Services Prescription Drug Profiles, which contains 100% of Medicare part D claims. RESULTS: Topical antibiotics accounted for 63% of all prescriptions. Patients ≥65 years utilized more oral tetracycline-class antibiotics and less topical retinoids. Specialists prescribed brand name drugs for the most common topical retinoids and most common topical antibiotics more frequently than family medicine/internal medicine (FM/IM) physicians by 6%-7%. Topical retinoids prescribed by specialists were, on average, $18-$20 more in total cost and $2-$3 more in patient cost than the same types of prescriptions from FM/IM physicians per 30-day supply. Specialists (60%) and IM physicians (56%) prescribed over twice the rate of branded doxycycline than FM doctors did (27%). The total and patient costs for tetracycline-class antibiotics were higher from specialists ($18 and $4 more, respectively) and IM physicians ($3 and $1 more, respectively) than they were from FM physicians. LIMITATIONS: The data might contain rare prescriptions used for conditions other than acne/rosacea, and suppression algorithms might underestimate the number of specialist brand name prescriptions. CONCLUSION: Costs of prescriptions for acne/rosacea from specialists are higher than those from primary care physicians and could be reduced by choosing generic and less expensive options.

Cost-effectiveness analysis of using dermatologists versus pediatricians to treat mild to moderate acne.

OBJECTIVE: To assess the cost-effectiveness from the payer perspective of using dermatologists versus pediatricians to treat acne in adolescents ages 10-18. METHODS: A Markov model was constructed to explore outcomes over a 2-year period from the US private payer perspective. Patients ages 10-18 with acne entered the model under the "dermatologist"and "pediatrician" conditions. In each 3-month cycle,each modeled patient received topical retinoids,benzoyl peroxide (BP), antibiotics, or no treatment,and could progress to an acne-free state or remain in an acne state. RESULTS: The average patient spent42.3% of the time in acne-free states under the dermatologist condition and 28.0% of the time in acne-free states under the pediatrician condition.The cohort of 1000 patients experienced 1900 total quality-adjusted life years (QALYs) at a cost of $2.33 million in the dermatologist condition and 1883 total QALYs at a cost of $1.62 million in the pediatrician condition, yielding an ICER of $40,000/QALY. Most sensitivity analyses confirmed the base case results. CONCLUSION: Dermatologist treatment appears cost-effective related to producing additional QALYs at a cost of less than $100,000 per QALY gained. Health plans should consider creating incentives to direct enrollees to dermatologists for acne treatment.

Phototherapy and photochemotherapy for psoriasis.

Phototherapy is a first-line option for the treatment of moderate to severe psoriasis. Systematic reviews indicate near comparable efficacy of the different forms of phototherapy. Localized phototherapy can be an adjunctive treatment of recalcitrant plaques during systemic treatment of psoriasis. More than 200 psoralen-UV-A therapy treatment sessions is associated with an increased risk of keratinocytic cancers, whereas no increased risk has been demonstrated for narrow-band UV-B therapy. The mechanism of action of phototherapy in psoriasis is via inhibition of keratinocyte proliferation; induction of apoptosis in keratinocytes, dendritic, and T cells; and inhibition of Th1 and Th17 pathways, but activation of Th2.

Assessment of the efficacy and tolerance of a new combination of retinoids and depigmenting agents in the treatment of melasma.

BACKGROUND: Melasma is a dermatosis with significant repercussions on patients' quality of life, and there is currently no standard treatment. Hydroquinone is deemed the treatment of choice, but its safety has been questioned in certain cases. AIMS: To determine the efficacy and safety of a new combination of retinoids in the improvement of melasma. PATIENTS/METHODS: Prospective, double-blind, vehicle-controlled, and randomized study in 30 patients with melasma. The product was applied on one side of the face and the vehicle on the other, twice daily during 3 months. Standardized photographs were taken using RBX technology on the three visits (basal, at one and a half months and at 3 months). The main variable to determine the efficacy was the improvement of the hemifacial Melasma Area Severity Index (MASI). Other variables were determined such as improvement perceived by the investigator, improvement perceived by the patient, impact on quality of life or side effects. RESULTS: The MASI improvement at 3 months of treatment was significant on the treated side vs. the vehicle side, reaching an improvement of 70%, which is comparable to the percentage of improvement described with hydroquinone. No notable side effects were detected, in spite of a significant percentage of patients included in the study citing a history that could be compatible with sensitive skin. CONCLUSIONS: This new combination of retinoids and depigmenting agents proved to be effective and safe in the treatment of melasma.

Summary of the Dutch S3-guidelines on the treatment of psoriasis 2011. Dutch Society of Dermatology and Venereology.

This document provides a summary of the Dutch S3-guidelines on the treatment of psoriasis. These guidelines were finalized in December 2011 and contain unique chapters on the treatment of psoriasis of the face and flexures, childhood psoriasis as well as the patient's perspective on treatment. They also cover the topical treatment of psoriasis, photo(chemo)therapy, conventional systemic therapy and biological therapy.

Cost-of-illness in psoriasis: comparing inpatient and outpatient therapy.

Treatment modalities of chronic plaque psoriasis have dramatically changed over the past ten years with a still continuing shift from inpatient to outpatient treatment. This development is mainly caused by outpatient availability of highly efficient and relatively well-tolerated systemic treatments, in particular BioLogicals. In addition, inpatient treatment is time- and cost-intense, conflicting with the actual burst of health expenses and with patient preferences. Nevertheless, inpatient treatment with dithranol and UV light still is a major mainstay of psoriasis treatment in Germany. The current study aims at comparing the total costs of inpatient treatment and outpatient follow-up to mere outpatient therapy with different modalities (topical treatment, phototherapy, classic systemic therapy or BioLogicals) over a period of 12 months. To this end, a retrospective cost-of-illness study was conducted on 120 patients treated at the University Medical Centre Mannheim between 2005 and 2006. Inpatient therapy caused significantly higher direct medical, indirect and total annual costs than outpatient treatment (13,042 € versus 2,984 €). Its strong influence on cost levels was confirmed by regression analysis, with total costs rising by 104.3% in case of inpatient treatment. Patients receiving BioLogicals produced the overall highest costs, whereas outpatient treatment with classic systemic antipsoriatic medications was less cost-intense than other alternatives.

Psoriasis treatments by payment type in the US outpatient office setting.

BACKGROUND: Many factors, including patients' methods of payment, may influence psoriasis treatment decisions. OBJECTIVE: To characterize psoriasis treatments by patients' types of payment in the US outpatient office setting. METHODS: Using the National Ambulatory Medical Care Survey (NAMCS), a large survey that samples outpatient office visits to US non-federally funded physicians, visits linked with sole diagnoses for psoriasis (ICD-9-CM: 696.1) were identified. There were 545 unweighted records. The types and number of treatments prescribed at these visits were categorized by expected major payment type to be used for the visit. RESULTS: Mainstay psoriasis therapies such as vitamin D analogs and clobetasol were prescribed regardless of payment type. Retinoids were also within the most frequently prescribed psoriasis medications for all payment types, however they were less frequently prescribed than vitamin D analogs. Payment type did not have a significant effect on the number of medications prescribed at psoriasis visits. LIMITATIONS: Data on treatment adherence and filling of prescriptions are not included in the NAMCS database. CONCLUSION: Prescribing patterns for psoriasis medications are similar across payment type. Additional factors appear to modulate therapy choice for patients with psoriasis.

Medication adherence, healthcare costs and utilization associated with acne drugs in Medicaid enrollees with acne vulgaris.

BACKGROUND: Acne vulgaris is a common chronic disease that may require long-term treatment. Medication adherence is critical to acne management; non-adherence is a common reason for treatment failure and can lead to poor quality of life. OBJECTIVE: The aim of the study was to examine medication adherence, healthcare costs, and utilization associated with acne drugs among acne patients in the USA. METHODS: This was a retrospective cohort study from January 2004 to December 2007 using the Marketscan Medicaid Database, a national healthcare claims database. The study followed acne patients aged 0-64 years for 90 days after the first acne drug prescription to measure acne medication adherence, acne-related outpatient visits, and total acne-related healthcare costs. Adherence was measured among different acne drug classes using medication possession ratio (MPR). Multivariate regression analyses were conducted to assess the outcomes. RESULTS: The study included 24,438 eligible patients, of whom 89.39 % were under 18 years old. The average adherence rate to acne drugs (MPR) was 0.34, and only 11.74 % of the patients were adherent (MPR ≥0.80). Patients with drug refills had a higher adherence rate (MPR = 0.74) than who those without refills (MPR = 0.27). Factors significantly associated with adherence were age, comorbidity, gender, number of drug refills and number of drug classes used. Patients were more adherent to oral retinoids than any other acne drug classes (MPR = 0.78, 57 % adherent). Patients were less adherent to oral antibiotics (MPR = 0.21) and topical retinoids (MPR = 0.31). After controlling for medication use behavior, the use of oral antibiotics decreased the number of acne-related outpatient visits by 50.9 % (p < 0.001) and lowered acne-related total costs by 51.7 % (p < 0.001). CONCLUSION: Medication non-adherence is generally prevalent among young acne patients enrolled in Medicaid. The combination of a topical retinoid and an antibiotic agent may be a good choice given their associated healthcare outcomes and costs. However, adherence to these agents is not satisfactory. Therefore, developing specific strategies to improve adherence to these drugs among teenage acne patients is warranted.

Effects of topical retinoid therapy on acne lesions: a psychometric assessment.

Topical retinoids are believed to increase inflammatory lesions within the first few weeks of treatment. We evaluated data from several clinical trials for evidence of a signal for retinoid aggravation of inflammatory lesions using a psychometric method and the proportion of participants who demonstrated varying degrees of increased lesion counts. We first determined the validity of a psychometric method based on Stevens' power law called the visual logarithmic scale (VLS) used to evaluate the perceived changes in inflammatory lesions. There was concurrence between the VLS model and the dermatologists' visual assessment of a flare in 80.0% (32/40) of participants (P=.0258). A subsequent analysis was performed using data from clinical trials to assess the occurrence of flares using the VLS model or percentage-based definitions (5%, 10%, or 20% increase) following the first week of treatment with various adapalene gel formulations. In this analysis, no evidence of worsening or a flare was seen by either the VLS model or percentage-based definitions. The VLS model is valid for assessing the changes in acne severity. Topical retinoid treatment was not associated with a flare as measured by either the VLS model or the proportion of participants who showed an increase in inflammatory lesions.

Acitretin for the treatment of psoriasis: an assessment of national trends.

BACKGROUND: Combination therapy is a common and appropriate treatment strategy for moderate-to-severe psoriasis, as it provides for enhanced efficacy and decreased toxicity compared to the use of a single agent. Acitretin is an effective oral retinoid for psoriasis that seems to find its greatest value when complemented by other topical and systemic treatments. OBJECTIVE: The primary aim of this study is to assess the use of acitretin in combination with other treatments for psoriasis. METHODS: We assessed the use of acitretin for the treatment of psoriasis using nationally representative survey data from the National Ambulatory Medical Care Survey (NAMCS). RESULTS: Among visits where acitretin was listed in the NAMCS, other psoriasis medications were co-prescribed in 62 percent of visits. The co-prescribed medications included topical corticosteroids (51%), calcipotriene (31%), biologics (6%), cyclosporine (5%), methotrexate (5%) and tazarotene (2%). CONCLUSION: The use of acitretin in combination with other psoriasis treatments, particularly topical corticosteroids and calcipotriene, is a common practice. Acitretin is co-prescribed with the biologics, likely because of the relative lack of overlapping effects on immune function. The immune-sparing method of action of acitretin makes combination treatment with the systemic agents an attractive treatment option, especially in patients where further immunosuppression is unwarranted.

High prevalence of potential drug-drug interactions for psoriasis patients prescribed methotrexate or cyclosporine for psoriasis: associated clinical and economic outcomes in real-world practice.

BACKGROUND: Methotrexate (MTX) and cyclosporine (CYC) may adversely interact with common medications in patients with psoriasis. OBJECTIVE: Our purpose was to investigate the prevalence and outcomes of MTX/CYC polypharmacy. METHODS: We evaluated rates of events that may be associated with drug-related toxicity, health care resource utilization and costs for patients with psoriasis in the Ingenix(R) Impact National Managed Care Database (1999-2007) who were exposed or not exposed to potential drug-drug interactions. RESULTS: Among 4,583 (57.6%) exposed and 3,372 (42.4%) nonexposed patients, nonsteroidal anti-inflammatory drugs and antibiotics were the most common drugs with potential interactions. The exposed patients had significantly greater risks of developing renal [adjusted odds ratio (OR): 2.58; p = 0.0145], gastrointestinal (OR: 1.36; p = 0.0197) and pulmonary events (OR: 1.20; p = 0.0470), and significantly greater health care resource utilization (e.g. OR for inpatient and emergency department visits: 1.47; p < 0.0001) and costs (adjusted incremental cost: USD 1,722; p < 0.0001). CONCLUSIONS: MTX/CYC polypharmacy is prevalent in patients with psoriasis and associated with significant risks.

Prescribing patterns for topical retinoids: analyses of 15 years of data from the national ambulatory medical care survey.

OBJECTIVE: To examine the prescribing patterns of topical retinoids in the United States. METHODS: A retrospective, cross-sectional study was employed. Data from the National Ambulatory Medical Care Survey (1990-2004) were used. The impact of patient diagnosis of acne and other covariates on the probability of getting a retinoid prescription was examined using weighted multivariate logistic regression models. RESULTS: Among the national cohort of patients aged 10 years and older (number of patient visits = 11.7 billion), 41.5 million patients received a topical retinoid prescription. In the retinoid cohort, more than 70% of patients had a diagnosis for acne vulgaris. Diagnosis of acne vulgaris was the strongest predictor of getting a retinoid prescription after controlling for other covariates (OR: 43.39; 95% CI: 32.44, 58.02). CONCLUSIONS: Requiring prior authorization for topical retinoids for all age groups seems unwarranted and may not be cost-beneficial for the managed care organizations based on these and previous findings.

Predictors of healthcare outcomes and costs related to medication use in patients with acne in the United States.

This study investigated the relationship among health status, costs linked with the treatment of acne in the United States, and other aspects related to medication use. The US Medical Expenditure Panel Survey (MEPS) database was analyzed for a cohort of people with acne. This cross-sectional study obtained costs, demographics, healthcare service utilization, and clinical patient variables from the MEPS database. The EuroQol Group's EQ-5D scores available in MEPS were used for health status information. Multivariate weighted analysis was performed for data for approximately 5 million patients (weighted sample size). Nearly 70% of the patients used some type of medication for acne. Acne-related medication accounted for approximately 36% of the total acne-related annual healthcare costs, with an average of 2 annual acne prescription refills per patient. Increased number of refills of acne-related medications was associated with an improvement in health status (P<.05). Increased physician office-based visits were the only predictors of higher acne-related annual healthcare costs (P<.01). Adherence to acne medications is an important component of better health status. Pharmacologic treatment of acne does not significantly add to acne-related annual healthcare costs.

The clinical impact of vehicle technology using a patented formulation of benzoyl peroxide 5%/clindamycin 1% gel: comparative assessments of skin tolerability and evaluation of combination use with a topical retinoid.

A major challenge encountered in clinical practice in patients with acne vulgaris is irritation related to topical medications used for treatment. Advances in vehicle technology have improved formulations containing active ingredients known to produce irritation in some patients, such as benzoyl peroxide (BP) and topical retinoids. Clinical studies, including combination therapy studies have demonstrated that certain additives, such as silicates and specific humectants, reduce irritation by maintaining barrier integrity. A patented gel formulation of BP 5%/clindamycin phosphate 1% (clindamycin) containing dimethicone and glycerin has been studied both as a monotherapy and in combination with topical retinoid use. This article evaluates specific vehicle additives included in this gel formulation and explains their role in reducing irritation. Data from clinical trials utilizing this technology in acne management are also reviewed.

Cost-effectiveness of moderate-to-severe psoriasis treatment.

Psoriasis is a common, chronic inflammatory disease that can cause as much disability as cancer, diabetes or other major medical illnesses. Traditional therapies for treating moderate-to-severe psoriasis include phototherapy, methotrexate, oral retinoids and ciclosporin. New biological treatments provide further therapeutic options, but add to the already considerable cost of managing psoriasis. Expert panels have published guidelines for the use of biological agents in managing moderate-to-severe psoriasis; however, few if any of these guidelines appropriately consider the cost-effectiveness of treatment options. When considering cost-effectiveness in addition to safety and efficacy, ultraviolet Type B phototherapy seems to be the best first-line agent for the control of moderate-to-severe psoriasis, despite a small potential for cumulative toxicity. The biologics should be considered as second-line agents alongside the traditional systemic treatments when phototherapy proves to be ineffective or is otherwise contraindicated, such as in patients with psoriatic arthritis.

Treatment of cutaneous T-cell lymphoma/mycosis fungoides.

The cause of mycosis fungoides is unknown and, with the possible exception of very early stage disease, no cure is available. Fortunately, patients with MF have a number of therapeutic options and partial and complete remissions are achievable. Because it is not curable, the burden for patients with this disease involves the need for lifelong therapy and monitoring, and meticulous skin care. Despite its indolent nature in most individuals, the disease has a tremendous psychological impact, not only because of the visible nature of the skin lesions, but also due to the rarity of the disease and its chronicity. Knowledge of this disease, therapeutic options, and expectations of therapy will enhance care of patients afflicted with mycosis fungoides. Ongoing research provides hope that in the future, therapy to induce long-lasting remission, or even cure, will become available. Since the submission of this manuscript, vorinostat (Zolinza), an orally administered histone inhibitor, has been FDA approved for treating skin manifestations in patients with CTCL.