RESUMEN
INTRODUCTION: Psoriatic arthritis (PsA) is a chronic, inflammatory, musculoskeletal disease that affects up to 30% of patients with psoriasis. Current challenges in clinical care and research include personalised treatment, understanding the divergence of therapy response and unravelling the multifactorial pathophysiology of this complex disease. Moreover, there is an urgent clinical need to predict, assess and understand the cellular and molecular pathways underlying the response to disease-modifying antirheumatic drugs (DMARDs). The TOFA-PREDICT clinical trial addresses this need. Our primary objective is to determine key immunological factors predicting tofacitinib efficacy and drug-free remission in PsA. METHODS AND ANALYSIS: In this investigator-initiated, phase III, multicentre, open-label, four-arm randomised controlled trial, we plan to integrate clinical, molecular and imaging parameters of 160 patients with PsA. DMARD-naïve patients are randomised to methotrexate or tofacitinib. Additionally, patients who are non-responsive to conventional synthetic (cs)DMARDs continue their current csDMARD and are randomised to etanercept or tofacitinib. This results in four arms each with 40 patients. Patients are followed for 1 year. Treatment response is defined as minimal disease activity at week 16. Clinical data, biosamples and images are collected at baseline, 4 weeks and 16 weeks; at treatment failure (treatment switch) and 52 weeks. For the first 80 patients, we will use a systems medicine approach to assess multiomics biomarkers and develop a prediction model for treatment response. Subsequently, data from the second 80 patients will be used for validation. ETHICS AND DISSEMINATION: The study was approved by the Medical Research Ethics Committee in Utrecht, Netherlands, is registered in the European Clinical Trials Database and is carried out in accordance with the Declaration of Helsinki. The study's progress is monitored by Julius Clinical, a science-driven contract research organisation. TRIAL REGISTRATION NUMBER: EudraCT: 2017-003900-28.
Asunto(s)
Antirreumáticos , Artritis Psoriásica , Piperidinas , Pirimidinas , Antirreumáticos/uso terapéutico , Artritis Psoriásica/tratamiento farmacológico , Biomarcadores , Ensayos Clínicos Fase III como Asunto , Etanercept/uso terapéutico , Furanos , Humanos , Factores Inmunológicos/uso terapéutico , Metotrexato/uso terapéutico , Estudios Multicéntricos como Asunto , Piperidinas/uso terapéutico , Pirimidinas/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Resultado del TratamientoRESUMEN
OBJECTIVES: The use of systemic glucocorticoids (SGCs) is traditionally discouraged in the treatment of PsA and psoriasis due to the risk of psoriatic flares. However, despite this recommendation, SGCs are frequently prescribed for these patients. In this study we reappraise the old paradigm that SGCs are contra-indicated in the treatment of PsA and psoriasis. METHODS: A systematic search of MEDLINE, EMBASE and the Cochrane Library databases was performed in November 2019 to identify articles on any SGC use compared with no use in the PsA and psoriasis population. Topical glucocorticoid treatment was excluded. Our two primary outcomes focused on the prescribing characteristics and the occurrence of any type of flare. RESULTS: Our search yielded 4922 articles, and of these 21 full-text articles were eligible for inclusion. There were 11 retro- and prospective cohorts involving a total of 4,171,307 patients. Of these, 6727 (37.82%) of the patients with PsA and 1â460â793 (35.17%) of the patients with psoriasis were treated with any type of SGC. Ten observational/interventional studies did not report an increased risk or occurrence of psoriatic flares related to SGC use. CONCLUSION: Our results indicate that SGCs are frequently prescribed for PsA and psoriasis patients. The occurrence of psoriatic flares appears to be low upon SGC exposure. In patients with a clear indication for SGCs, e.g. in need of rapid anti-inflammatory therapy or bridging of therapies, the use of SGCs should be considered in view of the low risk of skin flaring. It remains of importance to weigh risks for short- and long-term SGC-related side effects in clinical decision making.
Asunto(s)
Artritis Psoriásica , Psoriasis , Humanos , Artritis Psoriásica/tratamiento farmacológico , Glucocorticoides/uso terapéutico , Estudios Prospectivos , Psoriasis/epidemiología , Inmunoterapia/efectos adversosRESUMEN
Interleukin (IL)-12 and IL-23 are pro-inflammatory cytokines produced by dendritic cells (DCs) and associated with Psoriasis (Pso) and Psoriatic Arthritis (PsA) pathogenesis. Tofacitinib, a Janus kinase inhibitor, effectively suppresses inflammatory cascades downstream the IL-12/IL-23 axis in Pso and PsA patients. Here, we investigated whether Tofacitinib directly regulates IL-12/IL-23 production in DCs, and how this regulation reflects responses to Tofacitinib in Pso patients. We treated monocyte-derived dendritic cells and myeloid dendritic cells with Tofacitinib and stimulated cells with either lipopolysaccharide (LPS) or a combination of LPS and IFN-γ. We assessed gene expression by qPCR, obtained skin microarray and blood Olink data and clinical parameters of Pso patients treated with Tofacitinib from public data sets. Our results indicate that in DCs co-stimulated with LPS and IFN-γ, but not with LPS alone, Tofacitinib leads to the decreased expression of IL-23/IL-12 shared subunit IL12B (p40). In Tofacitinib-treated Pso patients, IL-12 expression and psoriasis area and severity index (PASI) are significantly reduced in patients with higher IFN-γ at baseline. These findings demonstrate for the first time that Tofacitinib suppresses IL-23/IL-12 shared subunit IL12B in DCs upon active IFN-γ signaling, and that Pso patients with higher IFN-γ baseline levels display improved clinical response after Tofacitinib treatment.
Asunto(s)
Interferón gamma , Subunidad p40 de la Interleucina-12 , Inhibidores de las Cinasas Janus , Piperidinas , Psoriasis , Pirimidinas , Piel , Artritis Psoriásica/tratamiento farmacológico , Células Dendríticas/inmunología , Humanos , Interferón gamma/metabolismo , Subunidad p40 de la Interleucina-12/antagonistas & inhibidores , Subunidad p40 de la Interleucina-12/sangre , Subunidad p40 de la Interleucina-12/metabolismo , Inhibidores de las Cinasas Janus/farmacología , Inhibidores de las Cinasas Janus/uso terapéutico , Lipopolisacáridos/inmunología , Piperidinas/farmacología , Piperidinas/uso terapéutico , Psoriasis/tratamiento farmacológico , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , Piel/efectos de los fármacos , Piel/inmunologíaRESUMEN
Background: In this study, biomechanical strength and bulkiness of the cow-hitch technique and Pulvertaft weave were compared. Our goal was to investigate whether the cow hitch can withstand equal strength in comparison with the Pulvertaft and to see if there is a difference in bulk, which could enhance gliding function and reduce friction and adhesion formation. Methods: Sheep tendons were used to perform 10 cow-hitch and 10 Pulvertaft repairs. Tensile strength was obtained with a cyclic loading tensile testing machine and tendon width and height measurements were obtained through digital analysis by photographs of the repairs. Results: The cow hitch showed significantly better ultimate strength and had less bulk. There was no statistical difference in displacement, defined as gain in total length of the tendon. Conclusions: The results in this study show that the cow hitch outperforms the Pulvertaft weave in both ultimate strength and bulk.