Safety of biologic therapy in combination with methotrexate in moderate to severe psoriasis: a cohort study from the BIOBADADERM registry.

BACKGROUND: Safety is an important consideration in decisions on treatment for patients with moderate-to-severe psoriasis and the study of drug safety is the main purpose of the BIOBADADERM registry. The combination of a biologic agent and a conventional systemic drug [generally methotrexate (MTX)] is a common treatment in clinical practice. However, there is a paucity of evidence from real-world practice on the safety of such combination regimens in the treatment of psoriasis. OBJECTIVES: The primary objective of this study was to ascertain whether the use of regimens combining biologic drugs with MTX in the management of moderate-to-severe psoriasis increases the risk of adverse events (AEs) or serious AEs (SAEs). We compared monotherapy using tumour necrosis factor (TNF), interleukin (IL)-17 and IL-23 inhibitors with the use of the same drugs in combination with MTX. METHODS: Using data from the BIOBADADERM registry, we compared biologic monotherapies with therapies that were combined with MTX. We estimated adjusted incidence rate ratios (aIRR) using a random effects Poisson regression with 95% confidence intervals for all AEs, SAEs, infections and serious infections and other AEs by system organ class. RESULTS: We analysed data from 2829 patients and 5441 treatment cycles, a total of 12 853 patient-years. The combination of a biologic with MTX was not associated with statistically significant increases in overall risk of AEs or SAEs in any treatment group. No increase in the total number of infections or serious infections in patients receiving combined therapy was observed for any group. However, treatment with a TNF inhibitor combined with MTX was associated with an increase in the incidence of gastrointestinal AEs (aIRR 2.50, 95% CI 1.57-3.98; P < 0.002). CONCLUSIONS: The risk of AEs and SAEs was not significantly increased in patients with moderate-to-severe psoriasis receiving different classes of biologic drugs combined with MTX compared with those on biologic monotherapy.

Neural Networks-Based On-Site Dermatologic Diagnosis through Hyperspectral Epidermal Images.

Cancer originates from the uncontrolled growth of healthy cells into a mass. Chromophores, such as hemoglobin and melanin, characterize skin spectral properties, allowing the classification of lesions into different etiologies. Hyperspectral imaging systems gather skin-reflected and transmitted light into several wavelength ranges of the electromagnetic spectrum, enabling potential skin-lesion differentiation through machine learning algorithms. Challenged by data availability and tiny inter and intra-tumoral variability, here we introduce a pipeline based on deep neural networks to diagnose hyperspectral skin cancer images, targeting a handheld device equipped with a low-power graphical processing unit for routine clinical testing. Enhanced by data augmentation, transfer learning, and hyperparameter tuning, the proposed architectures aim to meet and improve the well-known dermatologist-level detection performances concerning both benign-malignant and multiclass classification tasks, being able to diagnose hyperspectral data considering real-time constraints. Experiments show 87% sensitivity and 88% specificity for benign-malignant classification and specificity above 80% for the multiclass scenario. AUC measurements suggest classification performance improvement above 90% with adequate thresholding. Concerning binary segmentation, we measured skin DICE and IOU higher than 90%. We estimated 1.21 s, at most, consuming 5 Watts to segment the epidermal lesions with the U-Net++ architecture, meeting the imposed time limit. Hence, we can diagnose hyperspectral epidermal data assuming real-time constraints.

Assessing the effect of environmental and socio-economic factors on skin melanoma incidence: an island-wide spatial study in Gran Canaria (Spain), 2007-2018.

INTRODUCTION: Skin melanoma incidence has risen in the last decades becoming a major public health problem in many regions of the world. Geographic variation of rates is not well understood. PURPOSE: To assess the spatial distribution of skin melanoma in Gran Canaria Island (Canary Islands, Spain) and to evaluate the role of environmental, socio-economic, and demographic factors in this distribution. METHODS: We performed a small-area study with disease mapping at the census-tract level (CT) in Gran Canaria between 2007 and 2018. After testing for spatial autocorrelation, we integrated individual-level health data with census-based demographic and socio-economic indicators, and satellite-based environmental data. Finally, we assessed the role of demographic, socio-economic and environmental factors on skin melanoma incidence using a Bayesian analytical framework, with options for non-spatial and spatial random effects. RESULTS: 1058 patients were diagnosed with invasive skin melanoma in the study period and geolocated to a CT (number of CT in Gran Canaria = 565). We found evidence of global spatial autocorrelation in skin melanoma incidence (Moran's I = 0.09, pseudo p-value = 0.001). A few hotspots were detected, fundamentally in urban northern tracts. A radial pattern of high values was also observed in selected ravines with historical isolation. Multivariable conditional autoregressive models identified urbanicity, percent of females, and a high socio-economic status as risk factors for disease. Solar radiation did not show a significant role. CONCLUSION: Urbanicity and a high socio-economic status were identified as the main risk factors for skin melanoma. These associations might reflect differential melanoma susceptibilities or be explained by health inequalities in detection. This study also uncovered high-risk areas in particular ravines. Future targeted research in these regions might help better understand the role of genetic and toxic factors in melanoma pathogenesis.

The risk of hepatic adverse events of systemic medications for psoriasis: a prospective cohort study using the BIOBADADERM registry.

BACKGROUND: Limited information is available regarding the risk of incident liver disease in patients with psoriasis receiving systemic therapies. OBJECTIVES: To describe the liver safety findings of conventional and modern systemic therapies for moderate-to-severe psoriasis, and to compare the relative incidence rates of hepatic adverse events (AEs) for each drug. METHODS: All the patients on the BIOBADADERM registry were included. Crude and adjusted incidence rate ratios (cIRR and aIRR, respectively) of hepatic AEs, using anti-TNF drugs as reference, were determined. Outcomes of interest were hypertransaminasemia, nonalcoholic fatty liver disease (NADFLD) and a group of other, less represented, hepatic AEs. RESULTS: Our study included 3,171 patients exposed to systemic drugs (6279 treatment cycles). Incident hypertransaminasemia was the most frequent hepatic AE (incidence rate of 21 per 1000 patients-years [CI 95% 18-23]), followed by NAFLD (8 cases per 1000 patients-years [95% CI 6-10]). Methotrexate (aIRR 3.06 [2.31-4.4]; p = 0.000) and cyclosporine (aIRR 2.37 [1.05-5.35]; p = .0378) were associated with an increased risk for hypertransaminasemia when compared to anti-TNF-α agents. No differences were observed between different groups of biologics. Conventional therapies were not associated with new incident NAFLD. CONCLUSIONS: Comparative information of the incidence of hepatic AEs could facilitate drug selection in moderate-to-severe psoriasis.

The incidence of skin melanoma in Gran Canaria (Canary Islands, Spain) is lower than expected in Southern Europe despite high-risk environmental conditions: an island-wide cross-sectional study.

BACKGROUND: The Canary Islands are a leading European touristic destination. The ultraviolet index (UVI) in the region is the highest in Spain, and similar to indexes registered in Australia and New Zealand, which hold the highest incidence of skin melanoma worldwide. Yet according to cancer registry data, the incidence in the Canary Islands in the late 1990s was the lowest in Spain (among the lowest in Europe) and about six times lower than in New Zealand. PURPOSE: To analyze the incidence rates of skin melanoma in Gran Canaria island between 2007 and 2018. METHODS: The study was based in the two centres of the Canary Islands' Healthcare Service centralizing melanoma care in Gran Canaria. We analyzed crude and age-standardized (ASR) incidence rates of invasive cutaneous melanoma for the period 2007-2018 following the inclusion criteria of the International Agency for Research on Cancer (IARC). Clinical and histological characteristics of melanoma patients were assessed. RESULTS: A total of 1058 patients were included. The incidence rates obtained matched the latest available Canary Islands' cancer registry data, confirming its reliability (ASR, Segi-Doll world standard population: 6.4 cases per 100,000 habitants for 2008-2012). The incidence was also below the latest IARC predictions for Southern Europe (GLOBOCAN 2018). Histological characteristics of patients were similar to other Southern European series. CONCLUSIONS: The incidence of skin melanoma in Gran Canaria is unexpectedly low for a Southern European population exposed to such a high UVI. Further research in the Canary Islands could provide insight into a better understanding of melanoma pathogenesis.

Curve-Based Classification Approach for Hyperspectral Dermatologic Data Processing.

This paper shows new contributions in the detection of skin cancer, where we present the use of a customized hyperspectral system that captures images in the spectral range from 450 to 950 nm. By choosing a 7 × 7 sub-image of each channel in the hyperspectral image (HSI) and then taking the mean and standard deviation of these sub-images, we were able to make fits of the resulting curves. These fitted curves had certain characteristics, which then served as a basis of classification. The most distinct fit was for the melanoma pigmented skin lesions (PSLs), which is also the most aggressive malignant cancer. Furthermore, we were able to classify the other PSLs in malignant and benign classes. This gives us a rather complete classification method for PSLs with a novel perspective of the classification procedure by exploiting the variability of each channel in the HSI.

Genome-wide association analysis of psoriasis patients treated with anti-TNF drugs.

While anti-TNF therapies are effective against psoriasis, 30%-50% of patients do not show an adequate response to these drugs. Different candidate-gene pharmacogenetics studies have identified single nucleotide polymorphisms that may predict anti-TNF drugs response in psoriasis. Nevertheless, only one paper has undertaken a pharmacogenomic approach failing to find significant biomarkers of biological drug response along the whole genome. Furthermore, most of the pharmacogenetic candidate biomarkers identified previously have not been confirmed in a different cohort of patients. The objective of this study was to find biomarkers that could predict anti-TNF drugs response along the whole genome and validate biomarkers identified previously. A genome-wide association study (GWAS) was performed using the Human Omni Express-8 v1.2 Beadchips in 243 psoriasis patients treated with anti-TNF drugs. This study was multicentric and did not interfere with clinical practice. Associations between single nucleotide polymorphisms (SNP) and PASI75 (a 75% reduction with respect to baseline PASI) at 3 months were evaluated. Imputation was performed using SNPs with R2  > 0.7. There were two SNPs located in NPFFR2 that were close to the significant threshold of 5 × 10-8 . These data suggest that NPFFR2 might be associated with anti-TNF drug response. However, further studies involving a larger cohort of patients are needed in order to confirm these results.

Non-Invasive Skin Cancer Diagnosis Using Hyperspectral Imaging for In-Situ Clinical Support.

Skin cancer is one of the most common forms of cancer worldwide and its early detection its key to achieve an effective treatment of the lesion. Commonly, skin cancer diagnosis is based on dermatologist expertise and pathological assessment of biopsies. Although there are diagnosis aid systems based on morphological processing algorithms using conventional imaging, currently, these systems have reached their limit and are not able to outperform dermatologists. In this sense, hyperspectral (HS) imaging (HSI) arises as a new non-invasive technology able to facilitate the detection and classification of pigmented skin lesions (PSLs), employing the spectral properties of the captured sample within and beyond the human eye capabilities. This paper presents a research carried out to develop a dermatological acquisition system based on HSI, employing 125 spectral bands captured between 450 and 950 nm. A database composed of 76 HS PSL images from 61 patients was obtained and labeled and classified into benign and malignant classes. A processing framework is proposed for the automatic identification and classification of the PSL based on a combination of unsupervised and supervised algorithms. Sensitivity and specificity results of 87.5% and 100%, respectively, were obtained in the discrimination of malignant and benign PSLs. This preliminary study demonstrates, as a proof-of-concept, the potential of HSI technology to assist dermatologists in the discrimination of benign and malignant PSLs during clinical routine practice using a real-time and non-invasive hand-held device.

Low educational attainment is still associated with late melanoma diagnosis: A cross-sectional study from a European setting with universal healthcare.

BACKGROUND: An early diagnosis of cutaneous melanoma remains determinant for improved survival. Low educational attainment has been associated with a late-stage diagnosis in settings where access to healthcare is restricted. Little evidence is available from regions with universal healthcare. We aimed at analysing whether educational attainment was associated with Breslow thickness at diagnosis in a peripheral European region with universal healthcare (in the Canary Islands, Spain). METHODS: We conducted a cross-sectional study with prospectively collected data (2010-2017). Patients were recruited at diagnosis, and information about Breslow thickness, age at diagnosis, gender, highest educational attainment and site of melanoma were registered. Univariate and multivariate linear regression analyses were performed. RESULTS: Low educational attainment was associated with thicker tumours at diagnosis. The association remained true after adjustment for age, gender and site of melanoma. In the multivariate analysis, tumours diagnosed in patients with low educational attainment were on average 1.08 mm thicker (95% confidence interval: 0.36-1.81; p = 0.003) than those diagnosed in patients with high educational attainment. CONCLUSION: Public health strategies targeting this vulnerable group are currently needed in the Canary Islands (Spain).

Risk of serious infections, cutaneous bacterial infections, and granulomatous infections in patients with psoriasis treated with anti-tumor necrosis factor agents versus classic therapies: Prospective meta-analysis of Psonet registries.

BACKGROUND: Anti-tumor necrosis factor (TNF) therapy in psoriasis has been associated with an increased risk of serious infections compared with nonbiologic systemic therapies. OBJECTIVE: We sought to quantify the risk of: (1) serious infections (leading to hospitalization, sequelae, or death); and (2) "any infection," bacterial cutaneous infections, and granulomatous infections among patients receiving anti-TNF therapy compared with nonbiologics (acitretin, methotrexate, cyclosporine). METHODS: We used prospective meta-analysis to combine data from the Psocare registry (Italy), Biobadaderm registry (Spain), and Clalit Health Services database (Israel), including 17,739 patients and 23,357.5 person-years of follow-up. RESULTS: For serious infections, age, gender, and Charlson morbidity index adjusted hazard ratio of exposure to anti-TNFs compared with nonbiologics was 0.98 (95% confidence interval 0.80-1.19), for bacterial cutaneous infections it was 1.00 (95% confidence interval 0.62-1.61), and for granulomatous infections it was 1.23 (95% confidence interval 0.82-1.84). Using methotrexate as comparator and comparing first year of exposure with later exposure did not modify the results. For any infectious episode, risks and relative risks were heterogeneous among registries, probably because of different definitions of outcome. LIMITATIONS: There was lack of power to describe risk of single drugs. CONCLUSION: In current clinical practice, treatment with anti-TNF drugs was not associated with a higher risk of serious infections than treatment with nonbiologic systemic therapy.

Development of clinical prediction models for good or bad response to classic systemic drugs, anti-TNFs, and ustekinumab in psoriasis, based on the BIOBADADERM cohort.

BACKGROUND: Identifying patients likely to have very good or bad results from systemic psoriasis therapy could improve efficiency of therapy. OBJECTIVE: To develop prognostic models for good or bad response to classic systemic drugs, anti-TNFs, and ustekinumab in psoriasis. METHODS: Multivariable logistic regression of a prospective multicenter cohort of psoriatic patients in clinical practice (6449 person-years of follow-up). We used as possible predictors demographic characteristics, comorbidities, characteristics of the psoriasis (type, PASI, arthritis), history of past therapy at entry in the cohort, and history of response to previous cycles while in the cohort. We defined good response to a treatment cycle as either cycle end due to disease remission or a cycle longer than 2 years that does not end later due to inefficacy in the follow-up period. Bad response to a treatment cycle was defined as a cycle that is finished due to inefficacy, based on the physician judgment, after more than 3 months of treatment. RESULTS: Patients with fewer previous therapies, lower body mass index, older at start of therapy, and with previous history of good responses to therapy are more likely to have positive results of therapy. However, the predictive characteristics of models are poor. CONCLUSION: Predictive models of clinical response to systemic drugs in psoriasis with the studied variables do not seem to outperform drug selection by a dermatologist.

Long telomere length and a TERT-CLPTM1 locus polymorphism association with melanoma risk.

Telomere length has been associated with the development of cancer. Studies have shown that shorter telomere length may be related to a decreased risk of cutaneous melanoma. Furthermore, deregulation of the telomere-maintaining gene complexes, has been related to this oncogenic process. Some variants in these genes seem to be correlated with a change in telomerase expression. We examined the effect of 10 single nucleotide polymorphisms (SNPs) in the TERT gene (encoding telomerase), one SNP in the related TERT-CLPTM1L locus and one SNP in the TRF1 gene with telomere length, and its influence on melanoma risk in 970 Spanish cases and 733 Spanish controls. Genotypes were determined using KASP technology, and telomere length was measured by quantitative polymerase chain reaction (PCR) on DNA extracted from peripheral blood leucocytes. Our results demonstrate that shorter telomere length is associated with a decreased risk of melanoma in our population (global p-value, 2.69×10(-11)), which may be caused by a diminution of proliferative potential of nevi (melanoma precursor cells). We also obtained significant results when we tested the association between rs401681 variant (TERT-CLPTM1L locus) with melanoma risk (Odds ratio, OR; 95% confidence interval, CI=1.24 (1.08-1.43); p-value, 3×10(-3)). This is the largest telomere-related study undertaken in a Spanish population to date. Furthermore, this study represents a comprehensive analysis of some of the most relevant telomere pathway genes in relation to cutaneous melanoma susceptibility.

Involvement of ANXA5 and ILKAP in susceptibility to malignant melanoma.

Single nucleotide-polymorphisms (SNPs) are a source of diversity among human population, which may be responsible for the different individual susceptibility to diseases and/or response to drugs, among other phenotypic traits. Several low penetrance susceptibility genes associated with malignant melanoma (MM) have been described, including genes related to pigmentation, DNA damage repair and oxidative stress pathways. In the present work, we conducted a candidate gene association study based on proteins and genes whose expression we had detected altered in melanoma cell lines as compared to normal melanocytes. The result was the selection of 88 loci and 384 SNPs, of which 314 fulfilled our quality criteria for a case-control association study. The SNP rs6854854 in ANXA5 was statistically significant after conservative Bonferroni correction when 464 melanoma patients and 400 controls were analyzed in a discovery Phase I. However, this finding could not be replicated in the validation phase, perhaps because the minor allele frequency of SNP rs6854854 varies depending on the geographical region considered. Additionally, a second SNP (rs6431588) located on ILKAP was found to be associated with melanoma after considering a combined set of 1,883 MM cases and 1,358 disease-free controls. The OR was 1.29 (95% CI 1.12-1.48; p-value = 4×10-4). Both SNPs, rs6854854 in ANXA5 and rs6431588 in ILKAP, show population structure, which, assuming that the Spanish population is not significantly structured, suggests a role of these loci on a specific genetic adaptation to different environmental conditions. Furthermore, the biological relevance of these genes in MM is supported by in vitro experiments, which show a decrease in the transcription levels of ANXA5 and ILKAP in melanoma cells compared to normal melanocytes.

rs12512631 on the group specific complement (vitamin D-binding protein GC) implicated in melanoma susceptibility.

BACKGROUND: Solar radiation should be avoided in melanoma patients. Nevertheless, this is the main means by which the body produces vitamin D. Evidence suggests a protective role against cancer for vitamin D. Since vitamin D performs its function by binding the receptor encoded by the vitamin D-receptor gene (VDR), most studies have focused on polymorphisms (SNPs) within this gene. However, the gene encoding the vitamin D-binding protein (GC) appears in recent studies as a major player in the role of a serum vitamin D level regulator and in Cutaneous Melanoma (CM) predisposition. METHODS: We performed a case-control study of 12 polymorphisms on GC and 9 on VDR among 530 cases and 314 controls from Spanish population. RESULTS: We found association between SNP rs12512631, located 3'downstream of GC, and risk of CM that seems to fit a dominant model (OR 1.63 95%CI 1.23-2.17 p-value 7×10(-4)). This association remained Bonferroni's correction and after adjustment for potential confounders (p-value 3×10(-3)) and even after increasing the sample size to 1729 individuals (p-value 0.0129). Moreover, we confirmed evidence of an association between CM susceptibility and the linkage disequilibrium block marked by tag-SNP rs222016 (p-value 0.032). This block covers the GC intron 1 region, with probable regulatory functions. CONCLUSION: To our knowledge, this is the first vitamin D pathway-related polymorphism study in melanoma risk conducted in the Spanish population. Furthermore, we show an association between polymorphisms in GC and melanoma risk, confirming recent studies in different populations.

Risk of serious adverse events associated with biologic and nonbiologic psoriasis systemic therapy: patients ineligible vs eligible for randomized controlled trials.

OBJECTIVE: To describe the use of systemic therapy for psoriasis (biologic and nonbiologic [classic] drugs) in patients not adequately represented in randomized controlled trials (RCTs) and the risk of serious adverse events (SAEs) in these patients. DESIGN: A registry inception cohort was used. SETTING: Thirteen dermatology departments in Spain participated. PATIENTS: A consecutive sample of patients treated with biologics and a systematic sample of patients treated with classic systemic therapy were evaluated. A total of 1042 patients (2179 person-years) were included. EXPOSURE: Inadequate representation in trials was defined as the presence of any of the following factors: elderly age (>70 years); type of psoriasis other than chronic plaque psoriasis; history of infection caused by hepatitis B, hepatitis C, or human immunodeficiency virus; history of cancer (excluding nonmelanoma skin cancer); and chronic renal or hepatic disease. MAIN OUTCOME MEASURES: Serious adverse events as defined by the International Conference on Harmonization were evaluated. RESULTS: In all, 29.8% of patients receiving systemic therapy for psoriasis would not have been eligible for RCTs. These individuals had an increased risk of SAEs (incidence rate ratio, 2.7; 95% CI, 1.5-4.7). Patients exposed to biologics had an adjusted increased risk of SAEs (incidence rate ratio, 2.3; 95% CI, 1.1-4.8) that was similar in patients eligible and ineligible for RCTs. CONCLUSIONS: Patients ineligible for RCTs are an important proportion (30%) of those receiving systemic therapy for psoriasis. These patients have a higher risk of SAEs and should be closely monitored. Patients exposed to biologics (whether these patients are eligible for RCTs or ineligible) are susceptible to the same increase in risk of SAEs, but biologics add to a higher baseline risk in patients who are ineligible for RCTs. The risk-benefit ratio in ineligible patients receiving biologics might be different from the ratio in eligible patients.

A customized pigmentation SNP array identifies a novel SNP associated with melanoma predisposition in the SLC45A2 gene.

As the incidence of Malignant Melanoma (MM) reflects an interaction between skin colour and UV exposure, variations in genes implicated in pigmentation and tanning response to UV may be associated with susceptibility to MM. In this study, 363 SNPs in 65 gene regions belonging to the pigmentation pathway have been successfully genotyped using a SNP array. Five hundred and ninety MM cases and 507 controls were analyzed in a discovery phase I. Ten candidate SNPs based on a p-value threshold of 0.01 were identified. Two of them, rs35414 (SLC45A2) and rs2069398 (SILV/CKD2), were statistically significant after conservative Bonferroni correction. The best six SNPs were further tested in an independent Spanish series (624 MM cases and 789 controls). A novel SNP located on the SLC45A2 gene (rs35414) was found to be significantly associated with melanoma in both phase I and phase II (P<0.0001). None of the other five SNPs were replicated in this second phase of the study. However, three SNPs in TYR, SILV/CDK2 and ADAMTS20 genes (rs17793678, rs2069398 and rs1510521 respectively) had an overall p-value<0.05 when considering the whole DNA collection (1214 MM cases and 1296 controls). Both the SLC45A2 and the SILV/CDK2 variants behave as protective alleles, while the TYR and ADAMTS20 variants seem to function as risk alleles. Cumulative effects were detected when these four variants were considered together. Furthermore, individuals carrying two or more mutations in MC1R, a well-known low penetrance melanoma-predisposing gene, had a decreased MM risk if concurrently bearing the SLC45A2 protective variant. To our knowledge, this is the largest study on Spanish sporadic MM cases to date.

Utility of myeloperoxidase stain in the differential diagnosis of leukemia cutis vs. hystiocitoid Sweet syndrome.

Leukemia cutis is defined as a skin infiltration by leukemic cells. The diagnosis of myeloid leukemia cutis (MLC) can represent a challenge, especially in those cases without symptoms of systemic disease. The clinical appearance, histopathological analysis and immunohistochemical profile can be indistinguishable from those observed in cases of hystiocitoid Sweet syndrome (HSS). We present a case of MLC in which the cutaneous affectation was the first sign of the systemic leukemia. In this setting, the myeloperoxidase stain was the clue to rule out the possibility of HSS. We discuss the role and the utility of the myeloperoxidase stain in the differentiation of these two entities.