A CRPS-IgG-transfer-trauma model reproducing inflammatory and positive sensory signs associated with complex regional pain syndrome

Tékus, Valéria; Hajna, Zsófia; Borbély, Éva; Markovics, Adrienn; Bagoly, Teréz; Szolcsányi, Janós; Thompson, Victoria; Kemény, Ágnes; Helyes, Zsuzsanna; Göebel, Andreas

doi:10.1016/j.pain.2013.10.011

Cited by 85 publications

(71 citation statements)

References 35 publications

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“…Sera from patients with CRPS has been reported to harbor autoantibodies targeting autonomic neurons [64,65], and IgG extracted from these sera reproduce some CRPS features in mice [66]. These early passive transfer experiments suggest roles for B cells and IgM [67], and IgG autoantibodies [66].…”

Section: Complex Regional Pain Syndromementioning

confidence: 97%

Immunotherapy Prospects for Painful Small-fiber Sensory Neuropathies and Ganglionopathies

Oaklander

2016

Neurotherapeutics

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The best-known peripheral neuropathies are those affecting the large, myelinated motor and sensory fibers. These have well-established immunological causes and therapies. Far less is known about the somatic and autonomic "small fibers"; the unmyelinated C-fibers, thinly myelinated A-deltas, and postganglionic sympathetics. The small fibers sense pain and itch, innervate internal organs and tissues, and modulate the inflammatory and immune responses. Symptoms of small-fiber neuropathy include chronic pain and itch, sensory impairment, edema, and skin color, temperature, and sweating changes. Small-fiber polyneuropathy (SFPN) also causes cardiovascular, gastrointestinal, and urological symptoms, the neurologic origin of which often remains unrecognized. Routine electrodiagnostic study does not detect SFPN, so skin biopsies immunolabeled to reveal axons are recommended for diagnostic confirmation. Preliminary evidence suggests that dysimmunity causes some cases of small-fiber neuropathy. Several autoimmune diseases, including Sjögren and celiac, are associated with painful small-fiber ganglionopathy and distal axonopathy, and some patients with "idiopathic" SFPN have evidence of organ-specific dysimmunity, including serological markers. Dysimmune SFPN first came into focus in children and teenagers as they lack other risk factors, for example diabetes or toxic exposures. In them, the rudimentary evidence suggests humoral rather than cellular mechanisms and complement consumption. Preliminary evidence supports efficacy of corticosteroids and immunoglobulins in carefully selected children and adult patients. This paper reviews the evidence of immune causality and the limited data regarding immunotherapy for small-fiberpredominant ganglionitis, regional neuropathy (complex regional pain syndrome), and distal SFPN. These demonstrate the need to develop case definitions and outcome metrics to improve diagnosis, enable prospective trials, and dissect the mechanisms of small-fiber neuropathy.

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Section: Complex Regional Pain Syndromementioning

confidence: 97%

Immunotherapy Prospects for Painful Small-fiber Sensory Neuropathies and Ganglionopathies

Oaklander

2016

Neurotherapeutics

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“…We had expected that assay positivity would be restricted to a group of responders to IVIG treatment in the earlier RCT (up to 40% of cases), but half of the nonresponders were also positive. Should a pathogenetic role of CRPS serum-autoantibodies be confirmed [43], these results would provide a rationale for investigating IVIG nonresponders for their response to alternative antiautoimmune therapies. It is possible that a negative assay might predict nonresponse to IVIG, however, our numbers were too small to draw any firm conclusions.…”

Section: Discussionmentioning

confidence: 97%

“…Since we have recently shown that the ''passive transfer'' [41] of CRPS serum IgG to unilaterally hind paw-injured mice causes pertinent features of CRPS in the injured, but not the intact side [43], it should be possible to examine the effects of adrenergic manipulation in that animal model.…”

Section: Discussionmentioning

confidence: 99%

“…The cause of CRPS is unknown, but recent evidence suggests a role for autoantibody-mediated autoimmunity. There is evidence that CRPS serum immunoglobulin (IgG) binds to both autonomic and somatic peripheral nerves [6,24,34], injection of CRPS serum-IgG intraperitoneally to intact mice alters animal behaviour, and injection to hind paw-injured animals elicits CRPS-like signs, and increases substance P in the injured paws [20,43]. Moreover, intravenous immunoglobulins (IVIG) were effective in providing substantial pain relief in some patients, including in a double-blind cross-over study [19,22,23].…”

Section: Introductionmentioning

confidence: 99%

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Longstanding complex regional pain syndrome is associated with activating autoantibodies against alpha-1a adrenoceptors

Dubuis

Thompson

Leite

et al. 2014

Pain

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Complex regional pain syndrome (CRPS) is a limb-confined posttraumatic pain syndrome with sympathetic features. The cause is unknown, but the results of a randomized crossover trial on low-dose intravenous immunoglobulins (IVIG) treatment point to a possible autoimmune mechanism. We tested purified serum immunoglobulin G (IgG) from patients with longstanding CRPS for evidence of antibodies interacting with autonomic receptors on adult primary cardiomyocytes, comparing with control IgG from healthy and diseased controls, and related the results to the clinical response to treatment with low-dose IVIG. We simultaneously recorded both single-cell contractions and intracellular calcium handling in an electrical field. Ten of 18 CRPS preparations and only 1/57 control preparations (P<0.0001) increased the sensitivity of the myocytes to the electric field, and this effect was abrogated by preincubation with α-1a receptor blockers. By contrast, effects on baseline calcium were blocked by preincubation with atropine. Interestingly, serum-IgG preparations from all 4 CRPS patients who had responded to low-dose IVIG with meaningful pain relief were effective in these assays, although 4/8 of the nonresponders were also active. To see if there were antibodies to the α-1a receptor, CRPS-IgG was applied to α-1a receptor-transfected rat-1 fibroblast cells. The CRPS serum IgG induced calcium flux, and fluorescence-activated cell sorting showed that there was serum IgG binding to the cells. The results suggest that patients with longstanding CRPS have serum antibodies to α-1a receptors, and that measurement of these antibodies may be useful in the diagnosis and management of the patients.

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“…[32][33][34][35] These negative findings should be considered on the background of recent in vivo and in vitro results on functionally active, non-inflammatory autoantibodies in CRPs. [36][37][38] The target of effective immune-modulating therapy may be the production of such autoantibodies, rather than inflammatory processes. 39 Alternative immune-modulating technologies, such as plasma exchange therapy, disease modifying antirheumatic drugs, high-dose immunoglobulin or B-cell ablation therapies, should be explored; initial results have been encouraging, but RCTs are needed.…”

Section: Limb Temperature and Volumementioning

confidence: 99%

A randomised placebo-controlled Phase III multicentre trial: low-dose intravenous immunoglobulin treatment for long-standing complex regional pain syndrome (LIPS trial)

et al. 2017

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Background Complex regional pain syndrome (CRPS) is a rare, severe post-traumatic pain condition affecting distal limbs. Patients who do not spontaneously improve in 12 months are classed as having ‘long-standing CRPS’ and often cannot be effectively treated, leading to a poor prognosis. CRPS is associated with functional autoantibodies. Two small trials, including a randomised controlled trial, have suggested that low-dose intravenous immunoglobulin (IVIg) may be an effective treatment for some patients. Objective We hypothesised that low-dose IVIg is effective for reducing pain in long-standing CRPS. Methods A randomised, double blinded placebo-controlled multicentre trial in seven UK pain management centres. Patients were eligible if they had moderate or severe long-standing CRPS that they had experienced for up to 5 years. Participants were randomly allocated to receive 0.5 g/kg IVIg, the active intervention, or visually indistinguishable 0.1% albumin in saline placebo. Randomisation was initiated by study sites via an independent online randomisation system and was 1 : 1 with varying block sizes, stratified by study centre. Participants, investigators and assessors were blinded to group assignment. The study drug/placebo was infused intravenously at the study centres on day 1 and day 23 after randomisation. The primary outcome was the 24-hour average pain intensity between day 6 and day 42, on an 11-point (0–10) numeric rating scale, compared between the groups. Outcomes were analysed using a mixed-effects regression model that used 37 measurements of pain intensity (the primary outcome) per participant. All patients who received an infusion and provided any outcome were included in the intention-to-treat analysis. Results A total of 111 patients were recruited and assigned between 27 August 2013 and 28 October 2015. Three patients were excluded because they had been inappropriately randomised, five patients were withdrawn from the primary analysis because they provided no outcomes and 103 patients were analysed for the primary outcome. The average pain score in the IVIg group was 0.27 units (95% confidence interval –0.24 to 0.80 units) higher than in the placebo group. Therefore, there is no significant evidence of a treatment effect at the 5% level and there was no significant difference between groups. Six serious adverse events but no suspected unexpected serious adverse reactions were reported during the blinded and open-label phase. Conclusion and future work Low-dose immunoglobulin was not effective in relieving pain in patients with moderate to severe CRPS of 1–5 years’ duration. Better drug treatments for long-standing CRPS are urgently required. Trial registration Current Controlled Trials ISRCTN42179756. Funding This project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research partnership. Additional funding was obtained by the Pain Relief Foundation. Biotest UK Ltd provided the active study medication at no cost.

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A CRPS-IgG-transfer-trauma model reproducing inflammatory and positive sensory signs associated with complex regional pain syndrome

Cited by 85 publications

References 35 publications

Immunotherapy Prospects for Painful Small-fiber Sensory Neuropathies and Ganglionopathies

Immunotherapy Prospects for Painful Small-fiber Sensory Neuropathies and Ganglionopathies

Longstanding complex regional pain syndrome is associated with activating autoantibodies against alpha-1a adrenoceptors

A randomised placebo-controlled Phase III multicentre trial: low-dose intravenous immunoglobulin treatment for long-standing complex regional pain syndrome (LIPS trial)

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