Research Update: CRPS and the Immune system


Our understanding of the role of the immune system and pain has moved forwards enormously. The way in which the immune system affects sensitivity needs to be considered when designing a treatment programme. Thinking about ‘neuroimmune’ responses to movement, exercise, physical therapy and thoughts about the pain or movement (click here for an interesting study) is the contemporary way of reasoning how the body is dealing with the perceived threat.

The immune system: ‘dealing with healing’, protecting us and learning.

Immnue system and inflammation

Pain 2011 Aug 2. [Epub ahead of print]

Autoimmunity against the β(2) adrenergic receptor and muscarinic-2 receptor in complex regional pain syndrome.


Department of Neurology, Justus-Liebig-University, Giessen, Germany.


Complex regional pain syndrome (CRPS) is a painful condition affecting one or more extremities of the body, marked by a wide variety of symptoms and signs that are often difficult to manage because the pathophysiology is incompletely understood. Thus, diverse treatments might be ineffective. A recent report revealed the presence of autoantibodies against differentiated autonomic neurons in CRPS patients. However, it remained unclear how the antibodies act in the development of CRPS. We therefore aimed to characterize these antibodies and identify target antigens. Functional properties of affinity-purified immunoglobulin G of control subjects or CRPS patients were assessed using a cardiomyocyte bioassay. Putative corresponding receptors were identified using antagonistic drugs, and synthesized peptide sequences corresponding to segments of these receptors were used to identify the target epitopes. Chinese hamster ovary cells were transfected with putative receptors to ensure observed binding. Further, changes in the intracellular Ca(2+) concentration induced by agonistic immunoglobulin G were measured using the Ca(2+)-sensitive fluorescent dye fura-2 assay. Herein, we demonstrate the presence of autoantibodies in a subset of CRPS patients with agonistic-like properties on the β(2) adrenergic receptor and/or the muscarinic-2 receptor. We identified these autoantibodies as immunoglobulin G directed against peptide sequences from the second extracellular loop of these receptors. The identification of functionally active autoantibodies in serum samples from CRPS patients supports an autoimmune pathogenesis of CRPS. Thus, our findings contribute to the further understanding of this disease, could help in the diagnosis in future, and encourage new treatment strategies focusing on the immune system


Ann N Y Acad Sci. 2007 Jun;1107:168-73.

Autoimmunity in complex-regional pain syndrome.


Department of Neurology, Justus-Liebig-University, Giessen, Germany.


Complex regional pain syndrome (CRPS) is an etiologically unclear syndrome with the main symptoms being pain, trophic and autonomic disturbances, and functional impairment that develops after limb trauma or operation and is located at the distal site of the affected limb. Because autoantibodies against nervous system structures have been described in these patients, an autoimmune etiology of CRPS is discussed. These autoantibodies bind to the surface of peripheral autonomic neurons. Using a competitive binding assay, it can be shown that at least some of the CRPS sera bind to the same neuronal epitope. Autoimmune etiology of CRPS is a new pathophysiological concept and may have severe impact on the treatment of this often chronic disease.


Pain. 2009 Jun;143(3):246-51. Epub 2009 Apr 16.

Autoantibodies in complex regional pain syndrome bind to a differentiation-dependent neuronal surface autoantigen.


Dept. of Neurology, Justus-Liebig-University, Am Steg 14, 35392 Giessen, Germany.


Complex regional pain syndrome, which is characterised by pain and trophic disturbances, develops frequently after peripheral limb trauma. There is an increasing evidence of an involvement of the immune system in CRPS, and recently we showed that CRPS patients have autoantibodies against nervous system structures. Therefore we tested the sera of CRPS patients, neuropathy patients and healthy volunteers for surface-binding autoantibodies to primary cultures of autonomic neurons and differentiated neuroblastoma cell lines using flow cytometry. Thirteen of 30 CRPS patients, but none of 30 healthy controls and only one of the 20 neuropathy sera had specific surface binding to autonomic neurons (p<0.001). The majority of the sera reacted with both sympathetic and myenteric plexus neurons. Interestingly, 6/30 CRPS sera showed binding to undifferentiated SH-SY5Y neuroblastoma cells. However, differentiation of SH-SY5Y into a cholinergic phenotype induced a surface antigen, which is recognised by 60% of CRPS sera (18/30), but not by controls (p<0.001). Our data show that about 30-40% of CRPS patients have surface-binding autoantibodies against an inducible autonomic nervous system autoantigen. These data support an autoimmune hypothesis in CRPS patients. Further studies must elucidate origin and function of these autoantibodies in CRPS.


Clin Exp Immunol. 2011 Apr;164(1):108-17. doi: 10.1111/j.1365-2249.2010.04308.x. Epub 2011 Feb 8.

Elevated blood levels of inflammatory monocytes (CD14+ CD16+ ) in patients with complex regional pain syndrome.


Complex regional pain syndrome (CRPS) is a chronic pain disorder. Although its pathophysiology is not completely understood, neurogenic inflammation is thought to play a significant role. Microglia and astrocytes are activated following tissue injury or inflammation and have been reported to be both necessary and sufficient for enhanced nociception. Blood-borne monocytes/macrophages can infiltrate the central nervous system (CNS) and differentiate into microglia resulting in hypersensitivity and chronic pain. The primary aim of this study was to evaluate the proportion of the proinflammatory CD14(+) CD16(+) monocytes as well as plasma cytokine levels in blood from CRPS patients compared to age- and gender-matched healthy control individuals. Forty-six subjects (25 CRPS, 21 controls) were recruited for this study. The percentage of monocytes, T, B or natural killer (NK) cells did not differ between CRPS and controls. However, the percentage of the CD14(+) CD16(+) monocyte/macrophage subgroup was elevated significantly (P<0·01) in CRPS compared to controls. Individuals with high percentage of CD14(+) CD16(+) demonstrated significantly lower (P<0·05) plasma levels on the anti-inflammatory cytokine interleukin (IL)-10. Our data cannot determine whether CD14(+) CD16(+) monocytes became elevated prior to or after developing CRPS. In either case, the elevation of blood proinflammatoty monocytes prior to the initiating event may predispose individuals for developing the syndrome whereas the elevation of blood proinflammatory monocytes following the development of CRPS may be relevant for its maintenance. Further evaluation of the role the immune system plays in the pathogenesis of CRPS may aid in elucidating disease mechanisms as well as the development of novel therapies for its treatment.


J Clin Immunol. 2010 May;30 Suppl 1:S103-8.

Immunoglobulin responsive chronic pain.


Pain Research Institute, 3rd Floor, Clinical Sciences Centre, Liverpool University, Liverpool, UK.



Over the last 15 years, clinical and experimental data have emerged that suggest that peripheral and central, glial-mediated neuroimmune activation is both necessary and sufficient to sustain chronic pain. Immune modulation appears to be, therefore, a possible new therapeutic option.


The Medline database and international trial registry databases were searched using the keywords “intravenous immunoglobulin” or “IVIG,” “pain” or “chronic pain,” “neuropathic pain,” “CRPS,” “complex regional pain syndrome” or “fibromyalgia.”


Evidence from RCTs suggest that IVIG is effective to reduce pain in complex regional pain syndrome (low-dose IVIG) and post-polio syndrome (high-dose IVIG), and open trials have suggested efficacy in additional pain conditions.


IVIG therapy may emerge as a novel treatment modality for refractory cases. However, before this drug can be confidently used by clinicians, important questions need to be answered concerning optimal treatment doses, duration of treatment, and its effect on function and quality of life.


Ann Intern Med. 2010 Feb 2;152(3):152-8.

Intravenous immunoglobulin treatment of the complex regional pain syndrome: a randomized trial.



Treatment of long-standing complex regional pain syndrome (CRPS) is empirical and often of limited efficacy. Preliminary data suggest that the immune system is involved in sustaining this condition and that treatment with low-dose intravenous immunoglobulin (IVIG) may substantially reduce pain in some patients.


To evaluate the efficacy of IVIG in patients with longstanding CRPS under randomized, controlled conditions.


A randomized, double-blind, placebo-controlled crossover trial. (National Research Registry number: N0263177713; International Standard Randomised Controlled Trial Number Registry: 63918259)


University College London Hospitals Pain Management Centre.


Persons who had pain intensity greater than 4 on an 11-point (0 to 10) numerical rating scale and had CRPS for 6 to 30 months that was refractory to standard treatment.


IVIG, 0.5 g/kg, and normal saline in separate treatments, divided by a washout period of at least 28 days.


The primary outcome was pain intensity 6 to 19 days after the initial treatment and the crossover treatment.


13 eligible participants were randomly assigned between November 2005 and May 2008; 12 completed the trial. The average pain intensity was 1.55 units lower after IVIG treatment than after saline (95% CI, 1.29 to 1.82; P < 0.001). In 3 patients, pain intensity after IVIG was less than after saline by 50% or more. No serious adverse reactions were reported.


The trial was small, and recruitment bias and chance variation could have influenced results and their interpretation.


IVIG, 0.5 g/kg, can reduce pain in refractory CRPS. Studies are required to determine the best immunoglobulin dose, the duration of effect, and when repeated treatments are needed.


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