Les manifestations osseuses de la maladie de Gaucher à l'ère de l'enzymothérapie substitutive
Vous trouverez des articles traitant du même sujet dans la catégorie "Ostéoporose"
Les manifestations osseuses de la maladie de Gaucher à l'ère de l'enzymothérapie substitutive
L'enzymothérapie substitutive dans la maladie de Gaucher a prouvé son impact sur les troubles hématologiques, l'infiltration viscérale et la qualité de vie. Les complications osseuses incidentes sont moins fréquentes mais l'ostéonécrose déjà établie est au-delà de toute thérapeutique. Pour évaluer le fardeau de l'atteinte osseuse séquellaire, un bilan a été effectué chez 100 patients consécutifs suivis dans 3 centres spécialisés du Royaume-Uni. Les lésions osseuses étaient les suivantes: ostéonécrose 43 %, déformation d'Erlenmeyer 59 %, fracture de fragilité 28 %, ostéomyélite 6 % et lyse osseuse 4 %. La mobilité était altérée dans 32 % des cas et il existait des douleurs significatives chez 15 % des patients. La qualité de vie était diminuée, en corrélation avec l'ostéonécrose et les fractures de fragilité. Chez 8 patients une ostéonécrose est apparue après le début de l'enzymothérapie mais ses manifestations et son évolution étaient souvent atypiques. Dans 9 cas le traitement était en cours depuis l'enfance et l'évolution était excellente. L'ostéonécrose était associée à l'âge de début de la maladie et à la réalisation d'une splénectomie, avec un pic d'incidence au cours des 5 années suivant l'intervention qui est en faveur d'une relation causale. La présence des biomarqueurs PARC/CCL18 et chitotriosidase était associée à l'ostéonécrose, et en particulier à sa survenue sous traitement: cette corrélation offre des perspectives de stratégie de prise en charge basée sur une évaluation crédible du risque.
Medicine 2011; 90(1): 52-60
Professor Cox,who inspired the original application for this collaborative project to the Association, reports –
With the award of £168,000 from the Association for the then four Gaucher Specialist Centres in the United Kingdom, the Association made an enormous commitment. This commitment has been repaid by the work of the Group, which has conducted a truly collaborative exercise,despite all the cumbersome EU regulations and approvals required for multi-centre working of this kind.
The aim of the project was to document the extent and burden of the osseous manifestations of Gaucher disease in the mature therapeutic period, which it is now recognised by many patients as, in essence, a bone disease. Not only did we set out to document the extent of bone disease in UK patients,but to use correlates of severity of the bone
disease to identify, if possible, predictive markers that associate with the worst manifestations – fractures and vascular necrosis (or bone crises).
Over the three-year period, doctors in the Centres working with patients collected comprehensive clinical details from 100 adults and 11 children with Gaucher disease and thoroughly documented the extent of their condition. They collected blood samples from them, and reviewed their radiology and clinical histories.
I am pleased to announce that the two full manuscripts reporting original data from the UK Gaucher patient population participating in this work have been submitted for publication as collaborative ventures between Principal Investigators in all the Centres – a team effort brokered by the Association.
The original findings will be reported at length, but in essence the clinical studies documented severe clinical manifestations in Gaucher patients across the country.They also demonstrated that these were major determents of quality of life. In the primary clinical paper the first author, Dr Patrick Deegan, showed that splenectomy was a strong risk factor.While splenectomy has in the past been a focus of attention in Gaucher disease and was known to be associated with disease severity, no true cause-and-effect relationship has ever been established.
It was always said that if patients with very severe and early disease had had their spleens removed just because their disease was severe, any bone disease that occurred in this setting was simply a manifestation of the initial severity. By a careful temporal analysis between the onset of objectively defined bone necrosis events and the
timing of splenectomy, it was shown that there was a significant excess of bone necrosis (bone crises) in the first five years after splenectomy compared with other times, strongly indicating the cause and effect relationship.
“In a second manuscript, of which the first author is Dr. Elena Pavlova supported by the Gaucher Association, an extensive series of bioactive proteins have been quantified in the blood serum of patients previously categorised according to their bone disease. In this study, entitled ‘Potential Biomarkers of Osteonecrosis in Gaucher Disease’,
Dr. Pavlova investigated whether chemokines and cytokines are related to key bone manifestations of Gaucher disease. She was able to show that numerous serum cytokines are elevated in Gaucher disease, including those that were biomarkers previously discovered, such as chitotriosidase and CCL18/PARC. This CCLI8 is a biomarker identified in collaboration with the group of Professor Hans Aerts in The Netherlands and on the basis of support from the Gauchers Association for a PhD studentship for Dr Mary Teresa Moran (1997–2000).
Several cytokines were shown to be potential biomarkers associated with Osteonecrosis significantly later in patients failing to meet a key therapeutic goal (absence of bone necrosis) while taking enzyme replacement therapy. This was compared with a large group who had no evidence of Osteonecrosis who had had no further events, and
similar exposures to enzyme therapy. This ‘association’ study is very powerful and immediately suggests prospective studies to identify appropriate target values for easily measured parameters recommended for patients. These target values have the potential to significantly reduce the risk of ever developing avascular necrosis or other skeletal complications of Gaucher disease.
Together with my colleagues, I believe that these studies are very important in themselves, but also because they lay the groundwork for future studies which should improve the lives of Gaucher patients and allow for better management of their condition as a chronic disease in the long-termfuture.By identifying target biomarker values, it seemed very likely that it would be possible to further rationalize therapy for each patient in a more accurate and thus confident way. If successful, this might even allow for the development of improved nationally agreed
protocols of care.
I would like to again thank the Association for its huge investment in its own teams of national experts. I am sure that all the Directors and participants in the research felt the same gratitude for this team-building initiative. The award was an imaginative and adventurous enterprise by patients and their families, but despite all the complexities of the research and the organisation needed to see it through to completion, I am sure that genuine progress had been made, and that time would surely show just how much had been achieved.
Editor’s Note: Congratulations to Dr Patrick Deegan and his co- authors and investigators from the Gaucher centres – as well as the study participants – on the acceptance of the paper ‘Osseous Manifestations of Adult Gaucher Disease in the Era of Enzyme Replacement Therapy’ in Medicine (Baltimore).
http://www.gaucher.org.uk/enews.php?id=301
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