Autoimmun Rev. 2012 Dec 6.
Complex regional pain syndrome, prototype of a novel kind of autoimmune disease.
Goebel A, Blaes F.
Pain Research Institute, Department of Translational Medicine, Liverpool University, Liverpool, UK; The Walton Centre NHS Foundation Trust, Liverpool, UK. Electronic address: firstname.lastname@example.org.
Complex regional pain syndrome (CRPS) is a painful condition, which arises in a limb after trauma. CRPS can profoundly affect patients' quality of life, and there is no cure. CRPS is associated with limb-confined sensory, motor, skin, bone and autonomic abnormalities. Recent research has shown that some patients respond to treatment with immunoglobulins, and that a majority have IgG serum-autoantibodies directed against, and activating autonomic receptors. CRPS serum-IgG, when transferred to mice elicits abnormal behaviour. These results suggest that CRPS is associated with an autoantibody-mediated autoimmune process in some cases. CRPS has unusual features, including a non-destructive, and regionally-confined course. We propose that CRPS constitutes a prototype of a new kind of autoimmunity, which we term 'IRAM' (injury-triggered, regionally-restricted autoantibody-mediated autoimmune disorder with minimally-destructive course). Understanding autoimmune contribution to CRPS should allow the exploration of novel treatment modalities in the future. Additional 'functional' disorders, painful or painless may be autoimmune in nature.
Around the time when Paul Ehrlich described ‘horror autotoxicus’, the postulate that our body does not tolerate an immune reaction against itself, Paul Sudeck reported on a peculiar painful post-traumatic condition  and  (Weir Mitchell had first described in 1864, what was later recognized as a post-nerve injury form of the same condition; this rare subgroup is now classified as ‘CRPS II’; Mitchell had termed the condition ‘causalgia’ after the reported peculiar, burning pain). In 1900, Sudeck portrayed five patients admitted to the General Hospital in Hamburg, Germany, who had sustained peripheral limb trauma and developed disproportionate, un-abiding limb pain, associated with limb-confined swelling, sweating and reddening. He initially considered that these signs and symptoms were caused by a particular inflammatory reaction. He identified localized osteoporosis on X-ray and thus assigned the term ‘acute, entzuendliche Knochenatrophy’ (acute inflammatory bone atrophy). This syndrome subsequently received a number of additional names including ‘Sudeck's atrophy’ and ‘Reflex Sympathetic Dystrophy’, until in 1994 ‘complex regional pain syndrome’ (CRPS) was accepted . The diagnostic ‘Budapest’ criteria are based on the presence of pain and certain limb abnormalities including sensory, autonomic, trophic and motor changes . CRPS is costly to both the healthcare system and society. Only few patients with un-abiding CRPS return to work . There are only few treatments, and there is no cure  and . The condition has continued to puzzle investigators. Bizarre aspects of its presentation have continued to emerge over the past 110 years, and although we now understand that CRPS is indeed associated with an initial local inflammatory response – without reported neutrophil invasion or overt tissue destruction  – the underlying cause has remained elusive. Over the course of the disease, initial limb signs generally mellow , however about 15% of patients continue to have unrelenting pain ; these patients' quality of life remains amongst the lowest reported in medical conditions .
We propose that in some cases CRPS is autoimmune-mediated, caused by a novel kind of autoimmunity, which has unusual features. One important feature is, that CRPS is post-traumatic, and that certain parts of the body – the peripheral limbs – are susceptible . Stable regional restriction of autoimmunity within a larger organ is rare; it occurs, for example in ophiasis, an occipital form of alopecia areata, which is T-cell mediated . A ‘two-hit’ process may explain a regional restriction. Pre-existing circulating autoantibodies (the ‘first hit’) may become pathogenic only in the context, and around the area of regional trauma (the second hit, Fig. 1A). Peripheral limbs may provide a facilitating environment. One additional unusual CRPS feature is minimal tissue destruction, even after many years disease duration. Other CRPS characteristics accord with a ‘classical’ autoimmune presentation. CRPS is usually of adult onset . There are HLA associations, although most studies have been small . A number of investigators have described cases following viral and bacterial infections  and ; further we have provided preliminary serological evidence for antecedent infections with chlamydia, parvovirus and campylobacter ,  and .