Autoantibodies Directly Implicated in Arthralgia Pathogenesis

Joint pain may be directly influenced by the presence of certain autoantibodies as opposed to a non-specific consequence of rheumatoid arthritis disease development.

A common symptom of most autoimmune disorders, pain has been associated with reduced quality of life. Noting the pressing need to understand the pathophysiology linking  pain and autoimmunity, researchers recently reviewed evidence regarding pain in autoimmune disorders, including inflammatory arthritis, with a special focus on the role of antibodies.1

“If we can better understand how autoantibodies are altering or interfering with normal biological function to cause pain, we can develop more targeted therapeutics for patients,” co-author Katherine Ann Mifflin, a doctoral candidate at the University of Alberta Neuroscience and Mental Health Institute, told Clinical Pain Advisor.

There is extensive evidence indicating a role of microglial and T-cell activation in autoimmune disease-related pain, but emerging findings suggest that, in addition to their heterogeneous role in immune dysfunction, autoantibodies may also be a direct cause of the associated pain.

Autoantibodies may influence pain states by binding to voltage-gated potassium channels (VGKCs), thus affecting activation of nociceptors. This proposed mechanism is supported by research on Morvan’s syndrome, in which contactin-associated protein-like 2 (CASPR2) autoantibodies (IgGs) were associated with pain experience (P =.014).2

Researchers have postulated that presence of CASPR2 IgGs may lead to a reduced density of VGKCs at paranodes (where CASPR2 co-localizes with Kv1 channels), thus impairing repolarization, and leading to VGKCs hyperexcitability on nociceptors – and pain.2

Another mechanism whereby autoantibodies may mediate pain, is by affecting the structure of somatosensory neurons. This hypothesis is supported by Guillian-Barre syndrome and neuromyelitis optica studies.3,4 In Guillain-Barre syndrome, Aδ myelinated sensory nerve fibers and unmyelinated C fibers -both of which mediate pain signals- of rats injected with anti-ganglioside (GD2) antibodies had background activity.3 In addition, anti-GD2 antibodies lowered mean threshold of activation of Aδ, not C fibers, possibly underlying mechanical allodynia associated with the disorder.3

In the current review, the authors highlight recent evidence implicating autoantibodies in pain associated with chronic regional pain syndrome (CRPS), rheumatoid arthritis, and Sjögren syndrome.

Autoantibody-mediated activation of M2-muscarinic and β2-adrenergic receptors in CRPS, may result in pain through different mechanisms although precise underlying processes remain to be elucidated.5  Mice administered with anti-citrullinated antibodies (ACPA) from patients with RA showed behaviors indicative of pain, in the absence of inflammation, due to release of a nociceptive chemokine, leading to activation of sensory neurons.6

“Prior to this research cited in the review article, it was not thought that antibodies could directly act to cause pain,” noted Dr Mifflin. Although these new studies point to promising avenues for investigation into potential new treatments, the first step will be to elucidate the specific antibodies involved in each autoimmune disorder, since they vary so widely. “Once we better understand the role of each disease’s specific autoantibody and how they are causing pain, we can move on to developing targeted therapies,” she said.

Summary and Clinical Applicability

“The arthralgia that often precedes the onset of RA may be a direct consequence of the presence of certain ACPA[s], rather than an unspecific symptom unrelated to the pathogenesis of RA. This insight should dramatically alter our approach to diagnosing as well as treating ACPA+ arthralgia, and may indicate new potential targets for the prevention of development of clinical signs of RA in this early phase of disease development,” the authors of one study concluded.6

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  1. Mifflin KA, Kerr BJ. Pain in autoimmune disorders. J. Neurosci. Res. 2016; doi: 10.1002/jnr.23844.
  2. Klein CJ, Lennon VA, Aston PA, McKeon A, Pittock SJ. 2012. Chronic pain as a manifestation of potassium channel-complex autoimmunity. Neurology 79:1136–1144.
  3. Xiao WH, Yu AL, Sorkin LS. Electrophysiological characteristics of primary afferent fibers after systemic administration of anti-GD2 ganglioside antibody. Pain. 1997; 69:145–151.
  4. Hinson SR, Romero MF, Popescu BF, et al. Molecular outcomes of neuromyelitis optica (NMO)-IgG binding to aquaporin-4 in astrocytes. Proc Natl Acad Sci U S A. 2012; 109:1245–1250.
  5. Goebel A. Autoantibody pain. Autoimmun Rev. 2016;15(6):552-7.
  6. Wigerblad G, Bas DB, Fernades-cerqueira C, et al. Autoantibodies to citrullinated proteins induce joint pain independent of inflammation via a chemokine-dependent mechanism. Ann Rheum Dis. 2016;75(4):730-8.

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This article originally appeared on Clinical Pain Advisor