A multinational assessment of work-related productivity loss and indirect costs from a survey of patients with psoriasis.

BACKGROUND: Total work productivity loss (WPL) and associated indirect costs contribute to the economic burden of psoriasis. OBJECTIVES: To estimate total WPL and related indirect costs, and identify predictors of WPL associated with psoriasis severity in France, Germany, Spain, the U.K. and Italy (EU5) and the U.S.A. METHODS: Data from the 2015 Adelphi Real World Psoriasis Disease Specific Programme, analysed for absenteeism, presenteeism and total WPL, were quantified (0-100%) from participants who completed the Work Productivity and Activity Impairment (WPAI) instrument. These measures were converted to indirect costs using the human capital method. Univariate and multivariate statistical analyses controlling for patient demographic and clinical characteristics were conducted. RESULTS: Of the 936 respondents (29·6% U.S.A., 70·4% EU5) who completed the WPAI, 32·6%, 40·7% and 26·6% had mild [body surface area (BSA) 0-2%], moderate (BSA 3-10%) and severe (BSA > 10%) psoriasis, respectively. Average age, Dermatology Life Quality Index (DLQI) score and BSA were, respectively, 42·4 years, 5·1 and 9·6%; and 37·2% of respondents were female. Mean percentages of total WPL for respondents with mild, moderate and severe psoriasis were 10·1%, 18·9% and 29·4%, respectively. Presenteeism contributed considerably more to total WPL than did absenteeism across all countries and disease severity classes. Mean annual indirect costs per patient due to WPL ranged from 3742 U.S. dollars in Spain to 9591 U.S. dollars in the U.S.A. Multivariate regression showed that a one-unit increase in DLQI score increases total WPL by 1·8% (P < 0·001). CONCLUSIONS: WPL increased progressively with increasing DLQI scores and BSA, confirming the relationship between psoriasis severity and its economic burden. What's already known about this topic? The economic burden of psoriasis is exceptionally high given the high prevalence and lifelong nature of the condition. Several studies have attempted to assess the overall economic burden of psoriasis but there is a lack of comparative data from different countries, and issues around inconsistent methodologies, including statistical analyses. Total work productivity loss (WPL) and associated indirect costs are believed to contribute to the economic burden of psoriasis. What does this study add? This study measured total WPL and indirect costs via the same method and at the same time point in the U.S.A., France, Germany, Spain, U.K. and Italy. Total WPL increased progressively with psoriasis disease severity. Disease severity and Dermatology Life Quality Index scores significantly correlated with WPL after controlling for patient demographic and clinical characteristics. The U.S.A. had the highest annual mean indirect costs associated with total WPL. Linked Comment: Drabo et al. Br J Dermatol 2020; 183:420-421.

Extension of ustekinumab maintenance dosing interval in moderate-to-severe psoriasis: results of a phase IIIb, randomized, double-blinded, active-controlled, multicentre study (PSTELLAR).

BACKGROUND: Phase III studies showed that some patients maintained response for ≥ 6 months following ustekinumab discontinuation. OBJECTIVES: To assess clinical responses with extended ustekinumab maintenance dosing intervals. METHODS: Adults with moderate-to-severe plaque psoriasis received ustekinumab at weeks 0, 4 and 16 during open-label treatment. Patients achieving a week-28 Physician's Global Assessment (PGA) score of cleared/minimal (PGA = 0/1) were randomized 1 : 4 to group 1 [approved every 12 weeks (q12 wk) maintenance] or group 2 (q12-24 wk; response-based dosing determined by time to loss of PGA = 0/1). Key end points included the number of visits with PGA = 0/1 (primary end point) and ≥ 75% improvement in Psoriasis Area and Severity Index (PASI 75) between weeks 88 and 112, and PGA/PASI responses between weeks 28 and 112. RESULTS: Overall, 378 patients achieved PGA = 0/1 at week 28 and were randomized to group 1 (n = 76) or group 2 (n = 302). Patients in group 1 had numerically greater mean numbers of visits with PGA = 0/1 than group 2 and also with PASI 75 from week 88 to 112. A higher proportion of patients in group 1 (55%) than group 2 (39%) had PGA = 0/1 at all seven visits from week 88 to 112. Maintenance of response was observed with dose-interval extension beyond q12 wk in a subset of patients. Extending the dosing interval did not affect antibody development or safety. CONCLUSIONS: Efficacy was better maintained among week-28 PGA responders randomized to continue q12 wk ustekinumab vs. extending maintenance dosing based on clinical response, although some patients maintained high levels of efficacy with up to q24 wk dosing.

Drug survival of biologic therapy in a large, disease-based registry of patients with psoriasis: results from the Psoriasis Longitudinal Assessment and Registry (PSOLAR).

BACKGROUND: Drug survival is a marker for treatment sustainability in chronic diseases such as psoriasis. OBJECTIVE: The aim of these analyses was to assess survival of biologic treatments in the PSOriasis Longitudinal Assessment and Registry (PSOLAR). METHODS: PSOLAR is a large, prospective, international, disease-based registry of patients with psoriasis receiving (or eligible for) systemic therapy in a real-world setting. Drug survival is defined as the time from initiation to discontinuation (stop/switch) of biologic therapy on registry. The number of patients who discontinued each treatment and the duration of therapy were recorded. Using Kaplan-Meier survival curves and Cox-regression analyses [hazard ratios (HR) and 95% confidence intervals (CIs)], time to discontinuation was compared across cohorts undergoing first-, second- or third-line treatment with ustekinumab, infliximab, adalimumab or etanercept. RESULTS: As of the 2013 data cut, 12 095 patients with psoriasis were enrolled in PSOLAR. Of the 4000 patients initiating any new biologic therapy, approximately 3500 started a first-line, second-line or third-line biologic therapy during the registry. Lack of effectiveness was the most common reason for discontinuation across biologic therapies. Based on the multivariate analysis, significantly shorter times to discontinuation were observed for infliximab [HR (95%CI) = 2.73 (1.48-5.04), P = 0.0014]; adalimumab [4.16 (2.80-6.20), P < 0.0001]; and etanercept [4.91 (3.28-7.35) P < 0.0001] compared with ustekinumab [reference treatment]) for first-line biologic use; results were similar for treatment effects for second/third-line therapies. Although limited in power, analyses in patients with concurrent psoriatic arthritis confirmed by a rheumatologist reflect observations in the overall psoriasis population. CONCLUSION: Drug survival was superior for ustekinumab compared with infliximab, adalimumab and etanercept in patients with psoriasis.

Demography, baseline disease characteristics and treatment history of patients with psoriasis enrolled in a multicentre, prospective, disease-based registry (PSOLAR).

BACKGROUND: Psoriasis is associated with several comorbidities and behavioural risk factors. OBJECTIVES: To evaluate demographic and disease characteristics in patients enrolled in the Psoriasis Longitudinal Assessment and Registry (PSOLAR). METHODS: PSOLAR is a global, prospective, longitudinal, disease-based registry that includes a postmarketing commitment to evaluate safety in patients with psoriasis. Enrolled patients had to be receiving, or be eligible to receive, conventional systemic or biological agents. Demographic/disease characteristics, medical histories, lifestyle risk factors and previous treatments are collected at enrolment. Efficacy and safety data are collected every 6 months for 8 years, and data are extracted annually. Selected parameters are evaluated by age quartile using post hoc analyses. RESULTS: As of 23 August 2012, 11 900 patients were enrolled at 301 sites in North America, Europe and Latin America. Over half of the PSOLAR population (54·7%) is male, with a mean age of 48·6 years and mean body mass index of 30·9 kg m(-2) at enrolment. Mean duration of disease at enrolment was 17·5 years, and mean Physician's Global Assessment score was 2·0. Psoriatic arthritis (35·5%) and cardiovascular diseases (38·2%) were highly prevalent. Diabetes mellitus type II was reported in 11·4% of patients. Depression and anxiety were noted in 14·7% and 11·1% of patients, respectively; 79·0% reported any alcohol use and 56·7% reported smoking or a history of smoking. The occurrence of most comorbidities, including cardiovascular disease and risk factors, increased with age. CONCLUSIONS: In the PSOLAR population, multiple and age-appropriate comorbidities are associated with psoriasis and may affect the selection of psoriasis treatments.

Ustekinumab improves nail disease in patients with moderate-to-severe psoriasis: results from PHOENIX 1.

BACKGROUND: Most patients with psoriasis have nail changes, and treating nail psoriasis is challenging. OBJECTIVES: To assess improvement in fingernail psoriasis with ustekinumab treatment in the PHOENIX 1 trial. METHODS: Patients received ustekinumab 45 mg or 90 mg, or placebo at weeks 0 and 4. Ustekinumab-randomized patients continued maintenance dosing every 12 weeks, while patients receiving placebo crossed over to receive ustekinumab 45 mg or 90 mg at weeks 12/16 followed by dosing every 12 weeks. At week 40, initial responders [those with ≥ 75% improvement from baseline in Psoriasis Area and Severity Index (PASI 75)] were rerandomized either to continue maintenance dosing or to withdraw from treatment. Nail involvement was evaluated using the Nail Psoriasis Severity Index (NAPSI) on a target fingernail, Nail Physician's Global Assessment (Nail PGA) and mean number of nails involved. RESULTS: Of 766 randomized patients, 545 (71·1%) had nail psoriasis. At week 24, the percentage improvement from baseline NAPSI score was 46·5% (ustekinumab 45 mg) and 48·7% (ustekinumab 90 mg). Percentage improvements in NAPSI ranged from 29·7% (PASI < 50) to 57·3% (PASI ≥ 90). Mean NAPSI scores improved from 4·5 at baseline to 2·4 at week 24 (45 mg) and from 4·4 to 2·2 (90 mg). Nail PGA scores and the mean number of psoriatic nails improved by week 24. Further improvement was observed for all end points among initial responders continuing maintenance treatment through week 52. CONCLUSIONS: Ustekinumab significantly improves nail psoriasis, and improvements continue over time until up to 1 year of treatment in those receiving maintenance treatment.

Long-term efficacy of ustekinumab in patients with moderate-to-severe psoriasis: results from the PHOENIX 1 trial through up to 3 years.

BACKGROUND: An unmet need remains for safe and effective long-term treatments of psoriasis. OBJECTIVES: To evaluate ustekinumab efficacy and safety for up to 3 years in the PHOENIX 1 trial. METHODS: Patients (n = 766) with moderate-to-severe psoriasis were randomized to ustekinumab 45 mg or 90 mg at weeks 0 and 4, and then every 12 weeks, or placebo at weeks 0 and 4, with crossover to ustekinumab at week 12. Ustekinumab responders [≥ 75% improvement from baseline in the Psoriasis Area and Severity Index (PASI 75) at weeks 28 and 40] were re-randomized at week 40 to continue or withdraw from treatment until psoriasis recurrence. Partial responders (week 28: PASI 50-74; week 40: < PASI 75) switched to dosing every 8 weeks. Clinical efficacy was assessed by PASI, the Physician's Global Assessment (PGA), and the Dermatology Life Quality Index (DLQI) measures. RESULTS: Overall, 79·8% of the ustekinumab-treated patients remained in the study for 3 years. PASI 75 response rates (45 mg: 61·2%; 90 mg: 72·4%) at week 76 were maintained through year 3 (45 mg: 62·7%; 90 mg: 72·2%); PGA response was similarly durable. At year 3, 80·9% (45 mg) and 82·7% (90 mg) of week 40 responders continuing treatment every 12 weeks achieved a PASI 75 response, while 42·6% (45 mg) and 58·0% (90 mg) achieved a PASI 90 response. Among partial responders adjusted to dosing every 8 weeks, 50·9% (45 mg) and 52·0% (90 mg) had a PASI 75 response at year 3. DLQI responses paralleled the PASI responses. Through year 3, no dose response was observed in rates of adverse events (AEs), overall infections, serious AEs, or AEs leading to discontinuation; nor was there evidence of cumulative organ toxicity. CONCLUSIONS; Continuous, stable, maintenance dosing with ustekinumab was generally well tolerated and sustained durable efficacy for up to 3 years of treatment.

Comparison of the reliability and validity of outcome instruments for cutaneous dermatomyositis.

BACKGROUND: Reliable and validated measures of skin disease severity are needed for cutaneous dermatomyositis (DM). Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI), Dermatomyositis Skin Severity Index (DSSI) and Cutaneous Assessment Tool (CAT) skin indices have been developed as outcome instruments. OBJECTIVES: We sought to demonstrate reliability and validity of the CDASI, and to compare the CDASI with other potential tools for use in measuring disease severity in cutaneous dermatomyositis. PATIENTS AND METHODS: CDASI has four activity and two damage measures, with scores from 0 to 148. DSSI assesses activity based on body surface area and severity on a scale of 0-72. CAT uses 21 activity and damage items, for a range of 0-175 for activity and 0-33 for damage. Ten dermatologists used the instruments to score the same 12-16 patients in one session. Global validation measures were administered to physicians and patients. RESULTS: Global validation measures correlated with the three outcome instruments (P < 0.0001). CAT displayed lower inter- and intrarater reliability relative to the CDASI. All scales correlate better with physician than patient global skin measures. CONCLUSIONS: It appears that the CDASI may be a useful outcome measure for studies of cutaneous DM. Further testing to compare responsiveness of all three measures is necessary.

Correlation between factor VIII genotype and inhibitor development in hemophilia A.

The development of neutralizing antibodies, or inhibitors, against infused factor VIII represents a significant complication of treatment for hemophilia A. Although it is likely that both genetic and environmental factors influence whether patients form inhibitors, correlations between types of factor VIII mutations and inhibitor development are becoming apparent. Approximately 20% of all patients with severe hemophilia A generate inhibitors. Of these inhibitor patients, 90% have inversions, large deletions or nonsense mutations of the factor VIII gene that would be predicted to eliminate production of factor VIII antigen. In contrast to patients with severe disease, inhibitor formation in patients with mild/moderate hemophilia A is rare. Inhibitor patients with mild/moderate disease typically have missense mutations that may cause local conformational changes within immunogenic domains of factor VIII and lead to production of dysfunctional antigen. Taken together, hemophilia A patients are predisposed to inhibitor development with mutations causing infused factor VIII to be perceived as either 1) a completely novel antigen or 2) an immunologically altered antigen.

Correction of the coagulation defect in hemophilia A mice through factor VIII expression in skin.

To test the hypothesis that factor VIII expressed in the epidermis can correct hemophilia A, we generated transgenic mice in a factor VIII-deficient background that express human factor VIII under control of the involucrin promoter. Mice from 5 transgenic lines had both phenotypic correction and plasma factor VIII activity. In addition to the skin, however, some factor VIII expression was detected in other tissues that have stratified squamous epithelia. To determine whether an exclusively cutaneous source of factor VIII could correct factor VIII deficiency, we grafted skin explants from transgenic mice onto mice that are double knockouts for the factor VIII and RAG-1 genes. Two graft recipients had plasma factor VIII activity of 4% to 20% of normal and improved whole blood clotting compared with factor VIII-deficient mice. Thus, expression of factor VIII from the epidermis can correct hemophilia A mice, thereby supporting the feasibility of cutaneous gene therapy for systemic disease. (Blood. 2000;95:2799-2805)

Acute mixed-lineage leukemia t(4;11)(q21;q23) generates an MLL-AF4 fusion product.

A chromosomal translocation, t(4;11)-(q21;q23), is associated with an aggressive mixed-lineage leukemia. A yeast artificial chromosome was used to clone the chromosomal breakpoint of this translocation in the RS4;11 cell line. The breakpoint sequences revealed an inverted repeat bordered by a consensus site for topoisomerase II binding and cleavage as well as chi-like elements. The der(11) chromosome encodes a fusion RNA and predicted chimeric protein between the 11q23 gene MLL and a 4q21 gene designated AF4. The sequence of the complete open reading frame for this fusion transcript reveals the MLL protein to have homology with DNA methyltransferase, the Drosophila trithorax gene product, and the "AT-hook" motif of high-mobility-group proteins. An alternative splice that deletes the AT-hook region of MLL was identified. AF4 is a serine- and proline-rich putative transcription factor with a glutamine-rich carboxyl terminus. The composition of the complete MLL-AF4 fusion product argues that it may act through either a gain-of-function or a dominant negative mechanism in leukemogenesis.

Structure and organization of amplified DNA on double minutes containing the mdm2 oncogene.

We have been studying a transformed derivative of a mouse fibroblast line (3T3DM) that stably maintains double minute chromosomes (DMs). In this report we describe a comprehensive analysis of the structure of the DMs within this cell line, utilizing a combination of long-range mapping via pulsed-field gel electrophoresis, screening of DM-enriched genomic libraries, and DM sizing using contour-clamped homogeneous electric field (CHEF) gel electrophoresis. Our data indicate that the minute particles in these cells exist as a homogeneous population of circular molecules, roughly 4 Mb in size, upon which three genes are amplified. One of these is the mdm2 oncogene, which has also been found to be amplified in a number of human sarcomas. Further, we present evidence that these three genes are arranged as two identical inverted repeat units linked by spacer regions of heterogeneous size. This work has led to the first model for the structure of an entire double minute particle containing an amplified oncogene; this model provides clues to later events occurring in the gene amplification process in tumor cells.

Tumorigenic potential associated with enhanced expression of a gene that is amplified in a mouse tumor cell line.

We have carried out an analysis of amplified DNA sequences present in a tumorigenic mouse cell line, designated 3T3DM, to determine if the presence of cellular transforming activity is correlated with the elevated expression of any of the amplified genes. These studies utilized a selection protocol that allowed for DNA sequence amplification after the introduction of each gene into non-transformed recipient cells. Cell lines obtained from this selection protocol were assayed for tumorigenicity in nude mice. The results provided evidence that a gene, mdm2, that is amplified more than 50-fold in the 3T3DM cell line, induces tumorigenicity when experimentally overexpressed in NIH3T3 cells and in Rat2 cells. Analysis of the predicted amino acid composition of the mdm2 product(s) revealed features similar to those that have been shown to be functionally significant in certain DNA binding proteins/transcriptional activators. These include two potential metal binding motifs and a negatively charged domain rich in acidic amino acid residues. Overall, the data support the conclusion that mdm2 represents an evolutionarily conserved gene with tumorigenic potential and a predicted role in mechanisms of cellular growth control.

A gene amplified in a transformed mouse cell line undergoes complex transcriptional processing and encodes a nuclear protein.

We have explored the structure and pattern of expression of a gene designated mdm-1, which is amplified 25-30-fold in transformed mouse cells containing numerous double minute particles. This gene is expressed in all mouse tissues examined but exhibits elevated and altered patterns of expression in the testis. Multiple transcripts are generated from the mdm-1 gene via mechanisms of alternative splicing and polyadenylation signal choice. These mRNAs have the potential to produce a minimum of three distinct protein products ranging in size from 25 to 77 kilodaltons. Antiserum generated against a synthetic peptide from the mdm-1 gene was used in immunoblotting studies and revealed that at least one of the protein products is present in the nucleus. This antiserum stained nuclear structures producing a distinct punctate or speckled pattern.