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IL-17; Enfermedad del hígado graso asociada al metabolismo; Psoriasis IL-17; Metabolic-associated fatty liver disease; Psoriasis IL-17; Malaltia del fetge gras associada al metabolisme; Psoriasi Interleukin 17 (IL-17) is an effector cytokine that plays a key role in the pathogenesis of both psoriasis and metabolic-associated fatty liver disease (MAFLD), a condition that is more prevalent and severe in patients with psoriasis. In liver inflammation, IL-17 is mainly produced by CD4+ T (TH17) and CD8+ T cells (Tc17), although numerous other cells (macrophages, natural killer cells, neutrophils and Tγδ cells) also contribute to the production of IL-17. In hepatocytes, IL-17 mediates systemic inflammation and the recruitment of inflammatory cells to the liver, and it is also implicated in the development of fibrosis and insulin resistance. IL-17 levels have been correlated with progression from MAFLD to steatohepatitis, cirrhosis, and even hepatocellular carcinoma. Clinical trials have shown that inhibiting IL-17A in patients with psoriasis could potentially contribute to the improvement of metabolic and liver parameters. A better understanding of the key factors involved in the pathogenesis of these chronic inflammatory processes could potentially lead to more efficient treatment for both psoriasis and MAFLD, and help to develop holistic strategies to improve the management of these patients. Financial support for the expert meetings and manuscript preparation were provided by Novartis Farmacéutica S.A.

IntroductionPsoriasis is a chronic disease involving the skin, which significantly impacts the quality of life. Disease severity and treatment efficacy (i.e., response) are assessed through the Psoriasis Area and Severity Index (PASI). A PASI 75 response, i.e., an improvement of at least 75% with respect to the baseline PASI score, has traditionally been used as a therapeutic benchmark in clinical trials. Therapeutic advances have made PASI 90 or PASI 100 responses possible in most patients treated with some biologics. A greater response may generate social value beyond clinical outcomes that would benefit both patients and society.MethodsA 1-year economic model was applied to estimate the impact of having a PASI 75, PASI 90, or PASI 100 response in four areas of analysis (quality of life, activities of daily living, work productivity, and out-of-pocket expenditures) and the social value of having a PASI 90 or PASI 100 response in comparison with a PASI 75 response. A mixed-methods approach based on the scientific literature, a focus group with patient, and an advisory committee with psoriasis stakeholders was used. The model included three different scenarios: having a PASI 90 vs a PASI 75 response; a PASI 100 vs a PASI 90 response; and a PASI 100 vs a PASI 75 response. A sensitivity analysis was included.ResultsThe annual economic impact per patient with moderate-to-severe plaque psoriasis having a PASI 75 response was estimated at Ł 6,139, mainly related to labour productivity losses and quality of life reductions. Having a PASI 90 or a PASI 100 response would reduce this impact to €3,956 or €1,353, respectively. Accordingly, the social value of having a PASI 90 instead of a PASI 75 response was estimated at €2,183, and €4,786 with a PASI 100 response.DiscussionA PASI 90 or PASI 100 response would have a lower economic impact and a greater social value than a PASI 75 response for patients with moderate-to-severe plaque psoriasis.

Altres ajuts: acords transformatius de la UAB Data on the effectiveness and safety of a drug in real-world clinical practice complement the evidence from clinical trials, which are carried out in a different setting. Little has been published on the effectiveness and safety of guselkumab in the treatment of psoriasis in clinical practice. The ojective of this study was to assess the effectiveness and safety of guselkumab at 24 weeks in patients with moderate to severe plaque psoriasis in routine clinical practice. A retrospective, multicentre study of adult patients with moderate to severe plaque psoriasis treated with guselkumab for at least 24 weeks was carried out in Spain. We studied 343 patients, 249 of whom were followed for 24 weeks. By week 24, the mean (SD) psoriasis area severity index (PASI) had decreased from 11.1 (7.3) to 1.7 (2.8) (−9.3; [−10.2;-8.4]), 85.9% of the patients had achieved PASI score of 4 or less and 77.9% a PASI score of 2 or less. In terms of relative PASI response, 59.4% of the patients achieved a PASI-90 response and 49.0% a PASI-100 response. On multivariate analysis, two factors reduced the probability of a PASI of 2 or less at 24 weeks: a BMI ≥30 (OR, 0.44; 95% CI, 0.22-0.88) and a greater previous exposure to biologic therapy (OR, 0.69; 95% CI, [0.56-0.84]). Adverse events were rare (9.9%) and led to withdrawal from treatment in only nine patients (2.6%) by the end of the follow-up period. The results of this study confirm the high efficacy and safety of guselkumab indicated by the clinical trial data. In clinical practice, the absolute PASI score appears to be a better marker of response to treatment than the relative value.

Altres ajuts:This study was sponsored by LEO Pharma. Article-processing charges were funded by LEO Pharma. Medical writing support was provided by Mai Kurihara, PhD, from Mudskipper Business Limited, funded by LEO Pharma. Fixed-dose combination topical therapy with corticosteroid and vitamin D analog provides effective treatment and possible long-term management of psoriasis. The anti-inflammatory and immunomodulatory effects of corticosteroids and vitamin D analogs in treating psoriasis are well investigated; their complementary effects lead to the disruption of the inflammatory feedback loop underlying psoriasis pathogenesis. Recent preclinical data showed that combination therapy is more effective than monotherapies of the active ingredients in preventing activation of resting pro-inflammatory cells, inducing immunomodulation, reducing inflammatory responses by regulating T cell production, and normalizing keratinocytes. The increased understanding of the mechanism of action of fixed-dose combination therapy from preclinical studies is supported by several clinical studies. As the efficacy of topical therapy is correlated with the skin penetration of the active ingredients, new drug delivery systems have been developed. The fixed-dose combination Cal/BD aerosol foam creates a modified supersaturated formulation when applied to the skin, which is maintained for at least 26 h in the laboratory setting. Clinical studies have demonstrated superior efficacy of fixed-dose combination calcipotriol (Cal) 50 µg/g and betamethasone dipropionate (BD) 0.5 mg/g aerosol foam compared with monotherapies of the active ingredients. Furthermore, Cal/BD aerosol foam has shown significantly improved efficacy compared with more traditional formulations, such as Cal/BD ointment and gel, in other studies. Calcipotriol also mitigates risks associated with betamethasone dipropionate and vice versa, resulting in the favorable safety profile observed with fixed-dose combination treatment. Recent data also suggest that fixed-dose combination treatment could provide long-term management of psoriasis, although further clinical investigations are needed. Overall, these data support the value of fixed-dose combination therapy of corticosteroid and vitamin D analog and highlight the added potential of innovative drug delivery for the treatment of psoriasis. LEO Pharma.

Les dades d'efectivitat i seguretat d'un fàrmac a la vida real es consideren essencials per a ponderar els resultats dels assaigs pivotals per a la presa de decisions dels clínics. L'objectiu va ser el de avaluar l'efectivitat i seguretat de nous fàrmacs per al tractament de la psoriasi moderada-greu. Es van realitzar tres estudis multicèntrics, observacionals i retrospectius. El primer d'ells va avaluar l'efectivitat i seguretat d'ustekinumab 90mg en una cohort de pacients amb un pes ≤100kg a les 24 setmanes. Els altres dos van avaluar l'efectivitat i seguretat d'apremilast a les 52 setmanes i de guselkumab a les 24 setmanes. En el primer treball es van incloure 74 pacients. El PASI basal (DE) mig va ser de 7.9 (4.8), 3.3 (3.5) a la setmana 16 i 2.2 (2.4) a la setmana 24. En aquest punt temporal, el 69.7% dels pacients van aconseguir un PASI ≤3, el 56.1% el PASI 75 i el 31.8% el PASI 90. No es van observar diferències significatives segons l' IMC de sobrepès o obesitat (p=0.995). En el grup de pacients que havia estat tractat prèviament amb UST 45 mg amb resposta insuficient, el PASI mig (DE) va ser de 2.7 (2.6) a la setmana 24 i el 63% va aconseguir el PASI ≤3. Respecte a la seguretat, no es van informar esdeveniments adversos (EA) greus. La sèrie de guselkumab va incloure 343 pacients. A les 24 setmanes, el PASI mig va disminuir de 11.1 (7.3) a 1.7(2.8), un 85.9% de pacients va aconseguir el PASI ≤4 i un 77.9% el PASI ≤2. En paràmetres de milloria relativa, un 59.4% dels pacients van aconseguir el PASI 90 i el 49.0% el PASI 100. A l'anàlisi multivariant es va observar que un IMC ≥30 (OR 0.44;95% IC [0.22-0.88]) i una major exposició a teràpia biològica prèvia (OR 0.69; 95% IC [0.56-0.84]) disminueixen la probabilitat d'aconseguir el PASI ≤2 a les 24 setmanes: La presencia d'EA va ser infreqüent (9,9%), sent motiu de suspensió només en 9 pacients (2.6%). La cohort d' apremilast va incloure 292 pacients amb psoriasi en placa i 85 amb psoriasi palmoplantar. El PASI mig basal dels pacients amb psoriasi en placa va ser de 10.7 (7.0), disminuint a 3.0 (4.2) a les 52 setmanes. Als 12 mesos, un 73.6% dels pacients van aconseguir un PASI ≤3. En paràmetres de PASI relatiu, un 49.7 % va aconseguir el PASI 75 i un 26.5% el PASI 90 a la setmana 52. En el grup de psoriasi palmoplantar, el physician global assessment (PPPGA) mig inicial va ser de 4.2 (5.2) i es va reduir a 1.3 (1.3) a les 52 setmanes. La supervivència del fàrmac va ser del 54.9% als 12 mesos. Els principals motius de discontinuació van ser la pèrdua d'eficàcia (23.9%), seguida de la presencia d'EA (15.9%). A la nostra sèrie el 47% dels pacients va presentar algun EA, sent els més freqüents els de tipus gastrointestinal. Els treballs presentats en aquesta tesi representen un reflex encertat, contemporani i en temps real dels resultats de la revolució terapèutica en psoriasi i han estat les series més nombroses per a cadascun dels fàrmacs. Els estudis reflecteixen, per un costat, que l'objectiu terapèutic es diferent a la pràctica clínica dels assaigs clínics, destacant el PASI absolut com a paràmetre d'èxit terapèutic enfront a la millora relativa dels assaigs pivotals i, per un altre costat, que el perfil de pacient de la pràctica clínica diària real es més complex. Respecte a la seguretat dels fàrmacs, la pràctica clínica també reflexa la freqüència dels EA i la tolerabilitat dels diferents tractaments. Los datos de efectividad y seguridad de un fármaco en vida real se consideran esenciales para ponderar los resultados de los ensayos pivotales para la toma de decisiones de los clínicos. El objetivo fue evaluar la efectividad y seguridad de nuevos fármacos para el tratamiento de la psoriasis moderada-grave. Se realizaron tres estudios multicéntricos, observacionales y retrospectivos. El primero evaluó la efectividad y seguridad de ustekinumab (UST) 90mg en una cohorte de pacientes con un peso ≤100kg a las 24 semanas. Los otros dos evaluaron la efectividad y seguridad de apremilast a las 52 semanas y de guselkumab a las 24 semanas. En el primer trabajo se incluyeron 74 pacientes. El PASI basal (DE) medio fue de 7.9 (4.8), 3.3 (3.5) en la semana 16 y 2.2 (2.4) en la semana 24. En este punto temporal, el 69.7% de los pacientes alcanzaron un PASI ≤3, el 56.1% el PASI 75 y el 31.8% el PASI 90. No se observaron diferencias significativas según el IMC de sobrepeso u obesidad (p=0.995). En el grupo de pacientes que había sido tratado previamente con UST 45 mg con respuesta insuficiente, el PASI medio (DE) fue de 2.7 (2.6) en la semana 24 y el 63% alcanzó el PASI ≤3. Respecto a la seguridad, no se informaron acontecimientos adversos (AA) graves. La serie de guselkumab incluyó 343 pacientes. A las 24 semanas, el PASI medio descendió de 11.1 (7.3) a 1.7(2.8), un 85.9% de pacientes alcanzó el PASI ≤4 y un 77.9% el PASI ≤2. En términos de mejoría relativa, un 59.4% de los pacientes alcanzaron el PASI 90 y el 49.0% el PASI 100. En el análisis multivariante se observó que un IMC ≥30 (OR 0.44;95% IC [0.22-0.88]) y una mayor exposición a terapia biológica previa (OR 0.69; 95% IC [0.56-0.84]) disminuyen la probabilidad de alcanzar PASI ≤2 a las 24 semanas:. La presencia de AA fue infrecuente (9,9%), siendo motivo de suspensión únicamente en 9 pacientes (2.6%). La cohorte de apremilast incluyó un total de 292 pacientes con psoriasis en placa y 85 con psoriasis palmoplantar. El PASI medio basal de los pacientes con psoriasis en placa fue de 10.7 (7.0), descendiendo 3.0 (4.2) a las 52 semanas. A los 12 meses, un 73.6% de los pacientes alcanzaron un PASI ≤3. En términos de PASI relativo, un 49.7 % consiguió el PASI 75 y un 26.5% el PASI 90 a la semana 52. En el grupo de psoriasis palmoplantar, el physician global assessment (PPPGA) medio inicial fue de 4.2 (5.2) y se redujo a 1.3 (1.3) a las 52 semanas. La supervivencia del fármaco fue del 54.9% a los 12 meses. Los principales motivos de discontinuación fueron la pérdida de eficacia (23.9%), seguida de la presencia de AA (15.9%). En nuestra serie el 47% de los pacientes presentó algún AA, siendo los más frecuentes los de tipo gastrointestinal. Los trabajos presentados en esta tesis representan un reflejo certero, contemporáneo y en tiempo real de los resultados de la revolución terapéutica en psoriasis y han sido, las series más numerosas para cada uno de los fármacos. Los estudios reflejan, por un lado, que el objetivo de eficacia en la práctica clínica es distinto al de los ECA, destacando el PASI absoluto como parámetro de éxito terapéutico frente a la mejoría relativa de los ensayos pivotales y, por otro lado, que el perfil de paciente de la práctica clínica real es más complejo. Respecto a la seguridad de los fármacos, la práctica clínica también refleja la frecuencia de los AA y la tolerabilidad de los distintos tratamientos. Physicians must evaluate the results of pivotal trials together with real-world data on effectiveness and safety when making clinical decisions. The objective was to evaluate the safety and effectiveness of new drugs for the treatment of moderate to severe psoriasis in clinical practice. The research comprised three retrospective, observational, multicentre studies. The first evaluated the effectiveness and safety of ustekinumab 90 mg at week 24 in a group of patients weighing ≤100kg. The other two evaluated the effectiveness and safety of apremilast at 52 weeks and guselkumab at 24 weeks. The first study analysed data from 74 patients. Mean (SD) score on the Psoriasis Area and Severity Index (PASI) was 7.9 (4.8) at baseline, 3.3 (3.5) at week 16, and 2.2 (2.4) at week 24. By week 24, 69.7% of the patients had an absolute PASI score under 3, 56.1% presented a PASI 75 response (at least 75% reduction from baseline), and 31.8% a PASI 90 response. A body mass index corresponding to overweight or obesity was not associated with any significant differences (p = 0.995). In the group of patients who had presented an inadequate response to prior treatment with UST 45 mg, the mean PASI was 2.7 (2.6) at week 24, and 63% of the patients had a PASI score under 3. Analysis of the safety data did not reveal any serious adverse events (AE). The study of guselkumab analysed data from 343 patients. By week 24, the mean PASI score had fallen from 11.1 (7.3) to 1.7 (2.8); 85.9% of patients had a PASI of 4 or less and 77.9% a PASI of 2 or less. In terms of relative improvement, 59.4% of the patients studied achieved a PASI 90 response and 49.0% a PASI 100 response. On multivariate analysis, a BMI of 30 or less (OR, 0.44; 95% CI, 0.22-0.88) and greater prior exposure to biologic therapy (OR, 0.69; 95% CI, 0.56-0.84) reduced the moderate probability of the patient achieving a PASI score of 2 or less at 24 weeks. AE were rare (9.9%) and had led to withdrawal of treatment in only 9 patients (2.6%) The apremilast cohort included a total of 292 patients with plaque psoriasis and 85 with palmoplantar psoriasis. In the patients with plaque psoriasis, mean PASI was 10.7 (7.0) at baseline decreasing to 3.0 (4.2) at 52 weeks. After 12 months of treatment, 73.6% of the patients had a PASI score of 3 or less. In terms of relative improvement, 49.7% achieved PASI 75 and 26.5% PASI 90 at week 52. In the group with palmoplantar psoriasis, the mean physician global assessment (PGA) score fell from 4.2 (5.2) at baseline to 1.3 (1.3) at week 52. Drug survival was 54.9% at 12 months. The main reasons for discontinuing treatment were loss of efficacy (23.9%) and AE (15.9%). In this series, 47% of the patients experienced AE, with the most common being gastrointestinal effects. The studies reported in this thesis are an accurate, contemporary, and real-time reflection of the results of the revolution in the treatment of psoriasis and represent the largest published series for each of the drugs studied. These studies highlight two fundamental differences between pivotal trials and real-world practice. The first is the use of endpoints reflecting relative clinical improvement in RCTs as against the use of the absolute PASI score to measure treatment outcomes in clinical practice. The second difference is the greater complexity of the patient profile in real-world clinical practice. With respect to safety, analysis of the data from routine clinical practice evidences the frequency of AE and the tolerability of the different treatments.

Background Drug survival, defined as the length of time from initiation to discontinuation of a given therapy, allows comparisons between drugs, helps to predict patient's likelihood of remaining on a specific treatment, and achieving the best decision for each patient in daily clinical practice. Objective The aim of this study was to provide data on drug survival of secukinumab, ixekizumab, brodalumab, guselkumab, tildrakizumab, and risankizumab in a large international cohort, and to identify clinical predictors that might have an impact on the drug survival of these drugs. Methods This was a retrospective, multicentric, multi-country study that provides data of adult patients with moderate to severe psoriasis who started treatment with an interleukin (IL)-17 or IL-23 inhibitor between 1 February 2015 and 31 October 2021. Data were collected from 19 distinct hospital and non-hospital-based dermatology centers from Canada, Czech Republic, Italy, Greece, Portugal, Spain, and Switzerland. Kaplan-Meier estimator and proportional hazard Cox regression models were used for drug survival analysis. Results A total of 4866 treatment courses (4178 patients)-overall time of exposure of 9500 patient-years-were included in this study, with 3164 corresponding to an IL-17 inhibitor (secukinumab, ixekizumab, brodalumab) and 1702 corresponding to an IL-23 inhibitor (guselkumab, risankizumab, tildrakizumab). IL-23 inhibitors had the highest drug survival rates during the entire study period. After 24 months of treatment, the cumulative probabilities of drug survival were 0.92 (95% confidence interval [CI] 0.89-0.95) for risankizumab, 0.90 (95% CI 0.88-0.92) for guselkumab, 0.80 (95% CI 0.76-0.84) for brodalumab, 0.79 (95% CI 0.76-0.82) for ixekizumab, and 0.75 (95% CI 0.73-0.77) for secukinumab. At 36 months, only guselkumab [0.88 (95% CI 0.85-0.91)], ixekizumab [0.73 (95% CI 0.70-0.76)], and secukinumab [0.67 (95% CI 0.65-0.70)] had more than 40 patients at risk of drug discontinuation. Only two drugs had more than 40 patients at risk of drug discontinuation at 48 months, with ixekizumab demonstrating to have a higher cumulative probability of drug survival [0.71 (95% CI 0.68-0.75)] when compared with secukinumab [0.63 (95% CI 0.60-0.66)]. Secondary failure was the main cause for drug discontinuation. According to the final multivariable model, patients receiving risankizumab, guselkumab, and ixekizumab were significantly less likely to discontinue treatment than those receiving secukinumab. Previous exposure to biologic agents, absent family history of psoriasis, higher baseline body mass index (BMI), and higher baseline Psoriasis Area and Severity Index (PASI) were identified as predictors of drug discontinuation. Conclusion The cumulative probability of drug survival of both IL-17 and IL-23 inhibitors was higher than 75% at 24 months, with risankizumab and guselkumab demonstrating to have overall cumulative probabilities >= 90%. Biological agent chosen, prior exposure to biologic agents, higher baseline BMI and PASI values, and absence of family history of psoriasis were identified as predictors for drug discontinuation. Risankizumab, guselkumab, and ixekizumab were less likely to be discontinued than secukinumab.

Hem realitzat un estudi retrospectiu de les característiques de 25 pacients amb lupus eritematós túmid (LET) i hem dut a terme un estudi fotobiológic en 9 pacients. Resultats: tots els pacients presentaren les lesions característiques de LET. Només un 20% associaren ANA positius i tan sols un pacient anti Ro positius. Cap pacient presentà complicacions sistèmiques. El 40% de les biòpsies mostraren alteracions epidérmiques lleus, sent el més freqüent la vaquolització de la basal. Estudi fotobiológic: fou positiu en el 55'5% dels pacients, amb un 80% de lesions provocades per UVB. Conclusions: El LET és una variant de LEC amb unes característiques clíniques i evolutives particulars. Microscòpicament, la presència d'alteracions epidérmiques lleus és molt més habitual del que alguns treballs reflecteixen. La fotoprovocació fou positiva en un percentatge significatiu de casos, predominantment dins de l'espectre UVB. Hemos realizado un estudio retrospectivo revisando las características de 25 pacientes con lupus eritematoso túmido (LET) y hemos llevado a cabo un estudio fotobiológico en 9 pacientes. Resultados: todos los pacientes presentaron las lesiones características de LET. Sólo un 20% presentó ANA positivos y tan sólo un paciente anti Ro positivos. Ningún paciente presentó complicaciones sistémicas. El 40% de las biopsias mostraron alteraciones epidérmicas leves, el más frecuente vacuolización focal de la basal. Estudio fotobiológico: fue positivo en el 55'5% de los pacientes, con un 80% de lesiones por UVB. Conclusiones: El LET constituye una variante de LEC con unas características clínicas y evolutivas particulares. Microscópicamente, la presencia de alteraciones epidérmicas leves es mucho más habitual de lo que algunos trabajos reflejan. La fotoprovocación fue positiva en un porcentaje significativo de casos, de forma predominante dentro del espectro UVB.

El úso de anti-TNF-α se ha asociado a reactivación de infección tuberculosa latente (ITL). Los IGRAs son pruebas in vitro más sensibles y mas específicas que la prueba de la prueba de la tuberculina (PT). El objetivo de este trabajo es el de contrastar la correlación entre los resultados de las técnicas in vitro y la PT. Analizamos 103 pacientes con psoriasis en tratamiento sistémico. Los resultados de nuestra serie permiten sugerir una mayor sensibilidad y especificidad de los IGRAs en la detección de ITL respecto a la PT, de forma independiente al estado de inmunosupresión y al fármaco empleado, con alta concordancia entre los IGRAs. L'ús d'anti-TNF- α s'ha associat a reactivació de la infecció tuberculosa latent (ITL). Els IGRAs són proves in vitro més sensibles i més específiques que la prova de la tuberculina (PT). L'objectiu d'aquest treball és el de contrastar la correlació entre els resultats de les tècniques in vitro i la PT. Vam analitzar 103 pacients amb psoriasis en tractament sistèmic. Els resultats de la nostra sèrie permeten suggerir una major sensibilitat i especificitat dels IGRAs en la detecció d'ITL respecte la PT, de manera independent a l'estat d'immunosupressió i al fàrmac emprat, amb alta concordància entre els IGRAs.

L'objectiu de l'estudi fou avaluar el curs de la psoriasi després de la suspensió forçosa de l'efalizumab en un grup de 147 pacients procedents de 12 hospitals. Es recollí informació referida al perfil epidemiològic, al curs de la dermatosi durant el tractament i a l'evolució després de la suspensió. Durant el tractament, un 4% dels pacients fou diagnosticat d'exacerbació inflamatòria. Bona part dels pacients van ser classificats com a bons responedors, grup a priori de millor pronòstic. Tot i així, després de la suspensió, un 30% van desenvolupar rebot. La probabilitat de rebot fou independent de qualsevol dels paràmetres avaluats. El objetivo del estudio fue evaluar el curso de la psoriasis tras la suspensión forzosa de efalizumab en un grupo de 147 pacientes procedentes de 12 hospitales. Se recogió información referida al perfil epidemiológico, al curso de la dermatosis durante el tratamiento y a su evolución al suspenderlo. Durante el tratamiento, un 4% de los pacientes fue diagnosticado de exacerbación inflamatoria. La mayor parte de los pacientes pudieron ser clasificados como buenos respondedores, grupo a priori de mejor pronóstico. Sin embargo, un 30% presentaron rebote tras la suspensión. La probabilidad de rebote fue independiente de los distintos parámetros evaluados.