Inflammatory complications of CGRP monoclonal antibodies: a case series

Ray, Jason C; Allen, Penelope J; Bacsi, Ann; Bosco, Julian J.; Chen, Liming; Eller, Michael; Kua, Hock; Matharu, Manjit; Monif, Mastura; Ruttledge, Martin; Stark, Richard; Hutton, Elspeth

doi:10.1186/s10194-021-01330-7

Cited by 39 publications

(24 citation statements)

References 31 publications

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“…CGRP-targeting medication is effective in 50% of chronic and episodic migraine patients, but some recent studies have brought on concerns about potential immune effects. A series of 8 case studies from Australia and Ireland found potential immune complications from the CGRP antibodies erenumab or galcanezumab ( 142 ). Patients had complications such as a man who suffered from rheumatoid arthritis.…”

Section: Discussionmentioning

confidence: 99%

Dural Immune Cells, CGRP, and Migraine

Balcziak

Russo

2022

Front. Neurol.

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Migraine is the most common neurological disorder in the world, affecting 12% of the population. Migraine involves the central nervous system, trigeminal nerves and meninges. Recent advances have shown that targeting calcitonin gene-related peptide (CGRP) through either antibodies or small molecule receptor antagonists is effective at reducing episodic and chronic migraine episodes, but these therapeutics are not effective in all patients. This suggests that migraine does not have a singular molecular cause but is likely due to dysregulated physiology of multiple mechanisms. An often-overlooked part of migraine is the potential involvement of the immune system. Clinical studies have shown that migraine patients may have dysregulation in their immune system, with abnormal plasma cytokine levels either during the attack or at baseline. In addition, those who are immunocompromised appear to be at a higher risk of migraine-like disorders. A recent study showed that migraine caused changes to transcription of immune genes in the blood, even following treatment with sumatriptan. The dura mater is densely packed with macrophages, mast and dendritic cells, and they have been found to associate with meningeal blood vessels and trigeminal afferent endings. Recent work in mice shows activation and morphological changes of these cells in rodents following the migraine trigger cortical spreading depression. Importantly, each of these immune cell types can respond directly to CGRP. Since immune cells make up a large portion of the dura, have functional responses to CGRP, and interact with trigeminal afferents, CGRP actions on the dural immune system are likely to play key roles in migraine.

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Section: Discussionmentioning

confidence: 99%

Dural Immune Cells, CGRP, and Migraine

Balcziak

Russo

2022

Front. Neurol.

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“…The migraine animal model also induces an increase in circulating CGRP levels in plasma ( Cohen et al, 2021 ; Sun et al, 2021 ) and cerebrospinal fluid of the nestin/hRAMP1 transgenic mice ( Recober et al, 2009 ). Additionally, CGRP may trigger the release of pro-inflammatory cytokines ( Ray et al, 2021 ), particularly IL-6 and TNF-α, which are also increased in the plasm of migraine patients ( Yücel et al, 2016 ; Conti et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

“…CGRP may lead to the release of pro-inflammatory cytokines ( Ray et al, 2021 ), and the levels of interleukine-6 (IL-6) and tumor necrosis factor alpha (TNF-α) were increased in the plasm of migraine patients ( Ray et al, 2021 ). In fact, the application of IL-6 in the dura mater and cisterna magna causes both periorbital and hind paw cutaneous hypersensitivity ( Avona et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Unpredictable Sound Stress Model Causes Migraine-Like Behaviors in Mice With Sexual Dimorphism

et al. 2022

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Migraine represents one of the major causes of disability worldwide and is more prevalent in women; it is also related to anxiety symptoms. Stress, such as sound stress, is a frequently reported trigger in migraine patients, but the underlying mechanisms are not fully understood. However, it is known that patients with migraine have higher levels of plasma inflammatory cytokines and calcitonin gene-related peptide (CGRP). Stress mediated by unpredictable sound is already used as a model of painful sensitization, but migraine-like behaviors and sexual dimorphism have not yet been evaluated. This study characterized nociception and anxiety-related symptoms after the induction of sound stress in mice. C57BL/6 mice (20–30 g) were exposed to unpredictable sound stress for 3 days, nonconsecutive days. We observed enhanced plasma corticosterone levels on day 1 after stress induction. First, 7 days after the last stress session, mice developed hind paw and periorbital mechanical allodynia, grimacing pain behavior, anxiety-like symptoms, and reduced exploratory behavior. The nociceptive and behavioral alterations detected in this model were mostly shown in female stressed mice at day 7 post-stress. In addition, on day 7 post-stress nociception, these behaviors were consistently abolished by the CGRP receptor antagonist olcegepant (BIBN4096BS, 100 mg/kg by intraperitoneal route) in female and male stressed mice. We also demonstrated an increase in interleukine-6 (IL-6), tumor necrosis factor (TNF-α), and CGRP levels in stressed mice plasma, with female mice showing higher levels compared to male mice. This stress paradigm allows further preclinical investigation of mechanisms contributing to migraine-inducing pain.

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“…Nevertheless, one would postulate that anatomical separation between the hemispheres would occur, to give rise to the one-sidedness of migraine pain. CGRP even exerts anti-inflammatory properties in some tissue, questioning its role as a pro-inflammatory mediator and its safety as a systemic drug target, as blocking the anti-inflammatory properties could result in inflammation-related consequences elsewhere [ 150 ].…”

Section: Concluding On Cgrp and Inflammation—a Perspectivementioning

confidence: 99%

Could Experimental Inflammation Provide Better Understanding of Migraines?

Reducha

Edvinsson

Haanes

2022

Cells

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Migraines constitute a common neurological and headache disorder affecting around 15% of the world’s population. In addition to other mechanisms, neurogenic neuroinflammation has been proposed to play a part in migraine chronification, which includes peripheral and central sensitization. There is therefore considerable evidence suggesting that inflammation in the intracranial meninges could be a key element in addition to calcitonin gene-related peptide (CGRP), leading to sensitization of trigeminal meningeal nociceptors in migraines. There are several studies that have utilized this approach, with a strong focus on using inflammatory animal models. Data from these studies show that the inflammatory process involves sensitization of trigeminovascular afferent nerve terminals. Further, by applying a wide range of different pharmacological interventions, insight has been gained on the pathways involved. Importantly, we discuss how animal models should be used with care and that it is important to evaluate outcomes in the light of migraine pathology.

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Inflammatory complications of CGRP monoclonal antibodies: a case series

Cited by 39 publications

References 31 publications

Dural Immune Cells, CGRP, and Migraine

Dural Immune Cells, CGRP, and Migraine

Unpredictable Sound Stress Model Causes Migraine-Like Behaviors in Mice With Sexual Dimorphism

Could Experimental Inflammation Provide Better Understanding of Migraines?

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