Impact of Functional Polymorphisms on Drug Survival of Biological Therapies in Patients with Moderate-to-Severe Psoriasis

Biological therapies (BTs) indicated for psoriasis are highly effective; however, not all patients obtain good results, and loss of effectiveness is the main reason for switching. Genetic factors may be involved. The objective of this study was to evaluate the influence of single-nucleotide polymorphisms (SNPs) on the drug survival of tumor necrosis factor inhibitors (anti-TNF) medications and ustekinumab (UTK) in patients diagnosed with moderate-to-severe psoriasis. We conducted an ambispective observational cohort study that included 379 lines of treatment with anti-TNF (n = 247) and UTK (132) in 206 white patients from southern Spain and Italy. The genotyping of the 29 functional SNPs was carried out using real-time polymerase chain reaction (PCR) with TaqMan probes. Drug survival was evaluated with Cox regression and Kaplan-Meier curves. The multivariate analysis showed that the HLA-C rs12191877-T (hazard ratio [HR] = 0.560; 95% CI = 0.40-0.78; p = 0.0006) and TNF-1031 (rs1799964-C) (HR = 0.707; 95% CI = 0.50-0.99; p = 0.048) polymorphisms are associated with anti-TNF drug survival, while TLR5 rs5744174-G (HR = 0.589; 95% CI = 0.37-0.92; p = 0.02), CD84 rs6427528-GG (HR = 0.557; 95% CI = 0.35-0.88; p = 0.013) and PDE3A rs11045392-T together with SLCO1C1 rs3794271-T (HR = 0.508; 95% CI = 0.32-0.79; p = 0.002) are related to UTK survival. The limitations are the sample size and the clustering of anti-TNF drugs; we used a homogeneous cohort of patients from 2 hospitals only. In conclusion, SNPs in the HLA-C, TNF, TLR5, CD84, PDE3A, and SLCO1C1 genes may be useful as biomarkers of drug survival of BTs indicated for psoriasis, making it possible to implement personalized medicine that will reduce financial healthcare costs, facilitate medical decision-making and improve patient quality of life. However, further pharmacogenetic studies need to be conducted to confirm these associations.University of Granada and the Fundación de Investigación Biosanitaria de Andalucía Oriental (FIBAO)Virgen de las Nieves University Hospital Biobank was supported by grants co-funded by ERDF funds (EU) from the Instituto de Salud Carlos III (PT13/0010/0039)

Influence of Genetic Polymorphisms on Response to Biologics in Moderate-to-Severe Psoriasis

This work was partly supported by a contract for Cristina Membrive Jimenez from the University of Granada and the Fundacion de Investigacion Biosanitaria de Andalucia Oriental (FIBAO). The Virgen de las Nieves University Hospital Biobank was supported by grants co-funded by ERDF funds (EU) from the Instituto de Salud Carlos III (PT13/0010/0039).The results of this research are part of the doctoral thesis that will be presented by Cristina Membrive Jiménez at the University of Granada as part of the doctoral studies in “Pharmacy”.Psoriasis is a chronic inflammatory skin pathology of autoimmune origin and unknown etiology. There are various therapies for treating it, including a wide range of biopharmaceuticals indicated in moderate-to-severe psoriasis. Depending on their therapeutic target, they are classified as tumor necrosis factor inhibitors (anti-TNF) or cytokine inhibitors (interleukin-12, 23, and 17 antagonists). Although they have proved effective and safe, in clinical practice, many patients show a short- and long-term suboptimal response and even varying degrees of toxicity. This variability in response may be influenced by genetic factors, such as polymorphisms in the genes involved in the pathological environment, metabolism or mechanism of action of the drug that could affect the effectiveness and toxicity of biological therapies. This review assesses pharmacogenetic studies of the impact of genetic factors on response to biopharmaceuticals and toxicity in patients diagnosed with moderate-to-severe psoriasis. The results suggest that polymorphisms detected in the HLA genes, in genes that encode cytokines (TNF, IL genes, TNFAIP3), transporters (PDE3A-SLCO1C1, SLC12A8), receptors (TNFRSF1B, CD84, FCGR2A and FCGR3A, IL17RA, IL23R, TLR genes, PGLYRP4) and associated proteins (TNFAIP3, LY96, TIRAP, FBXL19), as well as other genes implicated in the pathogenesis of psoriasis (CDKAL1, CARD14, PTTG1, MAP3K1, ZNF816A, GBP6, CTNNA2, HTR2A, CTLA4, TAP1) can be used in the future as predictive markers of treatment response and/or toxicity with biological therapies in patients diagnosed with moderate-to-severe psoriasis, tailoring treatment to the individual patient.University of GranadaFundacion de Investigacion Biosanitaria de Andalucia Oriental (FIBAO)ERDF funds (EU) from the Instituto de Salud Carlos III PT13/0010/003

Single Nucleotide Polymorphisms in the Vitamin D Metabolic Pathway and Their Relationship with High Blood Pressure Risk

High blood pressure (HBP) is the leading risk factor for cardiovascular disease (CVD) and all-cause mortality worldwide. The progression of the disease leads to structural and/or functional alterations in various organs and increases cardiovascular risk. Currently, there are significant deficiencies in its diagnosis, treatment, and control. Vitamin D is characterized by its functional versatility and its involvement in countless physiological processes. This has led to the association of vitamin D with many chronic diseases, including HBP and CVD, due to its involvement in the regulation of the renin–angiotensin–aldosterone system. The aim of this study was to evaluate the effect of 13 single nucleotide polymorphisms (SNPs) related to the vitamin D metabolic pathway on the risk of developing HBP. An observational case-control study was performed, including 250 patients diagnosed with HBP and 500 controls from the south of Spain (Caucasians). Genetic polymorphisms in CYP27B1 (rs4646536, rs3782130, rs703842, and rs10877012), CYP2R1 rs10741657, GC rs7041, CYP24A1 (rs6068816, and rs4809957), and VDR (BsmI, Cdx2, FokI, ApaI, and TaqI) were analyzed by real-time PCR using TaqMan probes. Logistic regression analysis, adjusted for body mass index (BMI), dyslipidemia, and diabetes, showed that in the genotypic model, carriers of the GC rs7041 TT genotype were associated with a lower risk of developing HBP than the GG genotype (odds ratio (OR) = 0.44, 95% confidence interval (CI): 0.41–0.77, p = 0.005, TT vs. GG). In the dominant model, this association was maintained; carriers of the T allele showed a lower risk of developing HBP than carriers of the GG genotype (OR = 0.69, 95% CI: 0.47–1.03; TT + TG vs. GG, p = 0.010). Finally, in the additive model, consistent with previous models, the T allele was associated with a lower risk of developing HBP than the G allele (OR = 0.65, 95% CI: 0.40–0.87, p = 0.003, T vs. G). Haplotype analysis revealed that GACATG haplotypes for SNPs rs1544410, rs7975232, rs731236, rs4646536, rs703842, and rs10877012 were associated with a marginally significant lower risk of developing HBP (OR = 0.35, 95% CI: 0.12–1.02, p = 0.054). Several studies suggest that GC 7041 is associated with a lower active isoform of the vitamin D binding protein. In conclusion, the rs7041 polymorphism located in the GC gene was significantly associated with a lower risk of developing HBP. This polymorphism could therefore act as a substantial predictive biomarker of the disease.ERDF funds (EU) from the Instituto de Salud Carlos III (PT13/0010/0039) supported by co-funding grants from the Biobank of the Hospital Universitario Virgen de las Nieves

Polymorphisms in VDR, CYP27B1, CYP2R1, GC and CYP24A1 Genes as Biomarkers of Survival in Non-Small Cell Lung Cancer: A Systematic Review

The objective of this systematic review was to provide a compilation of all the literature available on the association between single-nucleotide polymorphisms (SNPs) in the genes involved in the metabolic pathway of vitamin D and overall survival (OS) and progression-free survival (PFS) in patients with non-small cell lung cancer (NSCLC). This systematic review was conducted in accordance with the PRISMA guidelines. It included all the literature published up to 1 November 2022 and was carried out in four databases (Medline [PubMed], Scopus,Web of Science, and Embase), using the PICO strategy, with relevant keywords related to the objective. The quality of the studies included was evaluated with an assessment tool derived from the Strengthening the Reporting of Genetic Association Studies (STREGA) statement. Six studies were included in this systematic review. Our findings showed that the BsmI (rs1544410), Cdx-2 (rs11568820), FokI (rs2228570), ApaI (rs7975232), TaqI (rs731236), rs4646536, rs6068816, rs7041, and rs10741657 SNPs in the genes that play a part in vitamin D synthesis (CYP2R1, CYP27B1), transport (GC), and metabolism (CYP24A1), as well as in the vitamin D receptor (VDR), are associated with OS and/or PFS in patients with NSCLC. The SNPs in VDR have been the most extensively analyzed. This systematic review summed up the available evidence concerning the association between 13 SNPs in the main genes involved in the vitamin D metabolic pathway and prognosis in NSCLC. It revealed that SNPs in the VDR, CYP27B1, CYP24A1, GC, and CYP2R1 genes could have an impact on survival in this disease. These findings suggest the identification of prognostic biomarkers in NSCLC patients. However, evidence remains sparse for each of the polymorphisms examined, so these findings should be treated with caution.The Virgen de las Nieves University Hospital Biobank was supported by grants co-funded by ERDF funds (EU) from the Instituto de Salud Carlos III (PT13/0010/0039)

Biomarkers predicting response and toxicity to treatment with biological therapies in patients diagnosed with psoriatic disease

Psoriasis is an autoimmune skin disease with a prevalence between 2-4%. It is characterized by the development of lesions in the form of erythematous plaques with whitish scales on the scalp, elbows, knees and back, mainly. In addition, it is associated with other potentially disabling pathologies. Consequently, psoriasis is considered a systemic pathology with a great impact on the quality of life of patients and generates high health costs. Genetic, immunological and environmental factors can trigger psoriatic lesions, which are maintained by alterations in cutaneous immune responses. In this process, dendritic cells activated by Toll-like receptors interfere, producing a cytokine cascade [TNF and interleukins (IL) IL-12, IL-17 and IL-23] that activates the hyperproliferation of keratinocytes in the epidermis and leads to the appearance of epidermal hyperplasia, typical of psoriasis lesions. The treatment of moderate-severe psoriasis is based mainly on biological therapies (BT). The first-line biologicals are inhibitors of tumor necrosis factor, known as “anti-TNF” [infliximab (INF), etanercept (ETN), adalimumab (ADA) and certolizumab (CTL)] and the inhibitor of the p40 subunit of IL12 and IL23 [ustekinumab (UTK)]. In addition, as a last option of treatment there are drugs inhibiting IL17 and IL23, authorized more recently. Anti-TNF and UTK drugs have proven to be highly effective and safe. However, not all patients achieve good results, loss of efficacy is the main reason for change or “switching” of BT (in the long term, especially). This implies a great economic burden for health systems, hindering medical decision-making and worsening the quality of life of patients. Genetic factors may be involved in the variability of pharmacological survival of BT in psoriatic patients. Numerous pharmacogenetic studies in patients with psoriasis treated with BT (specifically, anti- TNF and UTK) have been carried out to find biomarkers predicting efficacy and/or toxicity. So far it has been found that allelic variants and single nucleotide polymorphisms (SNPs) in human leukocyte antigen (HLA) genes, which collaborate identifying exogenous proteins and can trigger the immune response, could be associated with the response to BT. Likewise, SNPs in genes encoding proteins directly involved in the cytokine cascade (TNF and IL-1, IL-6, IL-12 and IL-17) or receptors that regulate or trigger this cytokine cascade, typical of psoriasis (CD84, FCGR, IL17RA, IL23R, SLC and TLR) have been shown to have an impact on the response of BT. Despite knowing the possible impact of the biomarkers mentioned above, it is currently not possible to translate this information into routine clinical practice of psoriasis due to the lack of scientific evidence. Therefore, it is necessary to study and confirm the effect of functional genetic polymorphisms in more studies so that they can be established as biomarkers predicting response to BT indicated in moderate-severe psoriasis. HYPOTHESIS Certain genetic polymorphisms involved in the pathogenesis of psoriasis and the target of biologic drugs that inhibit TNF or IL12 and 23 may influence the interindividual variability in response to these drugs in patients with moderate-severe psoriasis. Therefore, it is essential to study and validate the utility of these genetic polymorphisms as predictive biomarkers of drug retention in psoriasis, enabling the implementation of personalised medicine. OBJECTIVES Main objective To assess the impact of immunogenetic factors as prognostic and predictive biomarkers of response to biologic therapy in patients with moderate-severe psoriasis, specifically anti-TNF and IL12/23 inhibitors. Specific objectives • To determine the role of genetic polymorphisms involved in the response of patients diagnosed with moderate-severe psoriasis treated with anti-TNF and UTK drugs. • To assess drug survival of anti-TNF and UTK in Caucasian patients diagnosed with moderate-severe psoriasis, and the reasons for discontinuing TB therapy. • To evaluate the association between functional genetic polymorphisms and the longterm efficacy of biological treatment, as measured by pharmacological survival of anti- TNF and UTK. MATERIALS AND METHODS We conducted an ambispective cohort study of 379 therapeutic lines [anti-TNF (n = 247) and UTK (n = 132)] from 198 Caucasian patients with moderate-severe psoriasis in southern Spain and Italy [Hospital Universitario Virgen de las Nieves (HUVN) and Centro Hospitalario- Universitario Policlínico Umberto I (PUI)]. Sociodemographic and clinical variables were obtained from the review of patients' medical records and personal interviews. DNA samples were collected by buccal swab or blood and extracted using a DNA extraction kit from saliva or blood. Subsequently, 29 genetic polymorphisms were analysed by real-time PCR with TaqMan® probes: HLA-B/MICA (rs13437088), HLA-C (rs12191877), TNF-238 (rs361525), TNF-857 (rs1799724), TNF-308 (rs1800629), TNF-1031 (rs1799964), TNFRSF1B (rs1061622), TNFAIP3 (rs610604), IL1B (rs1143623 and rs1143627), IL6 (rs1800795), IL12B (rs3213094 and rs2546890), TIRAP (rs8177374), PGLYR4-24 (rs2916205), CDKAL1 (rs6908425), CD84 (rs6427528), IL17RA (rs4819554), IL23R (rs11209026), TLR2 (rs4696480 and rs11938228), TLR5 (rs5744174), TLR9 (rs352139), PDE3A (rs11045392), SLCO1C1 (rs3794271), FCGR2A (rs1801274), FCGR3A (rs396991), LY96 (rs11465996) and BCL2 (rs59532114). The effect of these functional genetic polymorphisms on anti-TNF and UTK drug survival was evaluated using R 3.5 software by applying the following statistical methods: chi-square test, Fisher's test and survival analysis by Cox regression and Kaplan-Meier regression method. RESULTS Multivariate Cox regression analysis showed that patients carrying the T allele of the HLA-C polymorphism rs12191877 (HR=0.560; 95%CI=0.40-0.78; p=0.0006) and the C allele of the TNF- 1031 polymorphism rs1799964 (HR=0.707; 95%CI=0.50-0.99; p=0.048) are associated with longer survival to anti-TNF drugs in our population (Table 1). In contrast, patients carrying the G allele of the TLR5 rs5744174 polymorphism (HR=0.589; 95%CI=0.37-0.92; p=0.02), the GG genotype for the CD84 rs6427528 polymorphism (HR=0.557; 95%CI=0.35-0.88; p=0. 013), and the T allele of the PDE3A rs11045392 polymorphism, which is in linkage disequilibrium with the SLCO1C1 rs3794271 polymorphism (HR=0.508; 95%CI=0.32- 0.79; p=0.002), had increased drug survival to UTK (Table 2). However, we observed no association between CDKAL1 (rs6908425), FCGR2A (rs1801274), FCGR3A (rs396991), HLA B/MICA(rs13437088), IL1B (rs1143623), IL6 (rs1800795), IL12B (rs3213094 and rs2546890) genetic polymorphisms, IL17RA (rs4819554), IL23R (rs11209026), PGLYR4-24 (rs2916205), TIRAP (rs8177374), TLR2 (rs4696480 and rs11938228), TLR9 (rs352139), TNF-857 (rs1799724), TNFAIP3 (rs610604), TNFRSF1B (rs1061622) and TB survival included in this study. In addition, the median TB duration was 24 months (9-51.5), with UTK showing the longest survival (Plong rank=0.07, 36 months vs. 24). Specifically, patients treated with anti-TNF had 1.32 higher risk of discontinuation than those treated with UTK (HR=1.32; 95%CI=1.02-1.7; p=0.0316). Loss of efficacy was the main reason for discontinuation (n=188; 67.14%), followed by the adverse events (n=55; 19.64%). Patients treated with UTK had 1.9 higher risk of discontinuation due to lack of efficacy (OR=1.895; 95%CI=1.05-3.52; p=0.024) than patients treated with anti- TNF drugs. CONCLUSIONS I. The median TB duration in the study was 24 months (9-51.5), with UTK showing the longest survival and anti-TNF-treated patients having the highest risk of biologic therapy discontinuation. The main reason for TB discontinuation or switching was loss of efficacy, followed by adverse events. II. The T allele of the HLA-C rs12191877 polymorphism and the C allele of the TNF-1031 rs1799964 polymorphism were associated with longer survival to anti-TNF drugs. This suggests that variants of the wild-type alleles in the HLA-C rs12191877 (C>T) and TNF- 1031 rs1799964 (T>C) genetic polymorphisms may modify these proteins, and thus reduce cytokine production and monocyte or T-cell activation, enhancing the effect of anti-TNF drugs and improving drug survival. III. We observed an association between UTK survival and the TLR5 rs5744174-G, CD84 rs6427528-A and PDE3A rs11045392 gene polymorphisms, along with SLCO1C1 rs3794271-T. Therefore, variations in the genes encoding receptors involved in the activation or signalling of the immune response typical of psoriasis may decrease the cytokine cascade and reinforce the effect of the IL-12/23 inhibitor drug, UTK, improving its survival. IV. No association was found between the genetic polymorphisms CDKAL1 (rs6908425), FCGR2A (rs1801274), FCGR3A (rs396991), HLA-B/MICA(rs13437088), IL1B (rs1143623), IL6 (rs1800795), IL12B (rs3213094 and rs2546890), IL17RA (rs4819554), IL23R (rs11209026), PGLYR4-24 (rs2916205), TIRAP (rs8177374), TLR2 (rs4696480 and rs11938228), TLR9 (rs352139), TNF-857 (rs1799724), TNFAIP3 (rs610604), TNFRSF1B (rs1061622) and TB survival included in this study. Overall conclusion, these results identify potential predictive biomarkers of pharmacological survival to different TBs in patients with moderate-severe psoriasis, useful for personalised medicine, allowing appropriate decision-making for each patient, saving healthcare costs and improving disease progression and patient quality of life.La psoriasis es una enfermedad cutánea autoinmune con una prevalencia entre el 2-4%. Se caracteriza por el desarrollo de lesiones en forma de placas eritematosas con escamas blanquecinas en cuero cabelludo, codos, rodillas y espalda, principalmente. Además, se asocia con otras patologías potencialmente invalidantes. En consecuencia, la psoriasis se considera una patología sistémica de gran repercusión en la calidad de vida de los pacientes y genera altos costes sanitarios. Factores genéticos, inmunológicos y ambientales pueden desencadenar las lesiones psoriásicas, que son mantenidas por las alteraciones en las respuestas inmunes cutáneas. En este proceso interfieren células dendríticas activadas mediante los receptores tipo Toll, produciendo una cascada de citoquinas [TNF e interleuquinas (IL) IL-12, IL-17 e IL-23] que activa la hiperproliferación de queratinocitos en la epidermis y da lugar a la aparición de hiperplasia epidérmica, típico de las lesiones de psoriasis. El tratamiento de la psoriasis moderada-grave se basa fundamentalmente en las terapias biológicas (TB). Se consideran biológicos de primera línea los inhibidores del factor de necrosis tumoral, conocidos como “anti-TNF” [infliximab (INF), etanercept (ETN), adalimumab (ADA) y certolizumab (CTL)] y el inhibidor de la subunidad p40 de IL12 e IL23 [ustekinumab (UTK)]. Además, como última opción de tratamiento se encuentran los fármacos inhibidores de IL17 e IL23, autorizados más recientemente. Los fármacos anti-TNF y UTK han demostrado ser altamente eficaces y seguros. Sin embargo, no todos los pacientes obtienen buenos resultados, la pérdida de eficacia es el principal motivo de cambio o “switching” de la TB (a largo plazo, sobre todo). Esto supone una gran carga económica para los sistemas sanitarios, dificultando la toma de decisiones médicas y empeora la calidad de vida de los pacientes. Factores genéticos pueden estar involucrados en la variabilidad de la supervivencia farmacológica de las TB de los pacientes psoriásicos. Numerosos estudios farmacogenéticos en pacientes con psoriasis tratados con TB, (concretamente, anti-TNF y UTK) han sido realizados para encontrar biomarcadores predictores de eficacia y/o toxicidad. Hasta ahora se han encontrado que, variantes alélicas y polimorfismos de un solo nucleótido (SNPs) en los genes de antígenos leucocitarios humanos (HLA), que colaboran identificando proteínas exógenas y pueden desencadenar la respuesta inmunológica, podrían estar asociados a la respuesta a las TB. Asimismo, SNPs en genes codificantes de proteínas directamente implicadas en la cascada de citoquinas (TNF e IL-1, IL-6, IL-12 e IL-17) o de receptores que regulan o desencadenan esta cascada de citoquinas, típica de la psoriasis (CD84, FCGR, IL17RA, IL23R, SLC y TLR) han demostrado tener un impacto sobre la respuesta de las TB. A pesar de conocer el posible impacto de los biomarcadores mencionados anteriormente, en la actualidad no es posible trasladar esta información a la práctica clínica habitual de psoriasis debido a la poca evidencia científica que existe. Por tanto, es necesario estudiar y confirmar el efecto de los polimorfismos genéticos funcionales en más estudios para que puedan ser instaurados como biomarcadores predictores de respuesta a las TB indicadas en psoriasis moderada-grave. HIPÓTESIS Determinados polimorfismos genéticos relacionados con la fisiopatogenia de la psoriasis y la diana de los fármacos biológicos inhibidores de TNF o IL12 y 23, pueden estar relacionados con la persistencia interindividual a dichos fármacos en pacientes con psoriasis moderada-grave. Por tanto, es fundamental estudiar y confirmar la utilidad de estos polimorfismos genéticos como biomarcadores predictores de supervivencia farmacológica en psoriasis, permitiendo la implementación de una medicina personalizada. OBJETIVOS Objetivo principal Evaluar la influencia de factores inmunogenéticos como biomarcadores pronósticos y predictivos de la respuesta al tratamiento con fármacos biológicos en pacientes con psoriasis moderada-grave, concretamente los fármacos anti-TNF y UTK. Objetivos específicos o Determinar la presencia de los polimorfismos genéticos implicados en la respuesta de pacientes diagnosticados con psoriasis moderada-grave tratados con los fármacos anti- TNF y UTK. o Medir la supervivencia farmacológica a anti-TNF y UTK en pacientes caucásicos diagnosticados con psoriasis moderada-grave, y las causas por que discontinúan las TB. o Evaluar la asociación entre polimorfismos genéticos funcionales y la efectividad del tratamiento biológico medido a largo plazo, mediante la supervivencia farmacológica a anti-TNF y UTK. MATERIALES Y MÉTODOS Se realizó un estudio de cohortes ambispectivo, que incluyó 379 líneas terapéuticas [anti-TNF (n = 247) y UTK (n = 132)] de 198 pacientes caucásicos provenientes del sur de España e Italia [Hospital Universitario Virgen de las Nieves (HUVN) y el Centro Hospitalario-Universitario Policlínico Umberto I (PUI)]. Las variables sociodemográficas y clínicas se obtuvieron a partir de la revisión de las historias clínicas de los pacientes y las entrevistas personales. Las muestras de ADN se recogieron mediante hisopo bucal o sangre y se extrajeron utilizando un kit de extracción de ADN de saliva o sangre. Posteriormente, se analizaron 29 polimorfismos genéticos mediante PCR a tiempo real con sondas TaqMan®: HLA-B/MICA (rs13437088), HLA-C (rs12191877), TNF-238 (rs361525), TNF-857 (rs1799724), TNF-308 (rs1800629), TNF-1031 (rs1799964), TNFRSF1B (rs1061622), TNFAIP3 (rs610604), IL1B (rs1143623 y rs1143627), IL6 (rs1800795), IL12B (rs3213094 y rs2546890), TIRAP (rs8177374), PGLYR4-24 (rs2916205), CDKAL1 (rs6908425), CD84 (rs6427528), IL17RA (rs4819554), IL23R (rs11209026), TLR2 (rs4696480 y rs11938228), TLR5 (rs5744174), TLR9 (rs352139), PDE3A (rs11045392), SLCO1C1 (rs3794271), FCGR2A (rs1801274), FCGR3A (rs396991), LY96 (rs11465996) y BCL2 (rs59532114). Se evaluó el efecto de estos polimorfismos genéticos funcionales sobre la supervivencia farmacológica de las TB anti-TNF y UTK, utilizando el software R 3.5 aplicando los siguientes métodos estadísticos: Test chicuadrado, Test de Fisher y análisis de supervivencia mediante el método de regresión de Cox y RESULTADOS El análisis multivariante de regresión de Cox mostró que los pacientes portadores del alelo T del polimorfismo HLA-C rs12191877 (HR=0.560; IC95%=0.40-0.78; p=0.0006) y el alelo C del polimorfismo TNF-1031 rs1799964 (HR=0.707; IC95%=0.50-0.99; p=0.048) se asocian a una mayor supervivencia a los fármacos anti-TNF en nuestra población (Tabla 1). Por otro lado, los pacientes portadores del alelo G del polimorfismo TLR5 rs5744174 (HR=0.589; IC95%=0.37-0.92; p=0.02), del genotipo GG para el polimorfismo CD84 rs6427528 (HR=0.557; IC95%=0.35-0.88; p=0.013), junto con el alelo T del polimorfismo PDE3A rs11045392, que se encuentra en desequilibrio de ligamiento con el polimorfismo SLCO1C1 rs3794271 (HR=0.508; IC95%=0.32-0.79; p=0.002), se relacionan con una mayor supervivencia farmacológica a UTK (Tabla 2). Sin embargo, no se observó ninguna asociaron entre los polimorfismos genéticos CDKAL1 (rs6908425), FCGR2A (rs1801274), FCGR3A (rs396991), HLA-B/MICA(rs13437088), IL1B (rs1143623), IL6 (rs1800795), IL12B (rs3213094 y rs2546890), IL17RA (rs4819554), IL23R (rs11209026), PGLYR4-24 (rs2916205), TIRAP (rs8177374), TLR2 (rs4696480 y rs11938228), TLR9 (rs352139), TNF-857 (rs1799724), TNFAIP3 (rs610604), TNFRSF1B (rs1061622) y la supervivencia a las TB incluidas en este estudio Además, la media de duración de las TB fue de 24 meses (9-51.5), siendo UTK el fármaco que alcanzó mayor supervivencia (Plong rank=0.07, 36 meses vs. 24). Concretamente, los pacientes tratados con anti-TNF tienen 1.32 más riesgo de discontinuar con la terapia que los pacientes tratados con UTK (HR=1.32; IC95%=1.02-1.7; p=0.0316). La pérdida de eficacia fue el principal motivo de discontinuación (n=188; 67.14%), seguido del desarrollo de acontecimientos adversos (n=55; 19.64%). Los pacientes tratados con UTK tiene 1.9 más riesgo de interrumpir debido a la falta de eficacia (OR=1.895; IC95%=1.05-3.52; p=0.024) en comparación con los pacientes tratados con fármacos anti-TNF. CONCLUSIONES I. La media de duración de las TB incluidas en el estudio fue de 24 meses (9-51.5), siendo UTK el fármaco que alcanzó mayor supervivencia y los pacientes tratados con fármacos anti-TNF los que presentan más riesgo de discontinuar con la terapia biológica. La pérdida de eficacia fue el principal motivo de discontinuación o “switching” de las TB, seguido del desarrollo de acontecimientos adversos. II. El alelo T del polimorfismo HLA-C rs12191877 y el alelo C del polimorfismo TNF-1031 rs1799964 se asocian a una mayor supervivencia a los fármacos anti-TNF. Esto indica que las variantes de los alelos wild-type en los polimorfismos genéticos HLA-C rs12191877 (C>T) y TNF-1031 rs1799964 (T>C), pueden modificar estas proteínas, y consecuentemente disminuir la producción de citoquinas, así como la regulación de la activación de los monocitos o células T, potenciando el efecto de los fármacos anti-TNF y por consiguiente, mejorando la supervivencia farmacológica. III. Se ha observado una asociación entre la supervivencia a UTK y los polimorfismos de los genes TLR5 rs5744174-G, CD84 rs6427528-A y PDE3A rs11045392, junto con SLCO1C1 rs3794271-T. Por lo que, variaciones en los genes que codifican receptores implicados en la activación o señalización de la respuesta inmune típica de psoriasis, suponen una disminución de la cascada de citoquinas y por tanto, un refuerzo del efecto del fármaco inhibidor de IL-12/23, UTK, mejorando la supervivencia de este. IV. No se encontró ninguna asociación entre los polimorfismos genéticos CDKAL1 (rs6908425), FCGR2A (rs1801274), FCGR3A (rs396991), HLA-B/MICA(rs13437088), IL1B (rs1143623), IL6 (rs1800795), IL12B (rs3213094 y rs2546890), IL17RA (rs4819554), IL23R (rs11209026), PGLYR4-24 (rs2916205), TIRAP (rs8177374), TLR2 (rs4696480 y rs11938228), TLR9 (rs352139), TNF-857 (rs1799724), TNFAIP3 (rs610604), TNFRSF1B (rs1061622) y la supervivencia a las TB incluidas en este estudio. Conclusión general, estos resultados muestran posibles biomarcadores predictivos de supervivencia farmacológica a las distintas TB en pacientes con psoriasis moderada-grave, útiles para realizar una medicina personalizada, que permita realizar una toma de decisiones adecuada para cada paciente, ahorrando gastos sanitarios y mejorando la progresión de la enfermedad y la calidad de vida del paciente de Kaplan-Meier.Tesis Univ. Granada

Clinical Application of Pharmacogenetic Markers in the Treatment of Dermatologic Pathologies

This work was partly supported by a contract for Cristina Membrive Jimenez from the University of Granada and the Fundacion de Investigacion Biosanitaria de Andalucia Oriental (FIBAO). The Virgen de las Nieves University Hospital Biobank was supported by grants co-funded by ERDF funds (EU) from the Instituto de Salud Carlos III (PT13/0010/0039).Dermatologic pathologies are the fourth most common cause of non-fatal disease worldwide; however, they produce a psychosocial, economic, and occupational impact equal to or greater than other chronic conditions. The most prevalent are actinic keratosis, followed by basal-cell carcinoma, in a lesser proportion acne vulgaris, psoriasis, and hidradenitis suppurativa, among others, and more rarely dermatitis herpetiformis. To treat actinic keratosis and basal-cell carcinoma, 5-fluorouracil (5-FU) 0.5% is administered topically with good results, although in certain patients it produces severe toxicity. On the other hand, dapsone is a drug commonly used in inflammatory skin conditions such as dermatitis herpetiformis; however, it occasionally causes hemolytic anemia. Additionally, biologic drugs indicated for the treatment of moderate-to-severe psoriasis and hidradenitis suppurativa have proved to be effective and safe; nevertheless, a small percentage of patients do not respond to treatment with biologics in the long term or they are ineffective. This interindividual variability in response may be due to alterations in genes that encode proteins involved in the pathologic environment of the disease or the mechanism of action of the medication. Pharmacogenetics studies the relationship between genetic variations and drug response, which is useful for the early identification of non-responsive patients and those with a higher risk of developing toxicity upon treatment. This review describes the pharmacogenetic recommendations with the strongest evidence at present for the treatments used in dermatology, highlighting those included in clinical practice guides. Currently, we could only find pharmacogenetic clinical guidelines for 5-FU. However, the summary of product characteristics for dapsone contains a pharmacogenetic recommendation from the United States Food and Drug Administration. Finally, there is an enormous amount of information from pharmacogenetic studies in patients with dermatologic pathologies (mainly psoriasis) treated with biologic therapies, but they need to be validated in order to be included in clinical practice guides.Cristina Membrive Jimenez from the University of GranadaFundacion de Investigacion Biosanitaria de Andalucia Oriental (FIBAO)ERDF funds (EU) from the Instituto de Salud Carlos III PT13/0010/003

<i>ABCC1</i>, <i>ABCG2</i> and <i>FOXP3</i>: Predictive Biomarkers of Toxicity from Methotrexate Treatment in Patients Diagnosed with Moderate-to-Severe Psoriasis

Background: Methotrexate (MTX) is one of the most extensively used drugs in the treatment of moderate-to-severe psoriasis (PS). However, it frequently must be suspended owing to the toxicity in certain patients. Objective: To evaluate the influence of ABCC1, ABCG2, and FOXP3 in the development of MTX toxicity in PS. Methods: Retrospective cohort study with 101 patients. Five single-nucleotide polymorphisms (SNPs) were genotyped using real-time polymerase chain reaction with TaqMan probes. Results: Patients carrying ABCC1 rs2238476-AG genotype (AG vs. GG: OR = 8.04; 95% CI = 1.48–46.78; p = 0.015); FOXP3 rs376154-GT and GG genotypes (GT vs. TT/GG: OR = 3.86; 95% CI = 1.17–13.92; p = 0.031) and ABCG2 rs13120400-T allele (T vs. CC: OR = 8.33; 95% CI = 1.24–164.79; p = 0.059) showed a higher risk of developing more than one adverse effect. The toxicity analysis by subtypes showed that the ABCC1 rs2238476-AG genotype (AG vs. GG: OR = 8.10; 95% CI = 1.69–46.63; p = 0.011) and FOXP3 rs376154-GT genotype (OR = 4.11; 95% CI = 1.22–15.30; p = 0.027) were associated with the appearance of asthenia. No association of the other ABCC1 polymorphisms (rs35592 and rs246240) with MTX toxicity was found. Conclusion: ABCC1, ABCG2, and FOXP3 polymorphisms can be considered to be risk biomarkers of toxicities in PS patients treated with MTX