Elsevier

The Lancet

Volume 366, Issue 9502, 10–16 December 2005, Pages 2058-2061
The Lancet

Hypothesis
The role of proinflammatory cytokines in the cause of neuropathic osteoarthropathy (acute Charcot foot) in diabetes

https://doi.org/10.1016/S0140-6736(05)67029-8Get rights and content

Summary

The pathogenesis of the acute Charcot foot of diabetes remains unclear. All patients with this condition have evidence of peripheral neuropathy, with loss of protective sensation and abnormal foot biomechanics. However, the acute Charcot foot is also characterised by a pronounced inflammatory reaction and the pathogenic significance of this inflammation has received little attention. We suggest that an initial insult—which may or may not be detected—is sufficient to trigger an inflammatory cascade through increased expression of proinflammatory cytokines, including TNFα and interleukin 1β. This cascade then leads to increased expression of the nuclear transcription factor, NF-κB, which results in increased osteoclastogenesis. Osteoclasts cause progressive bone lysis, leading to further fracture, which in turn potentiates the inflammatory process. The potential role of proinflammatory cytokines suggests the possibility of new treatments for this sometimes devastating complication of diabetes.

Introduction

Denervation-induced destruction of joints was described by Jean-Martin Charcot in 1868,1 although he acknowledged that the condition had been first reported by the American physician John Kearsley Mitchell (1798–1858) in 1831.2 Mitchell's cases were secondary to spinal damage caused by tuberculosis, whereas Charcot's were the result of tertiary syphilis. Sir James Paget suggested in 1881 that the condition should be called Charcot's disease. The Charcot foot was recognised as a complication of diabetic neuropathy in 1936,3 and diabetes is probably the commonest cause worldwide today, although leprosy is important in endemic areas. The deformity caused by Charcot's disease can be devastating (figure 1). Charcot was well aware of the part played by painlessness and abnormal foot biomechanics in the pathogenesis of the disorder, but he also emphasised that its onset was marked by an acute, inflammatory phase: “Les articulations étaient tuméfiées, rouges et quelque peu doloureuses, de manière à simuler les accidents de rhumatisme articulaire subaigu” (the joints were inflamed, red and rather painful, similar to exacerbations of subacute rheumatoid arthritis).1

This acute inflammation, as well as the results of detailed morphological analysis, led him to speculate that in addition to the motor and sensory consequences of denervation, there might be an additional abnormality of bone blood flow or nutrition. He wrote: “[Denervation] devra se traduire encore par des troubles de la circulation ou de la nutrition, si elle affecte, en outre, des tubes appartenant au groupe des éléments nerveux vaso-moteurs ou trophiques” (denervation will also be expressed by changes in the circulation or nutrition if it involves, in addition, nerve fibres which are vasomotor or trophic).1

This potential aspect of the pathogenesis was largely ignored during the 20th century, and most current practitioners regard the condition as the simple result of continuing damage caused by loss of protective sensation in a well perfused limb. Recent attention has, however, focused on several anomalies, which together suggest a more complex cause. These anomalies include the rarity of the condition, its asymmetry, and the fact that it is usually self-limiting.4, 5 The possible relation with reflex sympathetic dystrophy (complex regional pain syndrome, type 1) has also been noted.4, 6 Of note, early observations on conditions resembling this pain syndrome, including the case series reported by Silas Weir Mitchell, son of J K Mitchell,7, 8 drew attention to the possible link between inflammation and osteoarthropathy.

Our hypothesis is that the development of the acute Charcot foot is based on an exaggerated inflammatory response to trauma. If the role of proinflammatory cytokines is confirmed, it could lead to the adoption of new markers of the activity of the disease, and of effective new therapies.

Section snippets

Current concepts about pathogenesis

The acute Charcot process is thought to be triggered by a minor injury, whether noticed by the patient or not. The injury might lead to either microfracture or to subluxation or dislocation, which further changes the distribution of forces on the joints and bones of the foot. The damage increases and a vicious cycle is established, which is made worse because the pain is less than would be expected, leading to continued weight-bearing (figure 2). The initial microfracture can be more likely if

The role of inflammation

Local inflammation is invariable in the acute phase of the disorder, and is the main symptom or sign which leads to the diagnosis being suspected, whether there is radiological evidence of skeletal changes at presentation or not. The presentation is often mistaken for acute infection, and if bone changes are present, differentiation from osteomyelitis can be very difficult.23 The fact that soft tissue inflammation can predate detectable changes in bone and joints is indicative of its key role

Limitations of the hypothesis

The relation between TNFα and interleukin 1β in mediating acute inflammation is not known, and nor is the importance of numerous other hormones, cytokines, and metabolic factors that may be involved.34 The role of nerve-derived peptides calcitonin gene-related peptide and substance P is also unclear since their function is essentially proinflammatory and vasodilatory, and there is evidence that they augment the expression of both TNFα and interleukin 1β.32

Implications for clinical practice

If the basis of our hypothesis is correct, and the release of proinflammatory cytokines is key to the development and perpetuation of the acute Charcot foot, then measurement of TNFα, or of downstream products such as RANKL, may be used as markers of activity of the disease. Of even greater importance is the possibility that inhibitors of proinflammatory cytokines could be of benefit in clinical practice. Several inhibitors of RANKL, NF-κB, and interleukin 1β are available as research tools and

Testing the hypothesis

Our hypothesis can be tested simply in patients with an acute Charcot foot in three ways: (1) by measuring circulating concentrations of proinflammatory cytokines and RANKL and correlating concentrations with disease activity, although differences might be more pronounced in samples from the periphery, such as from the dorsal veins of the foot; (2) by measuring cytokine expression in bone specimens from patients with neuropathy with and without reduced bone density, and with and without acute

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