Burden of Psoriasis in Catalonia: Epidemiology, Associated Comorbidities, Health Care Utilization, and Sick Leave. / Carga de la psoriasis en Cataluña: datos epidemiológicos, comorbilidades asociadas, uso de recursos sanitarios e incapacidad laboral.

BACKGROUND AND OBJECTIVES: Epidemiologic and disease burden data are essential for disease control and optimal health care resource planning. The aims of this study were to estimate the epidemiologic burden of psoriasis and evaluate associated comorbidities, health care utilization, and sick leave. MATERIAL AND METHODS: We collected data from the 2016 Catalan Health Survey (ESCA), the Catalan Registry of Morbidity and Utilization of Health Care Services (MUSSCAT) (2016), and the database of the Catalan Medical Evaluations Institute (ICAM) (2012-2016). RESULTS: The prevalence of psoriasis in Catalonia according to 2016 ESCA data is approximately 1.8%. The MUSSCAT registry data indicate that the incidence has remained stable in recent years. The most common comorbidities associated with psoriasis are hypertension (35%) and diabetes (15%). Forty percent of patients with psoriasis have a moderate to high risk for death or high health resource utilization. Annual use of resources by psoriasis patients is high: they make a mean of 8.7 primary care visits, 2.8 outpatient visits, 0.5 emergency and day hospital visits, 0.2 mental health visits, and use 6.1 medications. Sick leave due to psoriasis or psoriatic arthritis accounted for 0.04% of all cases. CONCLUSIONS: The prevalence of psoriasis in Catalonia is high at 1.8%. The disease burden is also high, both in terms of comorbidities and health care utilization.

Changing Trends in Drug Prescription and Causes of Treatment Discontinuation of First Biologic Over Ten Years in Psoriasis in the Spanish Biobadaderm Registry. / Cambios en las tendencias de la prescripción y causas de la interrupción en los tratamientos biológicos indicados en la psoriasis durante los primeros 10 años. Datos obtenidos del registro español Biobadaderm.

BACKGROUND AND OBJECTIVES: Current psoriasis guidelines do not usually include recommendations about first line classical or biologic treatment. The objectives of this study were: to describe shifts in the prescription of the first biological treatment, and to compare treatment withdrawal and rates of adverse events over ten years. MATERIAL AND METHODS: Biobadaderm registry was analyzed to describe: first biological prescription in bio-naïve patients, adverse events rate and reasons for drug withdrawal comparing three periods of time (2008-2010, 2011-2014, 2015-2018). RESULTS: Anti-TNF drugs were the most prescribed biological drug from 2008 to 2010. Ustekinumab has become the most prescribed first biologic since 2014. The main reasons for drug discontinuation were adverse events, lack of efficacy and remission. In each period any treatment was less likely to be discontinued due to any of these three reasons comparing to the previous period. CONCLUSIONS: The present study identifies trends in prescription of the first biological antipsoriatic drug in clinical practice from 2008 to 2018. It suggests that we have become more comfortable with the safety profile and more exigent with the efficacy of the drugs.

Expert consensus on the persistence of biological treatments in moderate-to-severe psoriasis.

BACKGROUND: Treatment persistence is becoming a useful measure to evaluate long-term effectiveness and safety of biological therapies in real-world settings. OBJECTIVE: The main objective of this study was to explore the scientific opinion of a panel of dermatologists and hospital pharmacists to reach a consensus about the impact, causes, and best strategies and interventions that might be associated with improved drug persistence in patients with psoriasis in Spain. METHODS: This research was conducted using a modified Delphi method organized in two rounds and involving a panel of 90 dermatologists and 34 hospital pharmacists. A questionnaire of 70 items was developed. The items proposed to reach a consensus included topics such as definitions and measures in the treatment of psoriasis, analysis of treatment persistence, factors that may influence treatment persistence, impact of treatment persistence and economic cost of treatment. RESULTS: Dermatologists reached a consensus on 77.1% of the items proposed, and hospital pharmacists reached a consensus on 71.4%. Both groups agreed that it is important to use standardized measures in the evaluation of treatment maintenance over time. Dermatologists agreed that treatment survival, persistence and retention are synonymous, but hospital pharmacists considered only treatment persistence as a valid term. In addition, panelists agreed that drug persistence is an indicator of success in the treatment of psoriasis that may be influenced by a drug's effectiveness and safety profile, as well as by patient satisfaction. They agreed that the different causes of treatment discontinuation should be considered in Kaplan-Meier analysis of treatment persistence. Moreover, treatment persistence was agreed to decrease the cost of therapy. CONCLUSION: This Delphi consensus highlights the different perspectives of dermatologists and hospital pharmacists regarding the interpretation of treatment persistence, and the challenge of harmonizing the results obtained.

Usefulness and correlation with clinical response of serum ustekinumab levels measured at 6 weeks versus 12 weeks.

BACKGROUND: Monitoring serum drug levels has been proposed as a useful tool for improving and personalizing the management of psoriasis. However, in the case of ustekinumab the usefulness of such monitoring was not demonstrated when drug levels were measured at week 12. OBJECTIVES: To evaluate the correlation of serum ustekinumab levels measured at weeks 6 and 12 with clinical response. METHODS: In a prospective cohort study, we enrolled patients with psoriasis treated with ustekinumab 45 mg every 12 weeks for at least 24 weeks. We measured serum ustekinumab levels at weeks 6 and 12 in each patient. Using the absolute PASI score, response to treatment was defined as optimal (≤1), excellent (≤3), appropriate (>3 and ≤5), or inappropriate (>5). RESULTS: About 54 serum samples from 27 patients were analyzed. No correlation was found between serum drug levels and absolute PASI at week 12. At week 6, an inverse linear correlation was found (p = .0001). Moreover, serum levels at week 6 were higher in patients with optimal, excellent and appropriate responses than in patients with an inappropriate response. CONCLUSIONS: Assessment of ustekinumab serum levels at week 6 could provide useful information in routine clinical practice.

Description of Patients Treated with Biologic Drugs as First-Line Systemic Therapy in the BIOBADADERM Registry Between 2008 and 2016. / Descripción de los pacientes que reciben biológicos como primer tratamiento sistémico en el registro BIOBADADERM durante el periodo 2008-2016.

INTRODUCTION AND OBJECTIVES: Biologic drugs are usually prescribed as second-line treatment for psoriasis, that is, after the patient has first been treated with a conventional psoriasis drug. There are, however, cases where, depending on the characteristics of the patient or the judgement of the physician, biologics may be chosen as first-line therapy. No studies to date have analyzed the demographics or clinical characteristics of patients in this setting or the safety profile of the agents used. The main aim of this study was to characterize these aspects of first-line biologic therapy and compare them to those observed for patients receiving biologics as second-line therapy. MATERIAL AND METHOD: We conducted an observational study of 181 patients treated in various centers with a systemic biologic drug as first-line treatment for moderate to severe psoriasis between January 2008 and November 2016. All the patients were registered in the Spanish Registry of Adverse Events Associated with Biologic Drugs in Dermatology. RESULTS: The characteristics of the first- and second-line groups were very similar, although the patients receiving a biologic as first-line treatment for their psoriasis were older. No differences were observed for disease severity (assessed using the PASI) or time to diagnosis. Hypertension, diabetes, and liver disease were all more common in the first-line group. There were no differences between the groups in terms of reasons for drug withdrawal or occurrence of adverse effects. CONCLUSIONS: No major differences were found between patients with psoriasis receiving biologic drugs as first- or second-line therapy, a finding that provides further evidence of the safety of biologic therapy in patients with psoriasis.

The depth of follicular extension in actinic keratosis correlates with the depth of invasion in squamous cell carcinoma: implication for clinical treatment.

BACKGROUND: Actinic keratosis (AK) may show extension down follicles, not only in cases with full-thickness epidermal atypia ('bowenoid' AK), but also in cases with atypia limited to the epidermal basalis. Previous studies have demonstrated that, in bowenoid AK, follicular extension is usually superficial, being limited to the upper follicular segment. Little is known about the depth of follicular involvement in cases of invasive squamous cell carcinoma of the skin (iSCC) arising from AK and the role of the follicle in iSCC pathogenesis. OBJECTIVE: This study investigated the relationship between follicular extension of atypical keratinocytes in an AK and the development of iSCC from the follicular wall. The depth of follicular extension was correlated with the depth invasion of iSCC. Differences between the differentiated and classical pathways of iSCC were also examined. METHODS: We performed a retrospective histologic review of 193 biopsy specimens of iSCC with an associated AK. We assessed the presence and depth of follicular extension of atypical keratinocytes in the AK, using tumour (Breslow) thickness and the follicular unit level (infundibular, isthmic and subisthmic), as well as iSCC being present directly adjacent to the follicular basalis. RESULTS: Follicular extension was present in 25.9% of the cases (50 cases), usually extending into the lower follicular segment. The iSCC was present directly adjacent to the follicular basalis in 58% of the cases (29 cases), correlating highly with the depth of follicular extension (infundibular: 3/12; isthmic: 21/33; subisthmic 5/5). CONCLUSION: The depth of follicular extension of atypical keratinocytes in an AK correlates with the development of depth of invasion of an associated iSCC, irrespective of the pathway of origin. It is therefore important to note the presence and the depth of follicular extension when diagnosing an AK, as follicular extension likely accounts for a significant proportion of recurrent AK and the development of iSCC following superficial treatment modalities.

Epithelial-to-mesenchymal transition contributes to invasion in squamous cell carcinomas originated from actinic keratosis through the differentiated pathway, whereas proliferation plays a more significant role in the classical pathway.

BACKGROUND: Every actinic keratosis (AK) starts with atypia at the basal layers of the epidermis (AK I). Progression into invasive squamous cell carcinoma (iSCC) may occur following two main pathways, classical and differentiated. In the former, iSCC only occurs after involvement of the upper epidermal layers by atypical cells (AK III), while in the latter iSCC develops directly from AK I. In the anogenital mucosa, these two pathways are associated with differential expression of p53 and p16. OBJECTIVE: To explore differences between both pathways in the pathogenesis of AK, focusing on Ki67, p53, p16 and molecules that reveal epithelial-mesenchymal transition (EMT). METHODS: Tissue microarrays representative of superficial and deep portions of 80 consecutive iSCCs (53 DP/27CP) were studied immunohistochemically using antibodies against Ki67, p53, p16, vimentin, E-cadherin, ß-catenin and D2-40. The evaluation was performed by three researchers and the results compared to consensus. RESULTS: Invasive squamous cell carcinomas originated through the differentiated pathway exhibited significantly lower proliferative activity (Ki67) (30% vs 46%, P = 0.003) and significantly lower expression of vimentin (P < 0.001), E-cadherin (P < 0.001) and membranous ß-catenin (P < 0.001) than iSCCs developed through the classical pathway. The expression of E-cadherin and membranous ß-catenin was significantly correlated (Pearson's r = 0.386, Spearman's Rho < 0.001). There were no significant differences regarding the expressions of p53, p16 and D2-40. CONCLUSION: Epithelial-mesenchymal transition participates in transformation from AK I into iSCC (differentiated pathway), whereas a higher proliferative capacity facilitates intraepidermal extension in the classical pathway. Podoplanin, which is also involved in tumour invasion, does not seem to play a differential role in either pathway. Finally, the absence of differences in p53 and p16 expressions is at variance with other epithelia where the classical pathway is associated with human papillomavirus infection and can be explained by the fact that both AK pathways share identical mechanisms of actinic oncogenesis.

Correlation between trough serum levels of adalimumab and absolute PASI score in a series of patients with psoriasis.

BACKGROUND: The possibility of monitoring serum drug levels has opened the door to optimising biologic therapy. To consolidate this advance, it is imperative to demonstrate an adequate correlation between serum drug levels and clinical course. OBJECTIVES: To investigate whether a correlation exists between adalimumab levels and clinical response measured as absolute PASI. METHODS: In a prospective cohort study, we enrolled 51 patients with psoriasis treated with adalimumab for at least 16 s. Patients received approved doses of adalimumab, but after 52 s the dosing interval could be modified according to clinical criteria. Excellent response was defined as PASI ≤3, appropriate response as PASI >3 and ≤5 and inappropriate response as PASI> 5. Correlations were calculated using Spearman's correlation test. RESULTS: A total of 92 serum samples from 51 patients were analysed. Significant differences were found in serum trough levels between patients achieving an excellent response (6.46 µg/mL), versus an appropriate (2.5 µg/mL) and an inappropriate response (2 µg/mL). The therapeutic range for adalimumab serum levels was from 3.30 to 7.30 µg/mL. CONCLUSIONS: We found an adequate correlation between drug serum levels and PASI scores. Monitoring of absolute PASI and serum levels can provide a personalised and cost-effective evaluation.

Phototoxic reaction to a combined oral contraceptive (levonorgestrel/ethinylestradiol).

We present the case of a phototoxic skin reaction due to the regular intake of a combined oral contraceptive (levonorgestrel/ethinylestradiol). Upon spectrophotometer testing, we demonstrated high absorption in the UV-B region of the solar spectrum of the combined product (Ovoplex®), especially for the estrogen compound (ethinylestradiol).

Comparison of ixekizumab with ustekinumab in moderate-to-severe psoriasis: 24-week results from IXORA-S, a phase III study.

BACKGROUND: It has been shown that the interleukin (IL)-23/IL-17 axis is critical in the pathogenesis of psoriasis. OBJECTIVES: To present the primary end point (week 12) and safety and efficacy data up to week 24 from a head-to-head trial (IXORA-S) of the IL-17A inhibitor ixekizumab (IXE) vs. the IL-12/23 inhibitor ustekinumab (UST). METHODS: Randomized patients received IXE (160-mg starting dose, then 80 mg every 2 weeks for 12 weeks, then 80 mg every 4 weeks, n = 136) or UST (45 mg or 90 mg weight-based dosing per label, n = 166). The primary end point was the proportion of patients reaching ≥ 90% Psoriasis Area and Severity Index improvement (PASI 90). Hommel-adjusted key secondary end points at week 12 included PASI 75, PASI 100, static Physician's Global Assessment (sPGA) score of 0 or 1, sPGA score of 0, Dermatology Life Quality Index (DLQI) score of 0 or 1, ≥ 4-point reduction on the itch numerical rating scale (NRS) and changes in itch NRS and skin pain visual analogue scale. RESULTS: At week 12, IXE (n = 99, 72·8%) was superior to UST (n = 70, 42·2%) in PASI 90 response (response difference 32·1%, 97·5% confidence interval 19·8-44·5%, P < 0·001). Response rates for PASI 75, PASI 100 and sPGA (0,1) were significantly higher for IXE than for UST (adjusted P < 0·05). At week 24, IXE-treated patients had significantly higher response rates than UST-treated patients for PASI, sPGA and DLQI (unadjusted P < 0·05). No deaths were reported, and the treatments did not differ with regard to overall incidences of adverse events (P = 0·299). CONCLUSIONS: The superior efficacy of IXE demonstrated at week 12 persisted up to week 24. The safety profiles were consistent with those previously reported for both treatments.

Adverse events associated with discontinuation of the biologics/classic systemic treatments for moderate-to-severe plaque psoriasis: data from the Spanish Biologics Registry, Biobadaderm.

BACKGROUND: Little is known about the adverse events (AEs) that lead to suspension of systemic treatments for psoriasis in clinical practice. OBJECTIVE: The study aimed to investigate AEs associated with discontinuation of systemic therapy in patients with psoriasis in a clinical setting (Biobadaderm). MATERIALS AND METHODS: Multicentre, prospective, cohort study of patients with moderate-to-severe plaque psoriasis receiving systemic therapies from January 2008 to November 2015, in 12 hospitals in Spain. The incidence rate (IR) was used to compare biologics and classic systemic therapies. RESULTS: A total of 4218 courses of treatment were given to 1938 patients. A total of 447 (11%) treatments were discontinued due to AEs. The IR of AE associated with discontinuation of systemic therapies was 13 events/100 patient-years (PY) (95% CI: 12.14-13.93), 9.34 events/100 PY (95% CI: 8.44-10.33) for biologics and 19.67 (95% CI: 17.9-21.6) events/100 PY for classics (P < 0.001). Of 810 discontinuation-related AEs, 117 (14%) were serious. The highest IRs were for cyclosporine [49.18/100 PY (95% CI: 41.91-57.72)] and infliximab [26.52/100 PY (95% CI: 20.98-33.51). Ustekinumab presented the lowest IR (2.6/100 PY (95% CI: 1.83-3.69). LIMITATIONS: Observational study with potential selection bias. CONCLUSION: Biologic therapies are associated with a lower rate of discontinuation-related AEs than are classic therapies in real clinical practice. Ustekinumab showed the lowest incidence.

Reliability of the MDi Psoriasis® Application to Aid Therapeutic Decision-Making in Psoriasis. / Fiabilidad de una aplicación de ayuda a la toma de decisiones terapéuticas en el paciente con psoriasis (MDi Psoriasis®).

BACKGROUND: Therapeutic decisions in psoriasis are influenced by disease factors (e.g., severity or location), comorbidity, and demographic and clinical features. OBJECTIVE: We aimed to assess the reliability of a mobile telephone application (MDi-Psoriasis) designed to help the dermatologist make decisions on how to treat patients with moderate to severe psoriasis. METHOD: We analyzed interobserver agreement between the advice given by an expert panel and the recommendations of the MDi-Psoriasis application in 10 complex cases of moderate to severe psoriasis. The experts were asked their opinion on which treatments were most appropriate, possible, or inappropriate. Data from the same 10 cases were entered into the MDi-Psoriasis application. Agreement was analyzed in 3 ways: paired interobserver concordance (Cohen's κ), multiple interobserver concordance (Fleiss's κ), and percent agreement between recommendations. RESULTS: The mean percent agreement between the total of 1210 observations was 51.3% (95% CI, 48.5-54.1%). Cohen's κ statistic was 0.29 and Fleiss's κ was 0.28. Mean agreement between pairs of human observers only, excluding the MDi-Psoriasis recommendations, was 50.5% (95% CI, 47.6-53.5%). Paired agreement between the recommendations of the MDi-Psoriasis tool and the majority opinion of the expert panel (Cohen's κ) was 0.44 (68.2% agreement). CONCLUSIONS: The MDi-Psoriasis tool can generate recommendations that are comparable to those of experts in psoriasis.