Low-Dose Intravenous Immunoglobulin Treatment for Long-Standing Complex Regional Pain Syndrome

Göebel, Andreas; Bisla, Jatinder; Carganillo, Roy; Frank, Bernhard; Gupta, Rima; Kelly, Joanna; McCabe, Candy; Murphy, Caroline; Padfield, Nick; Phillips, Ceri; Sanders, Mark; Serpell, Michael; Shenker, Nick; Shoukrey, Karim; Wyatt, Lynne; Ambler, Gareth

doi:10.7326/m17-0509

Cited by 44 publications

(24 citation statements)

References 34 publications

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“…Antinuclear antibodies are found in a disproportionately large fraction of patients with CRPS [ 51 ]. Additional data exist showing that a subset of patients treated with weekly plasmapheresis to lower autoantibody levels experienced prolonged symptom improvement, although a recent large randomized trial with low-dose intravenous immunoglobulin (IVIG) was ineffective [ 52 – 54 ]. Studies using sera and purified IgG preparations from CRPS patients have identified sympathetic neurons, muscarinic receptors, and alpha-1 adrenergic receptors as targets of these autoantibodies [ 6 , 20 ].…”

Section: Discussionmentioning

confidence: 99%

Neuropeptide regulation of adaptive immunity in the tibia fracture model of complex regional pain syndrome

Guo

Shi

et al. 2018

J Neuroinflammation

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BackgroundBoth dysfunctional neuropeptide signaling and immune system activation are characteristic of complex regional pain syndrome (CRPS). Unknown is whether substance P (SP) or calcitonin gene-related peptide (CGRP) support autoantibody production and, consequently, nociceptive sensitization.MethodsThese experiments involved the use of a well-characterized tibia fracture model of CRPS. Mice deficient in SP expression (Tac1−/−) and CGRP signaling (RAMP1−/−) were used to probe the neuropeptide dependence of post-fracture sensitization and antibody production. The deposition of IgM in the spinal cord, sciatic nerves, and skin was followed using Western blotting, as was expression of the CRPS-related autoantigen cytokeratin 16 (Krt16). Passive serum transfer to B-cell-deficient muMT mice was used to assess the production of functional autoantibodies in CRPS model mice. The use of immunohistochemistry allowed us to assess neuropeptide-containing fiber distribution and Langerhans cell abundance in mouse and human CRPS patient skin, while Langerhans cell-deficient mice were used to assess the functional contributions of these cells.ResultsFunctional SP and CGRP signaling were required both for the full development of nociceptive sensitization after fracture and the deposition of IgM in skin and neural tissues. Furthermore, the passive transfer of serum from wildtype but not neuropeptide-deficient mice to fractured muMT mice caused enhanced allodynia and postural unweighting. Langerhans cells were increased in number in the skin of fracture mice and CRPS patients, and those increases in mice were reduced in neuropeptide signaling-deficient animals. Unexpectedly, Langerhans cell-deficient mice showed normal nociceptive sensitization after fracture. However, the increased expression of Krt16 after tibia fracture was not seen in neuropeptide-deficient mice.ConclusionsCollectively, these data support the hypothesis that neuropeptide signaling in the fracture limb of mice is required for autoantigenic IgM production and nociceptive sensitization. The mechanism may be related to neuropeptide-supported autoantigen expression.

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Section: Discussionmentioning

confidence: 99%

Neuropeptide regulation of adaptive immunity in the tibia fracture model of complex regional pain syndrome

Guo

Shi

et al. 2018

J Neuroinflammation

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“…While CRPS has been long thought to arise as a result of an inflammatory process, more current work has it to be deemed an autoimmune condition. 1 – 3 , 5 – 12 Several observations lend strong support to this assertion. (i) The passive transfer of serum immunoglobulin G (IgG) antibodies from a CRPS patient, but not a normal patient, elicits CRPS-like pathology in mice.…”

Section: Crps As An Autoantibody-mediated Syndromementioning

confidence: 83%

“… 9 , 10 Against this assertion serves the evidence from the multicenter randomized blinded placebo-controlled trial that 0.5 g/kg intravenous immunoglobulin immunotherapy produced no benefit in CRPS compared with placebo-treated patients. 8 …”

Section: Crps As An Autoantibody-mediated Syndromementioning

confidence: 99%

Structural homology of myelin basic protein and muscarinic acetylcholine receptor: Significance in the pathogenesis of complex regional pain syndrome

2018

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Complex regional pain syndrome is an extremely painful condition that develops after trauma to a limb. Complex regional pain syndrome exhibits autoimmune features in part mediated by autoantibodies against muscarinic‐2 acetylcholine (M2) receptor. The mechanisms underlying the M2 receptor involvement in complex regional pain syndrome remain obscure. Based on our recent work demonstrating that limb nerve trauma releases a potent proalgesic, immunodominant myelin basic protein fragment, our present sequence database analyses reveal an unexpected and previously undescribed structural homology of the proalgesic myelin basic protein fragment with the M2 receptor. As both complex regional pain syndrome and the proalgesic myelin basic protein activity are prevalent in females, this myelin basic protein/M2 homology presents an inviting hypothesis explaining the mechanisms of autoimmune pathogenesis and sexual dimorphism that underlies vulnerability toward developing complex regional pain syndrome and other pain states with neuropathic features. This hypothesis may aid in the development of novel diagnostic and therapeutic strategies to chronic pain.

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“…Ultimately, this PPI exercise would have accepted an even higher number of patients treated for each responder; however, patients were content to negotiate these numbers acknowledging real‐world information on health economics (in the absence of predictive factors, the intervention may become unaffordable to a public healthcare system such as the UK National Health Service if the number of responders is low) and burden (repeat‐cannulation of a large number of patients for a rare positive response). Notably, recent research results indicate that although treatment‐refractory persistent CRPS is rare (estimated <1:2000/population) delivery of trials with up to 200 participants is feasible …”

Section: Discussionmentioning

confidence: 99%

“…Notably, recent research results indicate that although treatment-refractory persistent CRPS is rare (estimated <1:2000/population) delivery of trials with up to 200 participants is feasible. 19,20 As the duration of pain relief following TPE would be an important outcome in a RCT, thus requiring long trial durations, and, equally, as data about any incremental treatment effect from repeat treatment would be advantageous, patients considered that a 12-months duration of such a trial would be acceptable provided that, as planned, all participants would be offered optional swop to the other treatment arm at the end of that time.…”

Section: Discussionmentioning

confidence: 99%

Patient consultation about a trial of therapeutic plasma exchange for complex regional pain syndrome

Göebel

Callaghan

Jones

et al. 2018

J of Clinical Apheresis

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Background Complex regional pain syndrome (CRPS) is a severe post‐traumatic chronic pain condition affecting distal limbs, for which few effective treatments exist. Complex regional pain syndrome is listed in the 2016 American Society for Apheresis guidelines as an indication for plasma exchange treatment, but patient perspectives are lacking. Study design and methods We convened a “patient and public consultation exercise.” Supervised by a clinical ethicist, the case for using therapeutic plasma exchange (TPE) was presented by a researcher and two TPE experts to five patients with severe, long‐standing CRPS and to one relative. Discussions were recorded and transcribed. Results Participants supported the technology's use but expressed concern that the small trauma of repeat cannulations of CRPS unaffected limbs might theoretically cause a spread of the condition, a risk which requires highlighting when taking consent. For a preliminary trial, the participants proposed to include no less than 10, preferably 20 participants. They suggested that the threshold for a decision to conduct a definite trial based on preliminary trial results should be set no higher than 1/5 patients achieving >30% pain reduction in the preliminary trial, with half of these responders achieving >50%. The use of sham‐TPE and a long trial duration (1 year) of a definite, parallel trial was considered acceptable, provided patients would be offered voluntary swap to the other trial arm at the end of the main trial period. Conclusion These results provide pertinent patient views about TPE treatment which can inform both clinical consultation and consent procedure and the design of future trials.

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Low-Dose Intravenous Immunoglobulin Treatment for Long-Standing Complex Regional Pain Syndrome

Abstract: Medical Research Council/National Institute for Health Research Efficacy and Mechanism Evaluation Program, Pain Relief Foundation, and Biotest United Kingdom.

Cited by 44 publications

References 34 publications

Neuropeptide regulation of adaptive immunity in the tibia fracture model of complex regional pain syndrome

Neuropeptide regulation of adaptive immunity in the tibia fracture model of complex regional pain syndrome

Structural homology of myelin basic protein and muscarinic acetylcholine receptor: Significance in the pathogenesis of complex regional pain syndrome

Patient consultation about a trial of therapeutic plasma exchange for complex regional pain syndrome

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