Abstract
Background
Alopecia is associated with erenumab post-marketing, but no cases have been described.
Methods
We describe two patients that reported temporary hair loss and review the FDA Adverse Event Reporting System (FAERS).
Results
The first patient experienced alopecia within three months of starting erenumab, which did not improve with ongoing use or transition to fremanezumab. The second patient reported alopecia within two weeks of starting erenumab, which continued after transition to galcanezumab; months later, there was also recurrent hair loss within one month of starting fremanzeumab. According to FAERS (last accessed 18 August 2022), alopecia was reported most with erenumab (1158), followed by galcanezumab (554), fremanezumab (175), eptinezumab (23), rimegepant (26), ubrogepant (4), and atogepant (3).
Conclusion
Most events were reported in women and non-serious. The potential mechanism of alopecia with drugs targeting calcitonin gene-related peptide or its receptor possibly includes disruptions in the microvascular circulation and other homeostatic mechanisms.
Introduction
Calcitonin gene-related peptide (CGRP) is the most potent vasodilator in the human body and plays a crucial role in trigeminovascular signaling (1). CGRP-inhibiting medications are the first migraine-specific preventive treatments with adverse event profiles similar to placebo. Alopecia was recently added as a post-marketing adverse event for erenumab on 11 May 2021 (2), a CGRP receptor antibody with Class I evidence for migraine prevention (3–5). In 2021, a disproportionality signal for alopecia, which are used to find possible causal relationships between drugs and adverse events, was detected (6). Alopecia was not evident in randomized controlled trials (RCTs), and no clinical descriptions have been published. We describe two patients who reported alopecia after CGRP monoclonal antibodies (MABs). We systematically evaluated the FDA Adverse Event Reporting System (FAERS) database for reports of alopecia with other CGRP MABs and review the literature for potential mechanisms of this effect (7).
We used descriptive statistics, including mean and standard deviation (SD), using Microsoft Excel 2021, and IBM SPSS Statistics 29 for quantification of certain classes of concomitant medications. Migraine diaries were used to confirm migraine frequencies.
Case 1
This 69-year-old woman, with migraine since age 15, had periods of high frequency episodic and chronic migraine. She reported bifrontal throbbing pain with associated photophobia, osmophobia, movement sensitivity, nausea, lightheadedness, and rhinorrhea. There were no aura symptoms. Premonitory symptoms included fatigue, irritability, neck pain, food cravings, and increased bowel movements. Triggers included skipping meals and previously menses. There was co-morbid anxiety and gastritis, which were well-controlled. Her grandmother, mother, and daughter had migraine. She has tried multiple prior preventive treatments. She discontinued topiramate, gabapentin, valproic acid, and venlafaxine due to hair loss, despite efficacy in migraine prevention. Escitalopram was used for anxiety. She also took esomeprazole, cyanocobalamin, vitamin D, coenzyme Q10, and magnesium. She had been on propranolol as a preventive treatment for migraine for nine years. Within three months, sumatriptan 100 mg was reduced to three times per month.
The patient began using erenumab 70 mg subcutaneously every month and noticed an improvement in monthly migraine days from six to an average of three migraine days for the first six months, followed by an increase to five monthly migraine days, but mild intensity until discontinuation. The onset of hair loss began within three months of initiation and persisted throughout treatment. Prior to erenumab, her Migraine Disability Assessment Test (MIDAS) score was 63 (Grade IV) and decreased to 18 (Grade III) after seven months. One month after stopping erenumab, she started fremanezumab 225 mg subcutaneously every month for three months: migraine frequency was five days per month, within the first month of use (MIDAS: 19 (Grade III). At six-months follow-up, she reported continual hair loss for five months, with minimal improvement at the sixth month (Figure 1A).
Timeline of Alopecia Reports After Exposure to Monoclonal Antibodies to the CGRP receptor and ligand: Case 1 is a 69-year-old woman with high frequency episodic and prior chronic migraine reporting alopecia after use of erenumab. Case 2 is a 33-year-old woman with chronic migraine reporting alopecia with erenumab followed by a recurrent bout after fremanezumab. The 2 photographs (front and back) show evidence of excessive hair thinning, consistent with telogen effluvium or early alopecia areata. However, the diffuse nature of the hair loss is more consistent with telogen effluvium.
She described trichodynia, hair thinning, and excessive loss while combing and washing. Dermatology notes mention “hair loss is diffuse, moderate in severity, gradual in onset” and she was diagnosed with alopecia in multiple scalp areas.
Her neurologic examination and brain imaging were normal. See Figure 1A for photograph showing excessive and diffuse hair thinning. Hemoglobin/hematocrit, ferritin, iron studies, vitamin B12, thyroid panel, vitamin D and comprehensive metabolic panel were all normal.
The patient described her perspective on her hair loss due to migraine treatment. “Every time I found a medication which was helpful for migraine, I experienced hair loss. When the medication works, this is the side effect that I have had. My migraines previously were horrible. I have an active life, so there were so many things I could do (walking at the beach in the heat, going on plane). Given this, I would definitely not mind having less hair, but I am concerned about not having any hair. What is worse: not having hair or not to have migraine? Definitely not, to have migraine.”
For therapeutic interventions, her dermatologist performed nine intralesional triamcinolone injections and prescribed clobetasol 0.05% scalp solution. For follow-up and outcomes, see Figure 1A. Hair loss persisted three months after complete discontinuation, but “maybe a little less”.
Case 2
This 33-year-old woman, with a history of migraine since age three, had chronic migraine for five years. Attacks are described as throbbing, pressure, and dull pain, located on both sides frontally. There was associated nausea and vomiting, photophobia, phonophobia, osmophobia, lightheadedness, and difficulty concentrating. There were no aura symptoms. Triggers include stress, skipping meals, weather changes, lack of sleep, dehydration, and menses. There was comorbid anxiety, depression, and a remote history of asthma and a kidney stone. Both grandmothers had migraine.
She has tried multiple preventive treatments over the prior years. Propranolol, candesartan, gabapentin and nortriptyline were discontinued due to bothersome side effects. OnabotulinumtoxinA was not effective. She currently was using venlafaxine for mood and migraine.
The patient began erenumab 70 mg subcutaneous every month: within three months of initiation, she improved from 14 to eight monthly migraine days. She noticed hair loss two weeks after the first dose of erenumab. Erenumab was stopped due to insurance, and she took galcanezumab 240 mg loading dose the next month. She stopped after this dose because of continued hair loss, which resolved in six weeks, and subsequently had an increase in monthly migraine frequency to 14 days. After eight months, she used one dose of fremanezumab 225 mg but noticed hair loss three weeks later. Her monthly migraine frequency on fremanezumb 225 mg was 13 days per month. She discontinued the medication and noticed the hair loss improved after six weeks. (Figure 1B). Her neurologic examination and brain imaging were normal.
The patient provided excerpts from her migraine diary. From December 2019, during erenumab use: “Hair started falling out. Not in chunks, but very large handfuls similar to after having a baby. Noticed largely increased irritability and depressive mood swings.” From January 2019 during galcanezumab use: “Hair is still falling out. Hard to say if it is still from (erenumab) or (galcanezumab). Will not do second dose because of side effects and only moderate improvement in migraine.”
Although this case does not have a photograph or dermatological evaluation, the diary description of hair falling out in “large handfuls” is consistent with telogen effluvium. When this process ends, it does so quite observably, as shedding is no longer noted as excessive accumulation in combs, floors, and showers.
Hair loss resolved with discontinuation of CGRP MABs. For follow-up and outcomes, see Figure 1B. Hair loss resolved after discontinuation of erenumab and galcanezumab. There was a three-month trial of rimegepant 75 mg every other day, which was not effective for migraine (28 monthly migraine days) but not associated with hair loss. Her MIDAS score was 62 (Grade IV). A trial of atogepant has been effective for migraine (reduced migraine days to 8 mild days per month after 4 months) and was not associated with hair loss. Her MIDAS score improved to 52 (Grade IV).
Discussion
Taken together, our cases and review of the literature support the potential role of CGRP in both promoting hair growth and preventing hair loss (8). The patients appear to have a susceptibility to recurrent bouts. At least for case one, her dermatologic description is most consistent with telogen effluvium, an excessive shedding of resting or telogen hair after a trigger. We attribute hair loss to the CGRP monoclonal antibodies but cannot rule out other causes. Little is known about the time course of alopecia onset or hair growth after discontinuation. Although variable, drug-induced telogen effluvium typically occurs within two-three months of drug use as in our cases (9). The prognoses were generally positive for the cases described. Duration of telogen effluvium does not depend on hair growth but instead on the hair cycle (telogen duration) which is usually three months but may also vary (9). The strength of the cases are their novelty and detailed timelines.
In an integrated safety analysis of the 12-week RTCs, the incidence of alopecia was 0.4% in the placebo group and 0.2% in the 70 mg dose, and 0.4% in the 140 mg dose; similar incidences were noted in the five-year open label studies with reports in 0.3% with erenumab 70 mg and 0.4% in erenumab 140 mg (Personal communications to TM from Amgen). According to FAERS, the events are common in females and are most commonly considered not serious (7). Although females are more predisposed to telogen effluvium, sex as a risk factor is unknown, given the higher prevalence of migraine in women and therefore the greater likelihood of using CGRP inhibitors. In addition, the numbers are too small to infer from clinical trial data. FAERS reporting was greatest for erenumab, but reports occurred across CGRP monoclonal antibodies. There were low rates among gepants: with reports for rimegepant (n = 26), ubrogepant (n = 4) and atogepant (n = 3). It is not clear if this will emerge as a class effect for CGRP MABs (Table 1). In a pharmacovigilance study, alopecia signals were consistently associated with CGRP inhibitors, although not in comparison to standard preventives, such as anticonvulsants (i.e. topiramate, divalproex sodium, valproate sodium, etc.) onabotulinumtoxinA, or beta-blockers (10).
Report of alopecia with CGRP inhibitors according to FAERS and clinical trials/pharmaceutical communications.
Legend: *Unspecified sex was not included in the analysis. For accuracy, estimates for levels of severity included reports of alopecia alone. According to FAERS, reports for gepants were less than 5 for ubrogepant and atogepant, and 26 for rimegepant. According to communications, there have been no signals to suggest alopecia as an adverse event. Among cases, alopecia areata were noted in only 4 reports in FAERS.
The use of the FAERS database for pharmacovigilance has limitations. It is compiled of voluntary reports from healthcare professionals and patients, which are often incomplete. Prevalence and causal relationships cannot be concluded given the voluntary nature of the reporting system, potential for underreporting or bias, and lack of controls. Temporal association is important diagnostically, given the prevalence of hair loss is not uncommon. Reports were much less common in the UK. The Yellow Card database has only four alopecia reports with erenumab, five reports with galcanezumab, and 16 reports with fremanezumab (11).
However, there are several studies that support the potential mechanistic link between CGRP receptor antagonism and hair loss but limited to alopecia areata (12). In one study of scalp biopsies of patients with alopecia areata, there was a reduction of cutaneous levels of CGRP and substance P but not of vasoactive intestinal polypeptide (13). CGRP has also been linked to the hair growth pathway via its effect of increasing IGF-1 (insulin-growth factor 1) levels (8). IGF-1 is an important component of the hair growth pathway as it regulates cellular proliferation and migration during hair follicle development. CGRP may also protect the immune privilege of hair follicles, which are susceptible to an increased immune response during the anagen phase, from interferon-γ-(IFN-γ)-induced collapse. The study showed that CGRP can significantly reduce the overexpression of MHC class 1 and MHC class 2 and the degranulation of perifollicular mast cells (10). Of unclear significance, one study of human scalp hair follicles showed that CGRP stimulates progression into the catagen phase (14). However, there were no translatable or reproducible changes in hair shaft reproduction in this study. We hypothesize that CGRP MABs may be associated with telogen effluvium through neurovascular mechanisms. The skin is heavily innervated by neuropeptidergic sensory nerves that assist in the regulation of the microvascular circulation (13).
In general, the management of adverse events in otherwise responders of preventive migraine medication can be challenging, in the setting of many previous preventive treatment failures. For patients that experience alopecia while on erenumab and good efficacy for migraine prevention, there are several considerations, such as other medications, vitamin deficiencies, and medical conditions such as acute stress states and hormonal factors. Neuromodulation for migraine prevention is an option depending on availability. Co-management with dermatology for specialized therapies or close monitoring with use of gepants are considerations. Expanded pharmacovigilance studies are needed in this area with additional databases internationally.
Article highlights
Erenumab, alongside other CGRP monoclonal antibodies, has been associated with disproportionality signals of alopecia in the FDA Adverse Events Reporting System. Most of the events were reported in women and were considered non-serious. Two patients reported hair loss within three months of erenumab usage for migraine prevention. One patient reported recurrent hair loss after switching to fremanezumab. Hair loss is thought to be due to telogen effluvium, rare, and typically reversible. Other systemic, nutritional, psychological factors and concurrent drug use associated with hair loss should be carefully considered.
Footnotes
Acknowledgements
We kindly thank our patients for sharing excerpts from their migraine diaries, perspectives on treatment trials, and insights into their journeys living with migraine.
Declaration of conflicting interests
The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: MR and AC do not report any significant disclosures or conflicts of interest. PJG reports, over the last 36 months, grants and personal fees from Eli-Lilly and Company, grant from Celgene, and personal fees from Aeon Biopharma, Allergan/Abbvie, Biohaven Pharmaceuticals Inc., CoolTech LLC, Dr Reddys, Epalex, Impel Neuropharma, Lundbeck, Novartis, Praxis, Sanofi, Satsuma and Teva Pharmaceuticals, Linpharma and personal fees for advice through Gerson Lehrman Group, Guidepoint, SAI Med Partners, Vector Metric, and fees for educational materials from CME Outfitters, Omnia Education, WebMD, and publishing royalties or fees from Massachusetts Medical Society, Oxford University Press, UptoDate and Wolters Kluwer, and for medicolegal advice in headache. TSM has received personal compensation for serving on advisory boards for Biohaven, Allegan/Abbvie, Lundbeck, Amgen, Teva, Linpharma and Impel Neuropharmaceuticals. She has also served as a site principal investigator without direct compensation for Teva, Eli Lilly, Electrocore, Amgen, Novartis. AT has served as a consultant or advisor for DS laboratories, Monat Global, Almirall, Thirty Madison, Ely Lilly, Capellux LLC, Pfizer, and Myovant.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
Informed consent
Informed consent was obtained from patients, including the use of photography. The Internal Review Board at the University of Miami was notified and waived the request for submission.
