International collaborative research on Charcot's disease

TY - JOUR

T1 - International collaborative research on Charcot's disease

AU - Boulton, Andrew JM

AU - Jeffcoate, William J.

AU - Jones, Teresa LZ

AU - Ulbrecht, Jan S.

N1 - Funding Information: Andrew JM Boulton a William J Jeffcoate b [email protected] Teresa LZ Jones c Jan S Ulbrecht d a Department of Medicine, Manchester Royal Infirmary, Manchester, UK b Foot Ulcer Trials Unit, Department of Diabetes and Endocrinology, Nottingham University Hospitals Trust, City Hospital Campus, Nottingham NG5 1PB, UK c DEM/NIDDK/NIH, Bethesda, MD, USA d Penn State Institute for Diabetes and Obesity, Pennsylvania State University, University Park, PA, USA On Sept 17–18, the US National Institute of Diabetes, Digestive and Kidney Diseases and the Office of Rare Diseases of the National Institutes of Health hosted an international symposium on Charcot's disease of the foot (neuroarthropathy) in diabetes, in Bethesda, MD, USA. The intention was to bring together experts from different countries with the aim of promoting international collaboration to investigate the causes and best treatment of this uncommon, but potentially devastating, complication of diabetic neuropathy. Research has hitherto been hampered by the rarity of the condition, its protean manifestations, and the lack of any specific diagnostic marker. Indeed, it is a disease without even a formal definition, though it is one that is often easily recognisable by those with a high index of suspicion. The timing is right, however, for such an initiative. Ideas concerning the causes of acute Charcot's disease were essentially stalled until the publication in The Lancet of a hypothesis suggesting that local inflammation played a key role in its development. Recognition of this hypothesis provided an explanation for clinical features which were superficially puzzling, 1 including the fact that the condition is both self-limiting as well as usually one-sided, whereas the underlying predisposing neuropathy is permanent and symmetrical. The suggested involvement of proinflammatory cytokines, such as tumour necrosis factor (TNF) α and interleukin 1β, together with the RANKL-NFκB signalling pathway, also provided a potential explanation for the association of acute Charcot's disease with bone lysis and calcification of the media of arterial walls (Mönckeberg's sclerosis), because both of these processes are now also thought to be mediated, directly or indirectly, by the expression of these same peptides. Despite the interest generated by these ideas, however, they remain hypothetical with few new data to substantiate them. A programme of research needs to be established that can address this lack of knowledge. Research is also needed into other factors that might be linked to the onset of acute Charcot's disease, such as the possibility of a genetic predisposition similar to that described in another disorder, Paget's disease of bone, which is characterised by osteoclast activation. Radiograph of Charcot's foot (neuropathic arthropathy), showing degeneration of joints and bones Wellcome Images Data are also urgently needed to justify management strategies, which currently rely almost entirely on mechanically protecting the foot to arrest the inflammatory process and minimise damage from further trauma. Although the use of bisphosphonate preparations has been suggested, none of the available studies has shown significant benefit in clinically relevant long-term outcomes. The role of bisphosphonates in the management of acute Charcot's disease needs to be established in a prospective trial that is adequately powered and that uses clinically relevant endpoints. Similarly, robust trials are needed into possible new therapeutic approaches, such as the use of agents to suppress the inflammatory process that typifies the acute disease, including, conceivably, the use of corticosteroids, antagonists of TNFα such as infliximab or etanercept, and antagonists of RANKL such as denosumab. Research is also needed on the role of surgery (in the acute, as well as less acute phases), and on fundamental issues such as definition and diagnostic markers. Every one of these studies, however, crucially depends on agreement on criteria for disease definition and for population selection. Education to raise awareness in patients and professionals is also urgently needed to ensure early diagnosis and correct treatment, and this effort should include major input from consumer groups. It was in recognition of these needs that the meeting was convened, with a view to enhancing understanding through a programme of coordinated international research. The National Institute of Diabetes, Digestive and Kidney Diseases has recently developed new mechanisms for supporting clinical research which can promote such collaborative efforts. The UK's National Institute of Health Research's Health Technology Assessment programme has confirmed its policy of considering applications for such collaborative funding, and is keen to support suitable applications in the field (either for UK-based sections of multinational trials, or for international studies which are UK-led). We hope that equivalent bodies in other countries will adopt a similarly positive approach. We declare that we have no conflict of interest.

PY - 2009

Y1 - 2009

UR - http://www.scopus.com/inward/record.url?scp=58149204187&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=58149204187&partnerID=8YFLogxK

U2 - 10.1016/S0140-6736(09)60019-2

DO - 10.1016/S0140-6736(09)60019-2

M3 - Comment/debate

C2 - 19135599

AN - SCOPUS:58149204187

SN - 0140-6736

VL - 373

SP - 105

EP - 106

JO - The Lancet

JF - The Lancet

IS - 9658

ER -