Genetic Variants Associated with Biological Treatment Response in Inflammatory Bowel Disease: A Systematic Review.

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the digestive tract usually characterized by diarrhea, rectal bleeding, and abdominal pain. IBD includes Crohn's disease and ulcerative colitis as the main entities. IBD is a debilitating condition that can lead to life-threatening complications, involving possible malignancy and surgery. The available therapies aim to achieve long-term remission and prevent disease progression. Biologics are bioengineered therapeutic drugs that mainly target proteins. Although they have revolutionized the treatment of IBD, their potential therapeutic benefits are limited due to large interindividual variability in clinical response in terms of efficacy and toxicity, resulting in high rates of long-term therapeutic failure. It is therefore important to find biomarkers that provide tailor-made treatment strategies that allow for patient stratification to maximize treatment benefits and minimize adverse events. Pharmacogenetics has the potential to optimize biologics selection in IBD by identifying genetic variants, specifically single nucleotide polymorphisms (SNPs), which are the underlying factors associated with an individual's drug response. This review analyzes the current knowledge of genetic variants associated with biological agent response (infliximab, adalimumab, ustekinumab, and vedolizumab) in IBD. An online literature search in various databases was conducted. After applying the inclusion and exclusion criteria, 28 reports from the 1685 results were employed for the review. The most significant SNPs potentially useful as predictive biomarkers of treatment response are linked to immunity, cytokine production, and immunorecognition.

Is erenumab an efficient alternative for the prevention of episodic and chronic migraine in Spain? Results of a cost-effectiveness analysis.

BACKGROUND: The reimbursement of erenumab in Spain and other European countries is currently restricted because of the cost of this novel therapy to patients with migraine who have experienced previous failures to traditional preventive treatments. However, this reimbursement policy should be preferably based on cost-effectiveness studies, among other criteria. This study performed a cost-effectiveness analysis of erenumab versus topiramate for the prophylactic treatment of episodic migraine (EM) and versus placebo for chronic migraine (CM). METHODS: A Markov model with a 10-year time horizon, from the perspective of the Spanish National Healthcare System, was constructed based on data from responder and non-responder patients. A responder was defined as having a minimum 50% reduction in the number of monthly migraine days (MMD). A hypothetical cohort of patients with EM with one or more prior preventive treatment failures and patients with CM with more than two treatment failures was considered. The effectiveness score was measured as an incremental cost per quality-adjusted life year (QALY) gained and cost per migraine day (MD) avoided. Data from clinical outcomes and patient characteristics were obtained from erenumab clinical trials (NCT02066415, STRIVE, ARISE, LIBERTY and HER-MES). Deterministic and probabilistic sensitivity analyses were performed to validate the robustness of the model. RESULTS: After a 10-year follow-up, the estimated QALYs were 5.88 and 6.11 for patients with EM treated with topiramate and erenumab, respectively. Erenumab showed an incremental cost per patient of €4,420 vs topiramate. For CM patients, erenumab resulted in 0.756 QALYs gained vs placebo; and an incremental cost of €1,814. Patients treated with erenumab achieved reductions in MD for both EM and CM (172 and 568 MDs, respectively). The incremental cost per QALY gained with erenumab was below the Spanish threshold of €30,000/QALY for both health and societal perspectives (EM €19,122/QALY and CM €2,398/QALY). CONCLUSIONS: Erenumab is cost-effective versus topiramate as a preventive treatment for EM and versus placebo for patients with CM from the perspective of the Spanish National Health System.

Determining value in the treatment of activated PI3Kδ syndrome in Spain: a multicriteria decision analysis from the perspective of key stakeholders.

Introduction: Activated phosphoinositide 3-kinase (PI3K)δ syndrome (APDS) is an ultra-rare inborn error of immunity (IEI) combining immunodeficiency and immune dysregulation. This study determined what represents value in APDS in Spain from a multidisciplinary perspective applying multicriteria decision analysis (MCDA) methodology. Methods: A multidisciplinary committee of nine experts scored the evidence matrix. A specific framework for orphan drug evaluation in Spain and the weights assigned by a panel of 98 evaluators and decision-makers was used. Re-evaluation of scores was performed. Results: APDS is considered a very severe disease with important unmet needs, including misdiagnosis and diagnostic delay. Current management is limited to treatment of symptoms with off-label use of therapies supported by limited evidence. Therapeutic benefit is partial, resulting in limited disease control. Haematopoietic stem cell transplantation (HSCT), the only potential curative alternative, is restricted to a reduced patient population and without evidence of long-term efficacy or safety. All options present a limited safety profile. Data on patients' quality of life are lacking. APDS is associated with high pharmacological, medical and indirect costs. Conclusions: APDS is considered a severe disease, with limited understanding by key stakeholders of how treatment success is assessed in clinical practice, the serious impact that has on patients and the associated high economic burden. This study brings to light how MCDA methodology could represent a useful tool to complement current clinical and decision-making methods used by APDS experts and evaluators.

Prevalencia de Eventos Cardiocerebrovasculares en Pacientes con Cáncer de Próstata en Manejo con Bloqueo Androgénico con Análogo de GNRH / Prevalence of Cardiovascular Events in Patients with Prostate Cancer that Require Androgen Deprivation Therapy with Gonadotroping Hormone-Releasing Hormone Agonists

Objetivo Determinar la prevalencia de eventos cardiocerebrovasculares en pacientes con cáncer de próstata que son manejados con bloqueo hormonal, con análogo de la GNRH. Materiales y Métodos Se realizó un estudio de corte transversal, en pacientes con cáncer de próstata que fueron manejados con bloqueo hormonal con análogo de la GNRH, con un mínimo de seguimiento de 2 años, entre los años 2004 y 2014. Paciente con eventos que acaecieron en el primer año de observación, fueron excluidos. Se evaluaron las comorbilidades de los pacientes y se clasificaron en diferentes grupos de riesgo, según el índice de comorbilidades ACE27. Se determinó la prevalencia de eventos cardiovasculares definidos como un episodio de infarto agudo de miocardio, de angina y de eventos cerebrovasculares durante la observación. Se comparó la prevalencia de acuerdo al subgrupo de riesgo ACE27. Resultados Se incluyeron 281 pacientes. La comorbilidad más común fue la hipertensión arterial con un 45% y por último la diabetes mellitus con un 17%. La prevalencia de eventos cardiovasculares y cerebrovasculares en la población general fue del 7,5% para cada evento. Se clasificaron los pacientes según el índice de comorbilidades ACE-27 tendiendo el 39% de los pacientes un índice de comorbilidad bajo y el 7% alto. La prevalencia de eventos cardiocerebrovasculares varía desde el 5% en bajo riesgo, hasta el 25% en grupo de alto riesgo. Conclusiones La prevalencia de eventos cardiocerebrovasculares fue del 7,5% en la población de estudio. En el grupo de alto riesgo ACE27 con el uso de análogo de GNRH, se determinó una mayor prevalencia de eventos cardiocerebrovasculares.

Objective To determine the prevalence of cardiovascular events in patients with prostate cancer who were being managed androgen deprivation therapy with gonadotroping hormone-releasing hormone (GHRH) agonists. Materials and Methods A cross-sectional analysis was done in patients with prostate cancer that were treated with androgen deprivation therapy with GHRH agonists, between 2004 and 2014. Follow-up of 2 years was required. Patients who developed cerebrovascular and cardiovascular events within the first year of treatment were excluded. Comorbidities were evaluated and classified in groups of risk, according to the adult comorbidity evaluation index (ACE27). General prevalence of cardiovascular events was established. Prevalence between comorbidity risk groups were quantified and compared. Results 281 patients were included. Among all comorbidities arterial hypertension was the most frequent (45%) and the less frequent was diabetes mellitus (17%). The prevalence of cardiovascular and cerebrovascular events in general population was 7.5%. Patients were classified according to the ACE27 index score resulting in 39% of patients having mild comorbidity score and 7% as severe comorbidity. Between patients classified as having mild comorbidity, prevalence of 5% was found and 25% of prevalence in the severe comorbidity group. Conclusion The prevalence of cardiovascular events was 7.5% in the studied population. In the severe risk group, according to the ACE 27 index, the prevalence of cardiovascular events increases till 25%.

Impacto económico asociado a la implementación de las recomendaciones con grado de evidencia A-I del documento de consenso de GeSIDA/PNS (2015) relativas a la optimización del tratamiento antirretroviral en adultos infectados por virus de la inmunodeficiencia humana con carga viral suprimida en España / Economic impact of optimising antiretroviral treatment in human immunodeficiency virus-infected adults with suppressed viral load in Spain, by implementing the grade A-1 evidence recommendations of the 2015 GESIDA/National AIDS Plan

Introducción: El objetivo de este estudio es estimar el impacto económico en España de la optimización del tratamiento antirretroviral (TAR) triple en pacientes con carga viral suprimida según las recomendaciones GeSIDA/PNS (2015) y su aplicabilidad en la práctica clínica. Métodos: A partir de los datos de prescripción del TAR de la encuesta hospitalaria 2014, siguiendo las recomendaciones de GeSIDA/PNS de optimización de TAR con grado de evidencia A-I, se desarrolló un modelo farmacoeconómico. Las pautas de optimización, la voluntad de optimización y demás asunciones y resultados del modelo fueron validados por un panel de expertos en la infección por VIH (infectológos y farmacéuticos hospitalarios). El análisis se realizó desde la perspectiva del SNS, considerando el coste farmacológico anual, precio de venta del laboratorio notificado, deducción RD-Ley-8/2010 e IVA. Resultados: El panel seleccionó 6 estrategias de optimización y estimó que en España de los 80.859 pacientes actualmente en TAR triple, 10.863 (13,4%) serían candidatos a optimizar su TAR según estas estrategias, generando ahorros de 15,9M euros /año (2,4% del coste farmacológico del TAR triple). Las estrategias más factibles (>40% del total de pacientes candidatos a optimizar, n=4.556) y asociadas a mayores reducciones del gasto (ahorro entre 653 y 4.797 euros /paciente-año según el TAR triple de partida) serían las optimizaciones a ATV/r+3TC. Conclusión: La aplicación a la práctica clínica española de las principales estrategias de optimización recomendadas en el documento GeSIDA/PNS (2015) generaría ahorros sustanciales, especialmente aquellas basadas en biterapia con ATV+3TC, contribuyendo así al control del gasto farmacéutico y a la sostenibilidad del SNS (AU)

Introduction: The objective of this study is to estimate the economic impact associated with the optimisation of triple antiretroviral treatment (ART) in patients with undetectable viral load according to the recommendations from the GeSIDA/PNS (2015) Consensus and their applicability in the Spanish clinical practice. Methods: A pharmacoeconomic model was developed based on data from a National Hospital Prescription Survey on ART (2014) and the A-I evidence recommendations for the optimisation of ART from the GeSIDA/PNS (2015) consensus. The optimisation model took into account the willingness to optimise a particular regimen and other assumptions, and the results were validated by an expert panel in HIV infection (Infectious Disease Specialists and Hospital Pharmacists). The analysis was conducted from the NHS perspective, considering the annual wholesale price and accounting for deductions stated in the RD-Law 8/2010 and the VAT. Results: The expert panel selected six optimisation strategies, and estimated that 10,863 (13.4%) of the 80,859 patients in Spain currently on triple ART, would be candidates to optimise their ART, leading to savings of 15.9M euros /year (2.4% of total triple ART drug cost). The most feasible strategies (>40% of patients candidates for optimisation, n=4,556) would be optimisations to ATV/r+3TC therapy. These would produce savings between 653 euros and 4,797 euros per patient per year depending on baseline triple ART. Conclusion: Implementation of the main optimisation strategies recommended in the GeSIDA/PNS (2015) Consensus into Spanish clinical practice would lead to considerable savings, especially those based in dual therapy with ATV/r+3TC, thus contributing to the control of pharmaceutical expenditure and NHS sustainability (AU)

Consenso español para la prevención y el tratamiento de la infección bronquial por Pseudomonas aeruginosa en el paciente con fibrosis quística / Spanish Consensus on the Prevention and Treatment of Pseudomonas aeruginosa Bronchial Infections in Cystic Fibrosis Patients

Pseudomonas aeruginosa es el patógeno más importante en la infección broncopulmonar en fibrosis quística (FQ). Solo se erradica en la infección inicial, mientras que la reducción de su carga bacteriana es el objetivo terapéutico en la infección crónica y exacerbaciones. El cribado neonatal y la farmacociné- tica/farmacodinámica han cambiado el manejo del paciente con FQ. Se debe realizar un seguimiento microbiológico en los pacientes sin infección por P. aeruginosa. En la infección inicial se recomienda tratamiento inhalado (28 días) con colistina (0,5-2 MU/8 h), tobramicina (300 mg/12 h) o aztreonam (75 mg/8 h) con o sin ciprofloxacino oral (15-20 mg/kg/12 h, 2-3 semanas). En la infección crónica se recomienda solo vía inhalada en tratamiento continuo con colistina, o en ciclos on-off de 28 días con tobramicina o aztreonam. Durante las exacerbaciones leves-moderadas se recomienda tratamiento oral (ciprofloxacino, 2-3 semanas) y en las graves tratamiento intravenoso (-lactámico asociado a un aminoglicósido o una fluoroquinolona). Estudios futuros sustentarán la rotación y nuevas combinaciones de antimicrobianos. Se deben establecer también medidas epidemiológicas que eviten nuevas infecciones y la transmisión cruzada de P. aeruginosa

Pseudomonas aeruginosa is the main pathogen in bronchopulmonary infections in cystic fibrosis (CF) patients. It can only be eradicated at early infection stages while reduction of its bacterial load is the therapeutic goal during chronic infection or exacerbations. Neonatal screening and pharmacokinetic/pharmacodynamic knowledge has modified the management of CF-patients. A culture based microbiological follow-up should be performed in patients with no infection with P. aeruginosa. At initial infection, inhaled colistin (0,5-2 MU/tid), tobramycin (300 mg/bid) or aztreonam (75 mg/tid) with or without oral ciprofloxacin (15-20 mg/kg/bid, 2-3 weeks) are recommended. In chronic infections, treatment is based on continuous administration of colistin or with a 28-day on-off regimen with tobramycin or aztreonam. During mild-moderate exacerbations oral ciprofloxacin (2-3 weeks) can be administered while serious exacerbations must be treated with intravenous combination therapy (beta-lactam with an aminoglycoside or a fluoroquinolone). Future studies will support antibiotic rotation and/or new combination therapies. Epidemiological measures are also recommended to avoid new P. aeruginosa infections and "patient-to-patient transmission" of this pathogen

Evaluación económica de la monoterapia con tocilizumab frene a adalimumab en artritis reumatoide / Economic evaluation of rheumathoid arthritis monotherapy with Tocilizumab and Adalimumab

FUNDAMENTO: Tocilizumab (TCZ) fue superior a adalimumab (ADA) en monoterapia en la reducción de los signos y síntomas de la artritis reumatoide del adulto (AR) en pacientes intolerantes o con respuesta inadecuada a metotrexato (MTX). El objetivo del estudio fue analizar el coste-efectividad de TCZ vs ADA en estos pacientes. Métodos: Evaluación económica del coste por respuesta o remisión con TCZ vs ADA a partir del estudio ADACTA (horizonte temporal: 24 semanas). Criterios de respuesta clínica ACR o de remisión de la enfermedad, índice DAS28. Ámbito: Sistema Nacional de Salud. Los costes incluidos (adquisición, administración y monitorización de los medicamentos en € de 2012) se obtuvieron de fuentes españolas. Se efectuaron análisis de sensibilidad simples univariantes. Resultados: Las tasas de respuesta ACR20, ACR50 y ACR70 con TCZ y ADA se obtuvieron en el 65% y 49,4% (p <0,01); 47,2% y 27,8% (p <0,01); y en el 32,5% y 17,9% (p <0,01) de los pacientes, respectivamente. La remisión DAS28 se produjo en el 39,9% y 10,5%, respectivamente (p <0,0001). El coste por respuesta fue menor con TCZ que con ADA (ACR20: 8.105 y 11.553 €; ACR50: 11.162 y 20.529 €; ACR70: 16.211 y 31.882 €) respectivamente. El coste de la remisión DAS28 fue de 13.204 € y 54.352 € respectivamente. En todos los escenarios el tratamiento con TCZ tuvo mayor eficacia y menores costes que con ADA. Conclusiones: Según este análisis, en España la monoterapia con TCZ es una estrategia eficiente frente a ADA para el tratamiento de los pacientes con AR intolerantes o con respuesta inadecuada a MTX

BACKGROUND: Tocilizumab (TCZ) was superior to adalimumab (ADA), as monotherapy, in reducing signs and symptoms of adult rheumatoid arthritis (RA) when methotrexate (MTX) treatment is poorly tolerated or inappropriate. The aim of the study was to analyze the cost-effectiveness of TCZ vs ADA in these patients. METHODS: Economic evaluation of the cost per response or remission of TCZ vs ADA from ADACTA (time horizon: 24 weeks). Clinical response criteria ACR or disease remission criteria, DAS28. Perspective: National Health System. The costs included (acquisition, administration and monitoring of medicines; € 2012) were obtained from Spanish sources. Simple univariate sensitivity analyzes were performed. RESULTS: ACR20, ACR50 and ACR70 response rates with TCZ and ADA were obtained in 65% and 49.4% (p <0.01), 47.2% and 27.8% (p <0.01); and 32.5% and 17.9% (p <0.01) of patients, respectively. DAS28 remission occurred in 39.9% and 10.5%, respectively (p <0.0001). The cost per response was lower with TCZ than with ADA (ACR20: € 8,105 and € 11,553; ACR50: € 11,162 and € 20,529; ACR70: € 16,211 and € 31,882) respectively. The cost of DAS28 remission was € 13,204 and € 54,352, respectively. Treatment with TCZ was dominant (more effective, with lower costs vs ADA) in all scenarios analyzed. CONCLUSIONS: According to this analysis, in Spain TCZ monotherapy is an efficient strategy vs ADA for treating RA patients intolerant to MTX or in which there is inappropriate response