Neuromyelitis optica spectrum disorder (NMOSD) is a chronic, rare, autoimmune disorder characterized by inflammation and demyelination of nerves in the central nervous system (CNS). NMOSD shares features of multiple sclerosis (MS) but mainly manifests as optic neuritis and longitudinally extensive transverse myelitis lesions with the presence of pathogenic autoantibodies (immunoglobulin G [IgG]) against aquaporin-4 (AQP4-IgG).1

Although autoantibodies targeting aquaporin-4 (AQP4) are present in the majority of patients, patients clinically diagnosed with NMOSD may be grouped as having either AQP4-IgG-seropositive autoimmune astrocytopathic disease, myelin oligodendrocyte glycoprotein (MOG)-IgG-seropositive inflammatory demyelinating disease, or double-seronegative disease.2

The Prevalence of Neuropathic Pain in NMOSD

Pain is common in NMOSD, with a frequency of over 80%, and pain syndromes include neuropathic, nociceptive, and mixed pain, which can appear in an acute relapse or become chronic during the disease course.3 It has also been demonstrated that neuropathic pain was present in around 80% of patients with both AQP4-IgG seropositive and AQP4-IgG seronegative NMOSD.4 


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However, conventional medications used to treat neuropathic pain in patients with NMOSD have limited efficacy, according to a systematic literature review of pathophysiology, symptoms, and treatment strategies of pain in this group of patients.3 

Given that neuropathic pain is frequent in NMOSD patients, conventional medications for neuropathic pain management are unsatisfactory, and there is an unmet medical need to explore novel therapeutic targets which may lead to the development of innovative treatments, Serizawa et al aimed to shed light on the evolving role of interleukin-6 (IL-6) in the management of neuropathic pain.5 In their recently published review article, they explored both clinical studies and preclinical experiments to evaluate the role of IL-6 signaling pathways in neuroimmunological disorders. 

Clinical Studies on the Analgesic Effects of IL-6 Signaling Inhibition 

There is accumulating evidence that the IL-6 signaling pathway has a role in NMOSD pathogenesis, making the pathway a possible treatment target. Several studies can be found in the scientific literature assessing the use of a humanized immunoglobulin G1 (IgG1) anti-IL-6 receptor (IL6R) monoclonal antibody in patients with NMOSD. Serizawa and colleagues review 6 of these studies: a case report, a pilot study, a retrospective observational study, a case series, and 2 randomized, placebo-controlled trials (RCTs) to reach an understanding of the analgesic effects of IL-6 signaling inhibition.

While the change from baseline in the visual analog scale (VAS) score for pain was not significant in either RCT, a reduction in the numerical rating scale (NRS) score was reported in the other 4 studies.5 As indicated by the authors of the review article, most probably because of the differences in study settings, the results on the analgesic benefits of IL-6 signaling inhibition are controversial and there is a need for further studies.

Animal Studies on the Role of IL-6 in Neuropathic Pain 

Animal studies included in the review article refer to several pathways and mechanisms that have demonstrated the role of IL-6 in neuropathic pain. According to these studies, IL-6 may cause neuropathic pain directly through the nociceptive effect or indirectly by increasing the synthesis of pain mediators, and it may cause touch-evoked allodynia in normal rats and thermal hyperalgesia in a rat model of neuropathic pain. Moreover, a neutralizing IL-6 antibody may reduce mechanical allodynia after peripheral nerve damage, and microinjection of recombinant human IL-6 into the lateral cerebroventricle of rats may cause hyperalgesia.5 

The animal model for MS known as experimental autoimmune encephalomyelitis (EAE) has also been used to explore the role of IL-6 in neuropathic pain. The research group of the authors of this review article has previously evaluated the efficacy of intraperitoneal injection of a rat anti-mouse IL6R antibody, MR16-1, on pain sensitivity in EAE mice in 2 experiments. MR16-1 significantly reduced mechanical allodynia and prevented the development of motor dysfunction in EAE mice in experiment 1. In experiment 2, MR16-1 raised the paw withdrawal threshold, which is indicative of mechanical allodynia; nevertheless, the clinical score (paralysis score) was about equal between mice given the control vehicle and that given MR16-1. The research group also used the Mouse Grimace Scale (MGS) to assess the antinociceptive effect of MR16-1 on spontaneous pain in EAE mice, and the MGS score in EAE mice on day 19 was significantly higher compared with that in control mice.6,7 

Mechanisms of anti-IL-6 therapies for neuropathic pain in EAE are also explained in the review article: the inhibition of microglial activation and the descending pain inhibitory system. Following peripheral nerve damage, microglial cells begin releasing a variety of cytokines including IL-6. Therefore, decreased mechanical allodynia by MR16-1 in EAE mice was attributed to the inhibition of microglial activation and proliferation in the spinal cord. Because of the dramatic plasticity and multiplicity of the descending pathways, as well as their active involvement in the development and maintenance of persistent pain after tissue or nerve injury, the potential to protect against pain in EAE mice by administration of MR16-1 was considered to be caused in part by impairment in the descending pain inhibitory system.5 

Future Perspectives

Pain is the most prominent complaint of patients with NMOSD and it is highly debilitating, having a significant impact on a patient’s quality of life. However, current treatment options such as gabapentinoids, tricyclic antidepressants, and selective serotonin-norepinephrine reuptake inhibitors are insufficient to reduce pain intensity and improve the patients’ quality of life. Therefore, discoveries in animal models may be a potential sign of new treatment options even though the pathophysiology of neuropathic pain in NMOSD is complicated.

As Serizawa et al indicated in their article: “Evaluation of the effects of anti-IL-6 therapies in ameliorating neuropathic pain as a primary endpoint in large clinical trials is warranted and may help address the unmet medical need in the management of neuropathic pain associated with neuroimmunological disorders such as MS and NMOSD.”

References

  1. Wingerchuk DM, Banwell B, Bennett JL, et al. International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology. 2015;85(2):177-189. doi:10.1212/WNL.0000000000001729 
  2. Hor JY, Asgari N, Nakashima I, et al. Epidemiology of neuromyelitis optica spectrum disorder and its prevalence and incidence worldwide. Front Neurol. 2020;11:501. doi:10.3389/fneur.2020.00501
  3. Asseyer S, Cooper G, Paul F. Pain in NMOSD and MOGAD: A systematic literature review of pathophysiology, symptoms, and current treatment strategies. Front Neurol. 2020;11:778. doi:10.3389/fneur.2020.00778
  4. Asseyer S, Schmidt F, Chien C, et al. Pain in AQP4-IgG-positive and MOG-IgG-positive neuromyelitis optica spectrum disorders. Mult Scler J Exp Transl Clin. 2018;4(3):2055217318796684. doi:10.1177/2055217318796684
  5. Serizawa K, Tomizawa-Shinohara H, Miyake S, Yogo K, Matsumoto Y. Interleukin-6: evolving role in the management of neuropathic pain in neuroimmunological disorders. Inflamm Regen. 2021;41(1):34. doi:10.1186/s41232-021-00184-5
  6. Serizawa K, Tomizawa-Shinohara H, Magi M, Yogo K, Matsumoto Y. Anti-IL-6 receptor antibody improves pain symptoms in mice with experimental autoimmune encephalomyelitis. J Neuroimmunol. 2018;319:71-79. doi:10.1016/j.jneuroim.2018.03.017
  7. Serizawa K, Tomizawa-Shinohara H, Yasuno H, Yogo K, Matsumoto Y. Anti-IL-6 receptor antibody inhibits spontaneous pain at the pre-onset of experimental autoimmune encephalomyelitis in mice. Front Neurol. 2019;10:341. doi:10.3389/fneur.2019.00341