scholarly journals Prior elicitation of the efficacy and tolerability of Methotrexate and Mycophenolate Mofetil in Juvenile Localised Scleroderma

2021 ◽  
Vol 3 ◽  
pp. 20
Author(s):  
Yasin Desai ◽  
Thomas Jaki ◽  
Michael W Beresford ◽  
Thomas Burnett ◽  
Despina Eleftheriou ◽  
...  
Keyword(s):  
Mycophenolate Mofetil ◽  
Bayesian Approach ◽  
Total Sample ◽  
Evidence Base ◽  
Relative Efficacy ◽  
Key Factors ◽  
First Line ◽  
International Consensus ◽  
Prior Opinion ◽  
Critical Aspects

Background Evidence is lacking for safe and effective treatments for juvenile localised scleroderma (JLS). Methotrexate (MTX) is commonly used first line and mycophenolate mofetil (MMF) second line, despite a limited evidence base. A head to head trial of these two medications would provide data on relative efficacy and tolerability. However, a frequentist approach is difficult to deliver in JLS, because of the numbers needed to sufficiently power a trial. A Bayesian approach could be considered. Methods An international consensus meeting was convened including an elicitation exercise where opinion was sought on the relative efficacy and tolerability of MTX compared to MMF to produce prior distributions for a future Bayesian trial. Secondary aims were to achieve consensus agreement on critical aspects of a future trial. Results An international group of 12 clinical experts participated. Opinion suggested superior efficacy and tolerability of MMF compared to MTX; where most likely value of efficacy of MMF was 0.70 (95% confidence interval (CI) 0.34-0.90) and of MTX was 0.68 (95% CI 0.41-0.8). The most likely value of tolerability of MMF was 0.77 (95% CI 0.3-0.94) and of MTX was 0.62 (95% CI 0.32-0.84). The wider CI for MMF highlights that experts were less sure about relative efficacy and tolerability of MMF compared to MTX. Despite using a Bayesian approach, power calculations still produced a total sample size of 240 participants, reflecting the uncertainty amongst experts about the performance of MMF. Conclusions Key factors have been defined regarding the design of a future Bayesian approach clinical trial including elicitation of prior opinion of the efficacy and tolerability of MTX and MMF in JLS. Combining further efficacy data on MTX and MMF with prior opinion could potentially reduce the pre-trial uncertainty so that, when combined with smaller trial sample sizes a compelling evidence base is available.

scholarly journals Interactive Web-Based Resource for Annotation of Genetic Variants Causing Hereditary Angioedema (HADA): Database Development, Implementation, and Validation (Preprint)

2020 ◽  
Author(s):  
Alejandro Mendoza-Alvarez ◽  
Adrián Muñoz-Barrera ◽  
Luis Alberto Rubio-Rodríguez ◽  
Itahisa Marcelino-Rodriguez ◽  
Almudena Corrales ◽  
...  
Keyword(s):  
Hereditary Angioedema ◽  
Genetic Condition ◽  
First Line ◽  
International Consensus ◽  
Web Based ◽  
Genetics And Genomics ◽  
User Friendly ◽  
Current Guidelines ◽  
Generation Sequencing ◽  
Esterase Inhibitor

BACKGROUND Hereditary angioedema is a rare genetic condition caused by C1 esterase inhibitor deficiency, dysfunction, or kinin cascade dysregulation, leading to an increased bradykinin plasma concentration. Hereditary angioedema is a poorly recognized clinical entity and is very often misdiagnosed as a histaminergic angioedema. Despite its genetic nature, first-line genetic screening is not integrated in routine diagnosis. Consequently, a delay in the diagnosis, and inaccurate or incomplete diagnosis and treatment of hereditary angioedema are common. OBJECTIVE In agreement with recent recommendations from the International Consensus on the Use of Genetics in the Management of Hereditary Angioedema, to facilitate the clinical diagnosis and adapt it to the paradigm of precision medicine and next-generation sequencing–based genetic tests, we aimed to develop a genetic annotation tool, termed Hereditary Angioedema Database Annotation (HADA). METHODS HADA is built on top of a database of known variants affecting function, including precomputed pathogenic assessment of each variant and a ranked classification according to the current guidelines from the American College of Medical Genetics and Genomics. RESULTS HADA is provided as a freely accessible, user-friendly web-based interface with versatility for the entry of genetic information. The underlying database can also be incorporated into automated command-line stand-alone annotation tools. CONCLUSIONS HADA can achieve the rapid detection of variants affecting function for different hereditary angioedema types, and further integrates useful information to reduce the diagnosis odyssey and improve its delay.

P19 Mycophenolate mofetil in paediatric uveitis: an early experience

Rheumatology ◽  
2019 ◽  
Vol 58 (Supplement_4) ◽  
Author(s):  
Amany Tadrous ◽  
Kishore Warrier ◽  
Archana Pradeep ◽  
Nikki Camina ◽  
Satyapal Rangaraj
Keyword(s):  
Mycophenolate Mofetil ◽  
Conflicts Of Interest ◽  
Cystoid Macular Oedema ◽  
Favourable Result ◽  
Topical Steroids ◽  
Second Line ◽  
First Line ◽  
Small Cohort ◽  
Third Line ◽  
Paediatric Uveitis

Abstract Background Juvenile idiopathic arthritis (JIA) is the commonest cause of uveitis in children. Uveitis is a significant cause of visual impairment in children with potential complications such as band keratopathy, cataract, posterior synechiae, glaucoma, cystoid macular oedema and a retinal problems. Following the initial treatment with topical and systemic corticosteroids, a wide variety of immunosuppressant agents have been used in the treatment of non-infective uveitis including methotrexate (MTX) and biologic therapy, most of which are administered parenterally. Mycophenolate Mofetil (MMF) is an oral immunosuppressant that inhibits the proliferation of T and B lymphocytes, which has been tried in children with uveitis with mixed results. We started using MMF in children seen in our paediatric uveitis clinic initially as a third line agent when the inflammation is not well controlled despite therapeutic doses of MTX and Adalimumab, as the NHS England Clinical Commissioning Policy does not recommend the use of Infliximab in uveitis not associated with JIA. Buoyed by some favourable result, we have since then used MMF as second line and even first line agent in children with uveitis. Methods Retrospective analysis of the clinical profile of children with uveitis on MMF at a tertiary paediatric rheumatology centre with focus on response to treatment. Results Of the 8 patients who received MMF, six (75%) were girls. Half of them (4/8) had idiopathic uveitis and the rest, associated with JIA. 2/8 patients had MMF as third line agent on top of MTX and Adalimumab, while five of them had it as second line agent on top of Adalimumab due to either MTX intolerance or needle phobia. One patient was started on MMF as first line agent following topical steroids. 6 (75%) of the patients responded/stayed in remission following the addition of/switch to MMF. Conclusion MMF has shown initial promise in the treatment of uveitis in children with uveitis in this small cohort, in line with some existing evidence. It was initially used in patients who were not keen on injections/intolerant to MTX or had failed all existing options. This is a small cohort of patients and we would welcome more research in this area. Conflicts of Interest The authors declare no conflicts of interest.

scholarly journals Cancer Surveillance Guideline for individuals with PTEN hamartoma tumour syndrome

2020 ◽  
Vol 28 (10) ◽  
pp. 1387-1393 ◽  
Author(s):  
Marc Tischkowitz ◽  
◽  
Chrystelle Colas ◽  
Sjaak Pouwels ◽  
Nicoline Hoogerbrugge ◽  
...  
Keyword(s):  
Multidisciplinary Approach ◽  
Cancer Colorectal ◽  
Evidence Base ◽  
Cancer Surveillance ◽  
Clinical Genetics ◽  
International Consensus ◽  
Comprehensive Literature Review ◽  
Increasing Risk ◽  
System Disorder ◽  
Current Guidelines

Abstract PTEN hamartoma tumour syndrome is a diverse multi-system disorder predisposing to the development of hamartomatous growths, increasing risk of breast, thyroid, renal cancer, and possibly increasing risk of endometrial cancer, colorectal cancer and melanoma. There is no international consensus on cancer surveillance in PHTS and all current guidelines are based on expert opinion. A comprehensive literature review was undertaken and guidelines were developed by clinicians with expertise from clinical genetics, gynaecology, endocrinology, dermatology, radiology, gastroenterology and general surgery, together with affected individuals and their representatives. Recommendations were put forward for surveillance for breast, thyroid and renal cancers. Limited recommendations were developed for other sites including endometrial, colon and skin. The proposed cancer surveillance recommendations for PHTS require a coordinated multidisciplinary approach and significant patient commitment. The evidence base for cancer surveillance in this guideline are limited, emphasising the need for prospective evaluation of the effectiveness of surveillance in the PHTS population.

Indirect Comparison of the Efficacy of Melphalan-Prednisone-Bortezomib Relative to Melphalan-Prednisone-Thalidomide and Melphalan-Prednisone for the First Line Treatment of Multiple Myeloma

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2367-2367
Author(s):  
Yating Yeh ◽  
James Chambers ◽  
Sabine Gaugris ◽  
Jeroen Jansen
Keyword(s):  
Multiple Myeloma ◽  
Meta Analysis ◽  
Indirect Comparison ◽  
Complete Response ◽  
Similar Efficacy ◽  
Line Treatment ◽  
Relative Efficacy ◽  
First Line ◽  
Overall Response ◽  
First Line Treatment

Abstract Melphalan-prednisone (MP) combination has been considered a standard of care for front line treatment of multiple myeloma in patients non eligible for transplant. Melphalan-prednisone-bortezomib (MPV) combination has been approved in the United States in patients non eligible for high-dose chemotherapy (HD-C) and has recently received a positive opinion from the CHMP in Europe. Melphalan-prednisone-thalidomide (MPT) was approved in Europe in patients >65 or not eligible for HD-C. There is no head-to-head trial directly comparing MPV to MPT. The objective of the current study was to compare the efficacy of MPV to MP and MPT as first line treatment of multiple myeloma in patients non eligible for transplant. Six randomized placebo controlled trials investigating the efficacy of MPT (5) and MPV (1) relative to MP were identified with a systematic literature review. The endpoints of interest were overall survival (OS), progression free survival (PFS) and overall and complete response. Relative efficacy estimates of MPT versus MP as obtained from the MPT-MP trials were combined with meta-analysis techniques and simultaneously indirectly compared with the relative efficacy of MPV versus MP from the MPV-MP trial (VISTA). This adjusted indirect comparison was performed with Bayesian fixed and random effects models. As compared to frequentist approach, Bayesian meta-analysis offers a more informative summary of the likely value of efficacy after observing the data and allows for direct probabilistic inferences. Of the three interventions compared, there was an 81% probability that MPV was the most efficacious intervention in terms of overall response and a >99% probability in terms of complete response. With MPV a patient was two times more likely to show a complete response than with MPT (Relative Risk=2.15; 95%Credible Interval (CrI): 0.99–4.45). Both MPV and MPT showed greater OS than MP (HR=0.61; 95%CrI: 0.42–0.88 and HR=0.61; 95%CrI: 0.47–0.78 respectively); the indirect comparison showed similar efficacy in terms of OS between MPV and MPT (MPV vs MPT: Hazard Ratio=1.00; 95%CrI 0.64–1.57). Both MPV and MPT also displayed greater PFS than MP (MPV versus MP: HR=0.61; 95%CrI 0.49–0.76 and MPT versus MP HR=0.51; 95%CrI 0.41–0.63 respectively) and showed similar efficacy (MPV vs MPT: HR=1.19; 95%CrI: 0.87–1.63). In this study, both MPV and MPT are more efficacious than MP in terms of response, PFS and OS. MPV is expected to result in a greater complete and overall response than MPT. No difference in OS or PFS was displayed. Further analyses will need to be undertaken once evidence base data is more mature.

Tacrolimus and mycophenolate mofetil as first line immunosuppression after lung transplantation

2009 ◽  
Vol 22 (6) ◽  
pp. 635-643 ◽  
Author(s):  
Claus Neurohr ◽  
Patrick Huppmann ◽  
Gregor Zimmermann ◽  
Hanno Leuchte ◽  
Rainer Baumgartner ◽  
...  
Keyword(s):  
Mycophenolate Mofetil ◽  
Lung Transplantation ◽  
First Line

scholarly journals Comparing and contrasting clinical consensus and guidelines for anal intraepithelial neoplasia in different geographical regions

2021 ◽  
Author(s):  
Danielle R. L. Brogden ◽  
Micol E. E. Lupi ◽  
Oliver J. Warren ◽  
Christos Kontovounisios ◽  
Sarah C. Mills
Keyword(s):  
Clinical Guidelines ◽  
Intraepithelial Neoplasia ◽  
Evidence Base ◽  
Anal Intraepithelial Neoplasia ◽  
International Consensus ◽  
Significant Discrepancy ◽  
Anal Squamous Cell Carcinoma ◽  
Geographical Variations ◽  
Geographical Regions

AbstractAnal Squamous Cell Carcinoma (ASCC) is an uncommon cancer with a recognised precursor Anal Intraepithelial Neoplasia (AIN). Although there are consistent evidence-based guidelines for the management of ASCC, historically this has not been the case for AIN and as a result there have been geographical variations in the recommendations for the treatment of AIN. More recently there have been updates in the literature to the recommendations for the management of AIN. To assess whether we are now closer to achieving an international consensus, we have completed a systematic scoping review of available guidelines for the screening, treatment and follow-up of AIN as a precursor to ASCC. MEDLINE and EMBASE were systematically searched for available clinical guidelines endorsed by a recognised clinical society that included recommendations on either the screening, treatment or follow-up of AIN. Nine clinical guidelines from three geographical areas were included. The most recent guidelines agreed that screening for AIN in high-risk patients and follow-up after treatment was necessary but there was less consensus on the modality of screening. Six Guidelines recommended the treatment of high-grade AIN and four guidelines describe a follow-up protocol of patients diagnosed with AIN. There appears to be increasing consensus on the treatment and follow-up of patients despite a poor evidence base. There is still significant discrepancy in guidance on the method to identify patients at risk of ASCC and AIN despite consensus between geographical regions on which patient subgroups are at the highest risk.

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