This work was supported by the NIH (R37-AI57966-AS and T32-AI07163-EF) and the Howard Hughes Medical Institute. Conflict of interest: The authors declare no financial or commercial conflict of interest. Detailed facts of importance to specialist readers are published as ”Supporting Information”. Such

documents are peer-reviewed, but not copy-edited or typeset. They are made available as submitted by the authors. “
“Complex regional pain syndrome (CRPS) was first described during the American Civil Regorafenib clinical trial War. Silas Weir Mitchell began to recognize unusual symptoms in soldiers with partial nerve injuries, such as the development of extreme pain in a distal limb, even when the acute injury had subsided. Today, cases of CRPS following partial nerve see more injury are rare, with the syndrome more often developing following non-nerve-injury trauma to a distal limb. Clinical presentation is extremely varied; the acute presentation can resemble septic inflammation. However, upon investigation there would be no neutrophils present and inflammatory markers

are always normal. It is thought that this clinical picture is caused in part by neurogenic inflammation with anti-dromic substance P and calcitonin gene-related peptide (CGRP) secretion. A rare complication of this can be malignant oedema, which can lead to repeated skin infection and eventual amputation [1]. Treatment options for CRPS are limited and have low efficacy, especially in patients with long-standing CRPS (>1 Etoposide supplier year duration) who are much

less likely to recover spontaneously. In recent years, an important role for immune mechanisms in sustaining chronic pain has been recognized, and evidence for immune involvement in CRPS suggests that immune modulation may be an effective treatment for the syndrome. A randomized clinical trial in 12 patients with long-standing CRPS set out to investigate the effect of intravenous immunoglobulin (IVIg), if any, on the symptoms of CRPS [2] and found that a subset of patients experienced important benefit. Twenty-five per cent (n = 3) of the subjects experienced an alleviation of their symptoms by more than 50%, while a further 17% (n = 2) experienced pain relief of between 30 and 50% (P < 0·001) [2]. Based on earlier results [3], it was postulated that patients who responded well to the immunoglobulin (Ig) treatment may have been suffering from an autoimmune condition, with secretion of antibodies directed against peripheral sensory nerves. These pre-existing serum autoantibodies may synergize with the consequences of trauma to cause or sustain chronic pain.