Showing papers by "Lluís Puig published in 2018"

Epidemiology of atopic dermatitis in adults: Results from an international survey.

Abstract: Background There are gaps in our knowledge of the prevalence of adult atopic dermatitis (AD). Objective To estimate the prevalence of AD in adults and by disease severity. Methods This international, cross-sectional, web-based survey was performed in the United States, Canada, France, Germany, Italy, Spain, United Kingdom, and Japan. Adult members of online respondent panels were sent a questionnaire for AD identification and severity assessment; demographic quotas ensured population representativeness for each country. A diagnosis of AD required subjects to be positive on the modified UK Working Party/ISAAC criteria and self-report of ever having an AD diagnosis by a physician. The proportion of subjects with AD who reported being treated for their condition was determined and also used to estimate prevalence. Severity scales were Patient-Oriented SCORAD, Patient-Orientated Eczema Measure, and Patient Global Assessment. Results Among participants by region, the point prevalence of adult AD in the overall/treated populations was 4.9%/3.9% in the US, 3.5%/2.6% in Canada, 4.4%/3.5% in the EU, and 2.1%/1.5% in Japan. The prevalence was generally lower for males vs females, and decreased with age. Regional variability was observed within countries. Severity varied by scale and region; however, regardless of the scale or region, proportion of subjects reporting severe disease was lower than mild or moderate disease. Conclusions Prevalence of adult AD ranged from 2.1% to 4.9% across countries. Severe AD represented a small proportion of the overall AD population regardless of measure or region.

Efficacy and safety of guselkumab in patients with psoriasis who have an inadequate response to ustekinumab: results of the randomized, double-blind, phase III NAVIGATE trial.

Abstract: SummaryBackground Guselkumab, an anti-interleukin-23 monoclonal antibody, has demonstrated significant efficacy in phase III psoriasis trials. Objectives To evaluate the efficacy and safety of guselkumab in patients with moderate-to-severe plaque psoriasis who had an inadequate response to ustekinumab. Methods In this phase III, randomized, double-blind study, 871 patients received open-label ustekinumab (45 mg or 90 mg) at weeks 0 and 4. At week 16, 268 patients with an inadequate response to ustekinumab [Investigator's Global Assessment (IGA) ≥ 2] were randomized (double-blind) to guselkumab 100 mg or to continue ustekinumab; 585 of 871 patients (67%) with IGA 0/1 at week 16 continued open-label ustekinumab. The primary end point was the number of visits at which randomized patients achieved IGA 0/1 and at least a two-grade improvement (from week 16) from week 28 to week 40. Improvement ≥ 90% or 100% in Psoriasis Area and Severity Index (PASI 90/100) and Dermatology Life Quality Index (DLQI) of 0/1 were also assessed. Results The mean number of visits at which patients achieved IGA 0/1 and at least a two-grade improvemen (week 28–40) was significantly greater in the guselkumab group vs. the randomized ustekinumab group (1·5 vs. 0·7; P < 0·001); greater proportions of patients in the guselkumab group achieved IGA 0/1 and at least a two-grade improvement at week 28 (31·1% vs. 14·3%; P = 0·001) and week 52 (36·3% vs. 17·3%; P < 0·001). Greater proportions of patients treated with guselkumab achieved PASI 90, PASI 100 and DLQI 0/1 at week 52. After week 16, 64·4% of patients in the guselkumab group and 55·6% in the ustekinumab group had at least one adverse event (AE); infections were the most frequent AE type. Overall, 6·7% (n = 9) of patients in the guselkumab group had at least one serious AE compared with 4·5% (n = 6) for the ustekinumab group. Conclusions Patients treated with ustekinumab who did not achieve an IGA of 0/1 by week 16 derived significant benefit from switching to guselkumab.

Paradoxical Reactions: Anti-Tumor Necrosis Factor Alpha Agents, Ustekinumab, Secukinumab, Ixekizumab, and Others.

Abstract: Paradoxical reactions during treatment with a biologic agent can be defined as the appearance or exacerbation of a pathological condition that usually responds to this class of drug while treating a patient for another condition, which usually remains under control (even though there may be a change in morphology or phenotype). Paradoxical reactions were initially described as isolated case reports or case series in patients treated with anti-tumor necrosis factor (TNF) α agents, first in inflammatory rheumatic diseases, later in psoriasis and inflammatory bowel disease. Paradoxical reactions have subsequently been reported with other biological drugs or classes (e.g., tocilizumab), even though in some cases insufficient efficacy or phenotype switch may be difficult to differentiate from true paradoxical reactions. This chapter will deal with the most frequently reported variants of paradoxical reactions: palmoplantar pustular and psoriasiform reactions, psoriatic arthritis, hidradenitis, inflammatory bowel disease, uveitis, pyoderma gangrenosum, granulomatous reactions, and vasculitis. The underlying pathomechanism in these complex diseases with involvement of multiple immunological pathways is most likely a cytokine imbalance, and substitution of the anti-TNFα agent by an alternative anti-p40 or anti-IL-17A biologic may be extremely helpful. Paradoxical reactions can cause serious handicap, and early recognition and treatment of these drug class effects is of paramount importance, especially when the primary disease is relatively devoid of therapeutic alternatives and its reactivation may have catastrophic consequences. Close surveillance of patients treated with newly available biologic drugs is necessary to detect and describe new paradoxical reactions.

Maintenance of skin clearance with ixekizumab treatment of psoriasis: Three-year results from the UNCOVER-3 study

Abstract: Background Psoriasis is a chronic disease that may require long-term treatment. Ixekizumab (IXE), which is a high-affinity monoclonal antibody that selectively targets interleukin 17A, is an approved therapy for patients with moderate-to-severe plaque psoriasis. Objective To evaluate the efficacy and safety of IXE through 156 weeks from the UNCOVER-3 study in patients who were treated with the recommended dose regimen (160 mg of IXE at week 0, 80 mg every 2 weeks up to week 12, and 80 mg every 4 weeks thereafter). Methods Patients randomized to IXE every 2 weeks, IXE every 4 weeks, etanercept twice weekly, or placebo were switched to IXE every 4 weeks during the long-term extension period. Efficacy data were summarized by using the as-observed, multiple imputation, and modified nonresponder imputation methods. Results At week 156, 80.5% of patients had achieved at least a 75% improvement from baseline in their Psoriasis Area Severity Index (PASI) score, 66.0% had achived at least a 90% improvement from baseline in their PASI score, and 45.1% had achieved a 100% improvement from baseline in their PASI score with use of the modified nonresponder imputation method, and 97.2% and 86.2% of patients had achived at least a 75% improvement from baseline in their PASI score with use of the as-observed and multiple imputation methods, respectively. Similar response rates were observed in patients with baseline scalp, nail, or palmoplantar involvement. No new safety signals were identified through year 3. Limitations No placebo or active comparison after week 12. Conclusion IXE sustained high responses with clearance of skin and nail lesions, with no new safety concerns through 3 years.

Redefining the therapeutic objective in psoriatic patients candidates for biological therapy

Abstract: The advances in psoriasis management currently allow achieving a good control of the disease. In particular, with the latest developed molecules, available evidence suggests that it is possible to pose an ambitious therapeutic goal, such as a Dermatology Life Quality Index 0/1, a Physician Global Assessment 0/1, or a Psoriasis Area and Severity Index 90/100 response. However, patients often fail to achieve the complete clearance of their cutaneous lesions or the improvement of disease factors that impair their quality of life. To optimize the treatment of psoriasis, it is not enough to define precisely the therapeutic objective, but also to adapt the therapeutic strategy to make the necessary modifications in case of not achieving it at the time point (at the end of the induction phase, or every 3–6 months) to be agreed with the patient (the so-called treat-to-target approach). In the present report, based on the Delphi methodology, 11 dermatologists from the Spanish Psoriasis Group addressed key ...

Topical Timolol for Paronychia and Pseudopyogenic Granuloma in Patients Treated With Epidermal Growth Factor Receptor Inhibitors and Capecitabine.

Abstract: This study evaluated the efficacy and tolerability of topical timolol, 0.5%, gel as a treatment of paronychia and pseudopyogenic granuloma induced by antineoplastic agents.

Multitrait genome association analysis identifies new susceptibility genes for human anthropometric variation in the GCAT cohort.

Abstract: Background Heritability estimates have revealed an important contribution of SNP variants for most common traits; however, SNP analysis by single-trait genome-wide association studies (GWAS) has failed to uncover their impact In this study, we applied a multitrait GWAS approach to discover additional factor of the missing heritability of human anthropometric variation Methods We analysed 205 traits, including diseases identified at baseline in the GCAT cohort (Genomes For Life- Cohort study of the Genomes of Catalonia) (n=4988), a Mediterranean adult population-based cohort study from the south of Europe We estimated SNP heritability contribution and single-trait GWAS for all traits from 15 million SNP variants Then, we applied a multitrait-related approach to study genome-wide association to anthropometric measures in a two-stage meta-analysis with the UK Biobank cohort (n=336 107) Results Heritability estimates (eg, skin colour, alcohol consumption, smoking habit, body mass index, educational level or height) revealed an important contribution of SNP variants, ranging from 18% to 77% Single-trait analysis identified 1785 SNPs with genome-wide significance threshold From these, several previously reported single-trait hits were confirmed in our sample with LINC01432 (p=19×10 −9 ) variants associated with male baldness, LDLR variants with hyperlipidaemia (ICD-9:272) (p=94×10 −10 ) and variants in IRF4 (p=28×10 −57 ) , SLC45A2 (p=22×10 −130 ) , HERC2 (p=28×10 −176 ) , OCA2 (p=24×10 −121 ) and MC1R (p=77×10 −22 ) associated with hair, eye and skin colour, freckling, tanning capacity and sun burning sensitivity and the Fitzpatrick phototype score, all highly correlated cross-phenotypes Multitrait meta-analysis of anthropometric variation validated 27 loci in a two-stage meta-analysis with a large British ancestry cohort, six of which are newly reported here (p value threshold −9 ) at ZRANB2-AS2 , PIK3R1 , EPHA7 , MAD1L1 , CACUL1 and MAP3K9 Conclusion Considering multiple-related genetic phenotypes improve associated genome signal detection These results indicate the potential value of data-driven multivariate phenotyping for genetic studies in large population-based cohorts to contribute to knowledge of complex traits

GCAT|Genomes for life: a prospective cohort study of the genomes of Catalonia

Abstract: Purpose The prevalence of chronic non-communicable diseases (NCDs) is increasing worldwide. NCDs are the leading cause of both morbidity and mortality, and it is estimated that by 2030, they will be responsible for 80% of deaths across the world. The Genomes for Life (GCAT) project is a long-term prospective cohort study that was designed to integrate and assess the role of epidemiological, genomic and epigenomic factors in the development of major chronic diseases in Catalonia, a north-east region of Spain. Participants At the end of 2017, the GCAT Study will have recruited 20 000 participants aged 40–65 years. Participants who agreed to take part in the study completed a self-administered computer-driven questionnaire, and underwent blood pressure, cardiac frequency and anthropometry measurements. For each participant, blood plasma, blood serum and white blood cells are collected at baseline. The GCAT Study has access to the electronic health records of the Catalan Public Healthcare System. Participants will be followed biannually at least 20 years after recruitment. Findings to date Among all GCAT participants, 59.2% are women and 83.3% of the cohort identified themselves as Caucasian/white. More than half of the participants have higher education levels, 72.2% are current workers and 42.1% are classified as overweight (body mass index ≥25 and 2 ). We have genotyped 5459 participants, of which 5000 have metabolome data. Further, the whole genome of 808 participants will be sequenced by the end of 2017. Future plans The first follow-up study started in December 2017 and will end by March 2018. Residences of all subjects will be geocoded during the following year. Several genomic analyses are ongoing, and metabolomic and genomic integrations will be performed to identify underlying genetic variants, as well as environmental factors that influence metabolites.

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.

Abstract: 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, β-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 β-catenin (P < 0.001) than iSCCs developed through the classical pathway. The expression of E-cadherin and membranous β-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.

Results of cement spacer sonication in the second stage of two-stage treatment of shoulder arthroplasty infection

Abstract: The objective of this study is to present the results of cement spacer sonication in the second stage of two-stage treatment of shoulder arthroplasty infection and to determine the rate of positive cultures in the second-stage surgery in shoulder arthroplasty and its meaning. Twenty-one patients (22 cement spacers) treated with two-stage surgery because of a shoulder arthroplasty infection were included. In the second stage, the cement spacer was sent for sonication and at least four tissue cultures were obtained. Epidemiological data, comorbidities, sensitivity of the microorganisms to the antibiotic loaded in the cement spacer in the first revision surgery, time elapsed since an antibiotic was last administered until second revision procedure, functional shoulder status at last follow-up, and any complication were recorded. Three out of the 22 cases (13.6%) presented positive cultures at the second-stage surgery. Periprosthetic tissue culturing detected the three positive culture cases in the second stage while the cement spacer sonication detected two and missed one. Considering periprosthetic tissue culturing as the standard procedure, the cement spacer sonication showed sensitivity at 66.6%. Recurrent infection over time was considered present in 3 patients; two of them had been previously diagnosed with a positive culture at the second stage (66.6%). A good number of patients (13.6%) present a positive culture at the second stage of the two-stage surgical procedure for infected shoulder arthroplasty, and those patients seem to be at high risk for recurrent infection. Periprosthetic tissue cultures have a higher sensitivity to detecting a positive culture at the second stage than cement spacer sonication.

Differential effects of secukinumab vs. ustekinumab for treatment of psoriasis on quality of life, work productivity and activity impairment: a structural equation modelling analysis.

Abstract: Purpose This study examined direct and indirect (mediated) effects of secukinumab vs. ustekinumab on quality of life, work productivity, and activity impairment based on psoriasis severity and symptoms. Methods Analyses were based on data from the CLEAR study. Structural equation modelling (SEM) examined the effects of secukinumab vs. ustekinumab on the Dermatology Life Quality Index (DLQI) and on the Work Productivity and Activity Impairment (WPAI) questionnaire using Psoriasis Area Severity Index (PASI) severity and symptoms (pain, itching, and scaling) as potential mediators. Analyses were conducted primarily for patients achieving PASI 90 response (indicating a 90% or greater reduction in PASI from baseline) at week 16 (repeated at week 52) and for PASI 50, 75, and 100. Results Results at weeks 16 and 52 showed that the effect of treatment on change in DLQI score was mediated by PASI 90 response and by improvements in itching and scaling. Achieving any PASI response as early as week 16 directly resulted in significantly better WPAI scores. At week 52, both PASI response and improvement in scaling directly resulted in significantly better WPAI scores. Pain, itching, and scaling were correlated (r = 0.51 to 0.68); improvement in any of these had a significant effect (directly or indirectly) on WPAI. All results favoured secukinumab over ustekinumab. Conclusion The results underscore the important role of both PASI response and reduction in symptoms on improvements in health-related quality of life and work and daily activity in favour of secukinumab vs. ustekinumab.

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

Abstract: 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.

Novel clinical and molecular findings in Spanish patients with naevoid basal cell carcinoma syndrome.

Abstract: BACKGROUND Naevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder characterized by developmental alterations and multiple basal cell carcinomas. Mutations in PTCH1, which encodes a membrane receptor for Sonic Hedgehog, are associated with the development of the disease. Most of them produce a truncated protein, which is unable to suppress Smoothened protein and continuously activates the downstream pathway. OBJECTIVES We aimed to characterize 22 unrelated Spanish patients with NBCCS, the largest cohort with Gorlin syndrome reported to date in Spain. METHODS Genomic analysis of PTCH1 was performed in patients with NBCCS and controls, and mutations were analysed using bioinformatics tools. RESULTS We report for the first time two young patients, one each with uterus didelphys and ganglioneuroma, within the context of NBCCS. One patient showing a severe phenotype of the disease had developed basal cell carcinomas since childhood. Sanger sequencing of PTCH1 in this cohort identified 17 novel truncating mutations (11 frameshift, five nonsense and one mutation affecting an exon-intron splice site) and two novel missense mutations that were predicted to be pathogenic. The patients showed great clinical variability and inconsistent genotype-phenotype correlation, as seen in relatives carrying similar mutations. CONCLUSIONS This study contributes to increase the pool of clinical manifestations of NBCCS, as well as increasing the number of pathogenic mutations identified in PTCH1 predisposing to the condition. The inconsistencies found between phenotype and genotype suggest the involvement of other modifying factors, genetic, epigenetic or environmental.

Oral ulcers in heart transplant patient.

Abstract: History A 40‐year‐old man, with a history of heart transplantation two years back, presented with painful oral ulcers of three‐weeks duration. Physical examination disclosed two large and deep, irregularly shaped ulcers on his lower lip and right buccal mucosa [Figure 1]. No fever or other systemic symptoms were observed. His usual medications included mycophenolate mofetil 360 mg daily and tacrolimus 8 mg daily. Culture specimens were negative for bacteria and herpes simplex virus type I and II. Blood cell counts only showed a mild leukopenia (3.23 × 109/L; normal value: 3.80–11.00 × 109/L) and neutropenia (1.17 × 109/L; normal value: 1.80–7.00 × 109/L); the rest of the analysis were normal. Skin biopsy revealed a dense perivascular and mixed interstitial infiltrate composed of neutrophils, eosinophils, lymphocytes, and plasma cells [Figures 2 and 3]. Endothelial cells demonstrated large eosinophilic inclusions, mostly intranuclear and occasionally intracytoplasmic, with some of them showing an “owl’s eye” appearance [Figure 4].

Verrucous Plaque With Unusually Large Candida Blastoconidia: A Unique Clinicopathological Presentation of Systemic Mucocutaneous Candidiasis.

Abstract: Mucocutaneous candidiasis is a common infection affecting both immunocompetent and immunosuppressed individuals. Diversity in the clinical and histopathological presentation of mucocutaneous candidiasis is well known. However, the occurrence of cutaneous verrucous lesions and giant yeast-like structures has been rarely reported. In this article, we describe a case of disseminated mucocutaneous candidiasis in an immunosuppressed patient who presented as a verrucous plaque on the scrotum with giant Candida blastoconidia. This peculiar presentation expands the clinicopathological spectrum of mucocutaneous candidiasis and highlights the wide range of clinical manifestations and great morphologic variability of this common fungal infection.