e22550 Background: Neurofibromatosis Type 1 (NF1) is a rare hereditary condition that predisposes to the development of a variety of tumors. Variability in disease manifestation, prevalence and severity, in combination with a low prevalence complicates the efficient conduct of clinical trials in NF1. NF1-associated tumors mainly but not exclusively affect the nervous system as well as the skin, and a percentage of those tumors exhibit a significantly increased risk of malignant transformation. There is an urgent need to identify effective treatments for NF1-associated tumors. The development of innovative trial designs that accelerate the ability to assess new investigational agents is essential. The European Patient-Centric Clinical Trial Platforms (EU-PEARL) is an Innovative Medicines Initiative (IMI) project, aiming to create platform trials for diseases with high unmet medical need. As part of EU-PEARL, we designed a basket-platform trial in NF1 that could serve as a prototype for accelerating drug studies in rare cancer predisposition syndromes. Methods: The trial was designed by NF1 experts, a dedicated statistician and a trial designer. Subprotocols were written for previously prioritized manifestations including plexiform neurofibroma, cutaneous neurofibroma, low-grade glioma, and optic pathway glioma. Collaboration with NF1 experts from the USA was sought to ensure alignment with trials for NF1 in the USA. Results: To optimally learn from a small number of potential participants, patients should be able to participate in both an observational and a treatment phase. The observational phase will serve as longitudinal natural history study, providing data that can be used as a comparator for the treatment arms. To enter the treatment phase, patients must meet additional eligibility criteria. Patients will be randomized to a sequence of available drugs, rather than one single drug. This may allow for the addition of newly identified drugs during the course of the trial. If a drug concept fails or unacceptable toxicity arises, patients may re-enter the observational phase or be re-randomized to a different treatment arm if eligible. Drug-specific eligibility criteria and endpoints are listed separately in Intervention-Specific-Appendices (ISAs), allowing flexibility and adaptability that is needed for a highly variable and progressive rare disorder like NF1. This trial design allows optimal learning from a limited number of patients. Conclusions: We designed a basket-platform trial for four manifestations of NF1. This trial design addresses challenges that may be encountered when designing a clinical trial for NF1. This trial will be the future of clinical trials for NF1 in Europe. Its design could serve as a prototype for other rare diseases: it enhances the chances of finding beneficial treatments by optimizing patient inclusion and invigorating international collaborations.
BackgroundAt this very moment, no systematic review evaluating the role of nailfold videocapillaroscopy (NVC) with standardised definitions, in interstitial lung disease (ILD) has been published.ObjectivesTo systematically identify and review all available literature evaluating the role of NVCin ILD in SSc, according to the definitions of the EULAR study group on microcirculation in Rheumatic diseases.MethodsA systematic literature search was performed in Pubmed, EMBASE and Web of Science. All retrieved articles were screened on title, abstract and full-text level. Reference lists and google scholar were additionally searched. Original research papers that documented an association between NVC and ILD in SSc were included. Subsequently, NVC parameters were subdivided in quantitative (density, dimension, morphology and haemorrhages), semi-quantitative (NVC score) and qualitative assessment (presence, severity and worsening of scleroderma pattern).ResultsThe systematic search identified 299 unique search results, of which 145 references were withheld after title screening. Abstract screening resulted in 39 references, only 16 were eligible for full-text review. Finally, 16 references were included in the final analysis after full-text screening (n=13) and bibliographic and google scholar search (n=3) (see table 1).Regarding cross-sectional studies, density has been evaluated in 5 studies and has been unequivocally associated with DLCO/AV, DLCO, FVC and inversely with GGO. Dimension has been evaluated in 4 studies, with no unequivocal results. Morphology has been evaluated in 1 study and has been unequivocally associated with HC on HRCT. Haemorrhages have not been evaluated. NVC score has been evaluated in 2 studies and has been unequivocally associated with GGO on HRCT and total lung score. Presence of scleroderma pattern has been evaluated in 3 studies and has been unequivocally associated with reduction of DLCO and severe lung involvement. Severity of scleroderma pattern has been evaluated in 4 studies and has been unequivocally associated with reduction of DLCO and FVC, ILD on chest X-ray and lung involvement.Regarding longitudinal studies, density has been evaluated in 2 studies and has been unequivocally associated with reduction of DLCO. Dimension, morphology and haemorrhages have all been evaluated in 1 study, with no association. NVC score has not been evaluated. Presence of scleroderma pattern has been evaluated in 2 studies and has been unequivocally associated with reduction of DLCO, ILD on HRCT and future severe lung involvement. Worsening of scleroderma pattern has been evaluated in 1 study and has been unequivocally associated with future lung involvement.ConclusionsThis systematic literature review, on behalf of the EULAR study group on microcirculation in Rheumatic diseases, is the first to investigate unequivocal associations between ILD and capillaroscopic alterations in a standardised way. Unequivocal associations were found in cross-sectional studies between density, morphology, NVC score, presen...
Background:Systemic sclerosis-associated interstitial lung disease (SSc-ILD) is the main cause of death in SSc and accounts for up to 30-35% of SSc-mortality (1-2). All SSc cases, irrespective of the extent of the skin disease, should be evaluated for ILD (3). The epidemiology of SSc-ILD in Belgium is unknown. In literature, the prevalence of ILD in SSc varies between 19% and 52%. However, different criteria were used to diagnose ILD (4). In 2008, Goh et al. proposed a flow diagram to diagnose SSc-ILD based on chest high-resolution CT-scan (HRCT) and pulmonary function tests (PFTs). Their categorization into limited or extensive ILD has prognostic value (5).Objectives:To determine the prevalence and incidence rate of SSc-ILD in Flanders.Methods:Up to 12-year follow-up data of consecutive SSc patients were obtained by 2 Flemish expert centres (University Hospitals Ghent and Leuven). Patients fulfilling the LeRoy and/or ACR-EULAR classification criteria were included consecutively in the prospective cohort (6). Patients received HRCT at baseline and on indication thereafter, as well as yearly PFT. All HRCTs were centrally analyzed (Ghent) and patients were categorized according to the Goh criteria as without ILD, with limited ILD (limILD) or with extensive ILD (extILD) (5).Results:Between 2006 and 2018, 797 SSc patients (557 Ghent/240 Leuven; 22% limited SSc (LSSc)/59% limited cutaneous SSc (LcSSc)/19% diffuse cutaneous SSc (DcSSc)) had baseline HRCT and PFT. The baseline characteristics are depicted in the table. The mean age (SD) was 53 +/-15 years and the majority of patients was female (76%).272 SSc patients had ILD at baseline, implicating a baseline prevalence of 34% (272/797). The baseline prevalences were 35% and 55% for the LcSSc and DcSSc subgroups respectively. During a median follow-up of 39 months (IQR: 11-79 months), 44 patients were diagnosed with incidental SSc-ILD, resulting in an incidence rate of 21,0/1000 person-years (PY), 95% CI:15,2-28,1. The incidence rates were 21,7/1000 PY, 95%CI: 14,3-31,6 and 43.9/1000PY, 95%CI: 22.7-76.8 for the LcSSc and DcSSc subgroups respectively.Table.Baseline characteristicsSSc (n=797)LcSSc (n=470)DcSSc (n=149)age (years) °53+/-1554+/-1554+/-14♂/♀ *193(24%)/604(76%)109(23%)/361(77%)58(39%)/91(61%)Disease Duration (months) #for 718: 22 (5-72)for 443: 25 (5-80)for 145: 16 (7-52)LSSc/LcSSc/DcSSc *178(22%)/470(59%)/149(19%)follow-up (months) #39 (11-79)38.5 (9.75-81)44 (17.5-78)Anti-centromere antibodies§252/538 (47%)163/317 (51%)19/108 (18%)Anti-topoisomeraseI antibodies§119/519 (23%)66/297 (22%)45/112 (40%)ILD at baseline, *272 (34%)163 (35%)82 (55%)LimILD, *230 (29%)139 (30%)67 (45%)ExtILD, *42 (5%)24 (5%)15 (10%)New ILD during follow-up, §44/52527/30712/67°: mean +/- standard deviation, *: number of patients (percent), #: median (interquartile range), §= number of patients/total number of patients with available data (%)Conclusion:In an unselected cohort of SSc patients, a third of the patients has ILD at baseline which is in line with previous prevalence reports. Importantly, this is the first study reporting incidence rates of SSc-ILD.References:[1]Steen VD and Medsger TA, Ann Rheum Dis 2007;66:940-4[2]Elhai M et al. Ann Rheum Dis 2017;76:1897-1905[3]Smith V et al. RMD Open 2019;4:e000782. doi:10.1136/rmdopen-2018-000782[4]Bergamasco A et al. Clinical Epidemiology 2019;11:257-73[5]Goh N et al. Am J Respir Crit Care Med 2008;177:1248-54[6]van den Hoogen et al. Arthritis Rheumatol 2013;65:2737-47Disclosure of Interests:Els Vandecasteele Grant/research support from: my institution has received a research grant from the Research Foundation Flanders FWO), Speakers bureau: my institution has received speaker fees from Actelion, Karin Melsens: None declared, Daniel Blockmans Consultant of: yes, Speakers bureau: yes, Charlotte Carton: None declared, Filip De Keyser: None declared, Ellen De Langhe Consultant of: member of advisory board for Boehringer, Bernard Lauwerys: None declared, Yves Piette: None declared, Amber Vanhaecke: None declared, Koen Verbeke: None declared, Wim Wuyts Grant/research support from: my institution has received a grant from Boehringer Ingelheim and Roche, Consultant of: my institution has received payments for consultancy from Boehringer Ingelheim and Roche, Speakers bureau: my institution has received speaker fees from Boehringer Ingelheim and Roche, Guy Brusselle: None declared, Vanessa Smith Grant/research support from: The affiliated company received grants from Research Foundation - Flanders (FWO), Belgian Fund for Scientific Research in Rheumatic diseases (FWRO), Boehringer Ingelheim Pharma GmbH & Co and Janssen-Cilag NV, Consultant of: Boehringer-Ingelheim Pharma GmbH & Co, Speakers bureau: Actelion Pharmaceuticals Ltd, Boehringer-Ingelheim Pharma GmbH & Co and UCB Biopharma Sprl
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