HypothesisThe role of proinflammatory cytokines in the cause of neuropathic osteoarthropathy (acute Charcot foot) in 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
References (34)
- et al.
Skeleton key to vascular disease
J Am Coll Cardiol
(2004) - et al.
Effects of antioxidants and nitric oxide on TNF-alpha-induced adhesion molecule expression and NF-kappaB activation in human dermal microvascular endothelial cells
Life Sci
(2004) - et al.
Differential effects of growth factors and cytokines on the synthesis of SPARC, DNA, fibronectin and alkaline phosphatase activity in humam periodontal cells
Cell Biol Int
(2004) - et al.
Normal blood flow response and vasomotion in the diabetic Charcot foot
J Diabetes Complications
(1998) Nuclear factor kappa B: molecular biomedicine—the next generation
Biomed Pharmacother
(2004)Sur quelques arthropathies qui paraissent dépendre d'une lésion du cerveau ou de la moëlle épinière
Arch Physiol Norm Pathol
(1868)On a new practice in acute and chronic rheumatism
Am J Med Sci
(1831)Neuritic manifestations in diabetes mellitus
Arch Intern Med
(1936)- et al.
The Charcot foot
Diabet Med
(2000) - et al.
Charcot neuroarthropathy in diabetes mellitus
Diabetologia
(2002)