Abstract
Background
Chilblains, characterized by swollen patches and blistering on peripheral extremities, commonly co-occur with Raynaud's Phenomenon. There is limited data to implicate CGRP-targeting migraine medications in these adverse events.
Methods
We describe one patient who developed chilblains during treatment with the CGRP monoclonal antibodies erenumab followed by galcanezumab and review the current literature on similar outcome reporting. We conducted a literature review in reports of Raynaud's Phenomenon in patients treated with medications of this drug class.
Results
A 38-year-old female patient developed chilblains while undergoing treatment with erenumab and then galcanezumab. The patient was transitioned to preventive treatment with rimegepant, which she has tolerated well without recurrence of chilblains. We also identified additional case reports, a cohort study, and an analysis of FAERS report data.
Conclusion
The case reports suggest chilblains can be associated with treatment with CGRP monoclonal antibodies but not during treatment with a CGRP oral antagonist. This adds to the current awareness of potential microvascular complications of migraine therapy, but future safety studies are needed.
Introduction
Chilblains, a condition of swollen patches and blistering on peripheral extremities, can be seen in patients with Raynaud's Phenomenon (RP) due to similar circulation pathology. 1 Chilblains occur when cold air causes blood vessels near the surface of the skin to constrict, which results in decreased oxygenation and inflammation in the exposed areas. RP, a more severe microvascular condition, occurs when these vessels constrict and undergo sympathetic vasospasm and inflammation, resulting in a characteristic evolving skin color change from pale to blue to red.
The calcitonin gene-related peptide (CGRP) pathway has been targeted in the treatment of both acute and chronic migraine. 2 CGRP is a potent vasodilator and may potentially be involved in peripheral and cerebrovascular circulation. 3 There is more to be learned about the unintended side effects of migraine therapies targeting CGRP. Interestingly, CGRP has previously been investigated as a treatment modality for RP.4,5 Patients experiencing RP have long demonstrated decreased peripheral levels of CGRP and marked improvement of symptoms with CGRP infusion therapy. There are limited reports of RP as a side effect of monoclonal antibodies to the CGRP ligand and receptor and no prior evidence to implicate CGRP targeting treatments in the development of chilblains. 6 We present a case report of a patient who developed chilblains after receiving treatment with two different CGRP monoclonal antibodies for prevention of migraine.
Case report
A 38-year-old non-smoking female with a history of asthma and hypertension presented to the clinic for evaluation and treatment of migraine in October 2020. She had suffered from migraine for more than 20 years, and for two years prior to her presentation, she had experienced daily headaches of at least moderate severity, with 2–3 severe headache episodes per month. The pain was described as bilateral infra-orbital and right retro-orbital, with occasional radiation to the apex. The more severe pain was localized to the right retro-orbital area but could change sides. The headache was characterized by a pressure-like, pounding quality, often triggered by missing sleep, stress, or eating. The patient also reported associated symptoms including sinus pressure, bilateral nasal congestion, nausea without vomiting, lethargy, phonophobia, and dizziness without vertigo. She did not experience any aura. Severe episodes were triggered by missing sleep, stress, and, sometimes, eating. Her blood pressure, pulse, general, and neurological examination were normal. Physical exertion and weather changes typically worsened the headaches. The patient had no family history of migraine. A general and neurological examination, including blood pressure and pulse, was unremarkable. At the time of presentation, her hypertension was managed with atenolol, which was switched to diltiazem in August 2021, due to exercise intolerance. She had also been acutely using sumatriptan (50 mg) for migraine attacks but switched to rizatriptan (10 mg) in December 2020. In February 2021, she started using ubrogepant (100 mg) acutely, alternating with rimegepant (75 mg) the following April depending on her use of Invisalign.
The patient was initially treated with the CGRP monoclonal antibody erenumab, 140 mg monthly, beginning in October 2020. The first symptom, itching, began that same month soon after starting this treatment, affecting her palms, stomach, and legs. Then, in December 2020, she developed chilblains bilaterally on the digits. Symptoms included swollen patches, itching affecting 3–7 digits at a time, and cold intolerance. The patient had no prior history of Raynaud's Phenomenon (RP), chilblains, or autoimmune disease, and no differential diagnosis was performed to investigate other potential causes.
In September 2021, 11 months after starting erenumab, the patient was switched to galcanezumab (240 mg loading dose, followed by 120 mg monthly). Despite the switch, she again developed chilblains in December 2021, 4 months after starting galcanezumab. Her symptoms were similar to those experienced the previous winter. These included itching, cold intolerance, and stress due to the visual appearance of the digits. She noted that the second winter was less severe on galcanezumab compared to erenumab. In both instances, the patient developed chilblains in the winter, 3–4 months after starting the new treatment and the symptoms improved in warmer months but returned in the winter. While erenumab and galcanezumab both decreased the frequency of her migraine episodes, the patient reported that adverse effects, notably chilblains, outweighed the therapeutic benefits. In September 2022, the patient was switched to rimegepant as a preventative treatment (75 mg every other day) and galcanezumab was discontinued after 12 doses. During December-January of 2022–2023, while on rimegepant, she reported the symptoms of chilblains lessened significantly. By February 2023, she reported no recurrence of chilblains. In May 2023, the patient noted that only weather changes trigger headaches and are resolved without acute medication. Since that time, the patient has continued with the prescribed treatment plan, exhibiting no alterations in the pattern of their episodes of migraine.
No additional work-up, such as blood tests, autoimmunity screening, or dermatological evaluation, was performed after the appearance of chilblains, and the diagnosis was based on clinical presentation alone. The patient's migraine episodes did increase in frequency the first month after stopping galcanezumab, but rimegepant effectively managed the symptoms.
Methodology
The literature review focused on identifying cases and studies related to Raynaud's Phenomenon and other microvascular adverse events in patients treated with CGRP-targeting medications, particularly erenumab, galcanezumab, fremanezumab, and rimegepant. The key search terms were: CGRP, chilblains, Raynaud's Phenomenon, erenumab, galcanezumab, and migraine. The search included published case reports and adverse event data from the FDA Adverse Event Reporting System (FAERS) and other pharmacovigilance databases.
Reports and studies were included if they documented adverse events that could be attributed to CGRP-targeting treatments, specifically those involving Raynaud's Phenomenon or chilblains. The review emphasized identifying patterns or mechanisms related to these adverse events in patients on these therapies.
Relevant data extracted from the identified reports included the type of adverse events, specific medications involved, and the number of subjects affected. The analysis focused on the frequency of these events and potential underlying mechanisms, such as CGRP inhibition's role in microvascular complications.
Literature review
Previous studies including case reports as well as the FDA Adverse Event Reporting System (FAERS) demonstrate similar circulation pathology associated with CGRP targeting drugs. RP has been suggested as a possible adverse event of treatment with CGRP targeting treatments (Table 1). One case report described the onset of RP after two treatments with erenumab. 7 In addition, an earlier case series demonstrated two cases where RP was exacerbated by fremanezumab and galcanezumab and reported one new onset of RP associated with erenumab. 6 Interestingly, in contrast to our findings, there are several case reports indicating that gepants can be associated with RP. One case report showed both rimegepant and ubrogepant used separately for different migraine attacks led to development of RP. 8 In another case report, atogepant, used as a preventive treatment for migraine, also induced RP.
Case reports and studies reporting microvascular adverse events.
Larger-scale studies have revealed similar adverse event data trends. One study investigated reports of RP from the World Health Organization's Pharmacovigilance Database. Among the 99 reports reviewed, erenumab emerged as the most frequently mentioned CGRP-targeting drug, with a median onset time for RP reported at 84 days. 9 Moreover, the authors of the study found there was disproportionate reporting of RP with CGRP-targeting drugs compared to triptans and β-blockers, which they attribute to the absent vasorelaxation and dilation of blood vessels in CGRP disruption. A retrospective cohort study from the Mayo Clinic Health System examined patients with RP while undergoing CGRP antagonist therapy for migraine treatment from 2018 to 2020. 10 Of the 169 patients reviewed, 5% experienced some form of microvascular complication. More than half had developed RP in the past, while the rest were newly diagnosed. The implicated drugs in this study were galcanezumab, erenumab, and fremanezumab. Gepants were not available at that time.
A similar case study was recently published in Cephalalgia Reports as well. 11 Gunasekera and Ray reported on a 50-year-old female patient who developed significant pain and swelling in her fingers after her second dose of galcanezumab. A rheumatologist confirmed the diagnosis of chilblains, which was related to the use of the injectable. While experiencing this adverse event, the patient did report a notable reduction in the frequency of her migraine episodes. This finding suggests that while CGRP mAbs are generally effective for migraine prevention, some individuals may experience rare but serious side effects, such as chilblains. These side effects can occur even if the individuals have no history of autoimmune or inflammatory diseases, as is the case with this presented patient. The study highlights the need for vigilance in monitoring patients for adverse reactions and indicates a need for careful patient selection when prescribing CGRP injectables.
The FAERS is a database for post marketing safety surveillance of approved drug and therapeutic biologic products. 12 A search of the CGRP targeting drugs, RP and chilblains yielded 20 documented events of RP associated with erenumab and seven events associated with galcanezumab. There are documented cases of erythema and blistering, but it is unclear whether this could be attributed to chilblains. Since chilblains are less severe than RP, patients on these medications may be less likely to report chilblains as a side effect, which may lead to an underestimated incidence rate on the FAERS.
A review of the literature indicates that patients with migraine treated with CGRP monoclonal antibodies may be at risk of developing chilblains as an adverse event. Additionally, an oral CGRP receptor antagonist appears to provide a more tolerable alternative for those susceptible to this side effect. Previous studies, including case reports and data from the FAERS, have identified similar symptoms linked to CGRP-targeting drugs, with reports of RP associated with treatments like erenumab, fremanezumab, and galcanezumab. Notably, gepants have also been associated with RP. This is crucial to note as the cases involving gepants are limited but instances RP have still emerged with this type of medication. Overall, the findings underscore the importance of ongoing monitoring and research to better understand the safety profiles of CGRP inhibitors across patient populations. Further investigation is needed to determine the mechanisms behind these associations and to identify which patient demographics may be at higher risk for developing Raynaud's phenomenon while on CGRP antagonist therapy.
Discussion
Our case report suggests that patients with migraine receiving treatment with CGRP monoclonal antibodies can potentially be at risk of developing chilblains as an adverse event. We also found that an oral CGRP receptor antagonist offered a more tolerable alternative for this patient susceptible to the side effect.
Despite having no family history of RP or chilblains, it is possible that the patient had a predisposition to chilblains, which was exacerbated by the use of CGRP monoclonal antibodies. We cannot exclude that a milder winter while the patient was on rimegepant could have differentially influenced the occurrence of chilblains. The risk of chilblains and RP with CGRP monoclonal antibody treatment may be related to the pathway target point or the longer half-life of antibody therapies. While some monoclonal antibodies, like fremanezumab and galcanezumab, bind directly to CGRP and neutralize it, others, such as erenumab, block the CGRP receptor instead. On the other hand, CGRP receptor antagonists (gepants) prevent CGRP from binding to its receptor, and they typically have half-lives of several hours. In contrast, subcutaneous monoclonal antibodies have half-lives of approximately one month. The mechanism of action and long-acting nature of subcutaneous CGRP monoclonal antibody treatment may result in more significant and continuous disruption of vasodilation, contributing to the risk of developing chilblains.
Review of the literature highlights a concerning association between CGRP-targeting treatments and the development of RP and chilblains, with multiple case reports and studies indicating a higher incidence of these adverse events among patients receiving such therapies. While CGRP monoclonal antibodies like erenumab, fremanezumab, and galcanezumab have been frequently implicated, patients using gepants have also presented RF. Our case is just one that illustrates the importance of ongoing monitoring and further research. These are essential to elucidate the underlying mechanisms of these associations and to identify at-risk patient populations.
As CGRP targeting drugs become more popular and accessible treatment options, more large-scale studies will be needed to further understand the exact mechanisms of how these medications exacerbate and induce peripheral circulation disorders. Future studies will need to carefully document skin findings in order to differentiate chilblains from RP and allow for complete and accurate FAERS reporting.
Clinical implications
The case reports suggest chilblains can be associated with treatment with CGRP monoclonal antibodies but not during treatment with a CGRP oral antagonist. This adds to the current awareness of potential microvascular complications of migraine therapy, but future safety studies are needed.
Footnotes
Declaration of conflicting interests
The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: B.T. received honoraria for consulting or speaker's bureau from AbbVie, Amgen, Impel, Ipsen, Lilly, Lundbeck, Neurolief, Pfizer, Teva, and Theranica. S.A. received honoraria for consulting or teaching from Allergan/AbbVie, Eli Lilly, Impel NeuroPharma, Linpharma, Lundbeck, Pfizer, Satsuma, Teva, and Theranica.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
