CGRP Monoclonal Antibodies and Inhibitors: Can they trigger alopecia areata?

What is the Risk of Alopecia Areata Flare with CGRP Blocking Drugs? Do we know?

I’ve selected this question below for this week’s question of the week. It allows us to review some concepts related to the relationship between alopecia areata, CGRP signalling and drugs that block this pathway.

QUESTION

I have been diagnosed with diffuse alopecia areata. I am currently treated with 2 mg bacicitinib (Olumiant), 1.25 mg oral minoxidil and a topical steroid. My shedding is under control and I’ve regrown much of my hair. I also suffer from migraines and my neurologist prescribed Atogepant (Qulipta). I haven’t started it yet because I’m worried about hair loss associated with these drugs. Is someone with alopecia areata more likely to have hair loss while taking a CGRP medication?

Thank you.

ANSWER

Thanks for the great great question.

Theoretically speaking, one would think that patients with alopecia areata would be more likely than patients in the general population to have hair loss from these drugs. The reality, however, is we really haven’t seen that signal or evidence of this thus far. I haven’t really seen it commonly in my patients either. In other words, in the 5 years since the CGRP monoclonal antibodies came to market and in the 2-3 years since the CGRP receptor antagonists came to market, we really haven’t seen good evidence that there is an increase in cases of alopecia areata.

For most of my patients with alopecia with migraines, I advise follow the advice of their general physicians, internists or neurologists regarding management of the headaches and not let alopecia areata factor too much into the decision. We really are not seeing good evidence that these drugs worsen alopecia areata. It’s true that more studies are needed and it’s true that these drugs haven’t been out all that long. However, it’s also true that if there was a very strong connection between these drugs and alopecia areata - we probably would have seen something by now. Is there a weak connection? That’s not known but it does not seem so.

Let’s back up and talk about a) CGRP blocking medications and the risk of hair loss then b) then talk about alopecia areata and CGRP signalling and then talk about c) the relationship between alopecia areata and migraines and then d) make some sort of a summary about what we know in 2023 about using these drugs in patients with alopecia areata.

1) Hair Loss from CGRP Monoclonal antibodies and CGRP Receptor Antogonists

Calcitonin gene-related peptide-targeted drugs have proven safe and effective for migraine prevention in large randomized-controlled, double-blind trials with an average duration of six months.

There are two types of CGRP inhibitors – monoclonal antibodies and CGRP receptor antagonists (gepants).

The monoclonal antibodies include: Aimovig (erenumab), Ajovy (fremanezumab), Emgality (galcanezumab), Vyepti (eptinezumab). The “gepants” (like you refer to) include: Ubrelvy (ubrogepant), Nurtec ODT (rimegepant sulfate), Qulipta (atogepant) and Zavegepant (Zavzpret).

Hair loss can certainly occur with these drugs. The hair loss seems to be in the form of a telogen effluvium. The study by Evers and Wald estimated the risk of hair loss at around 2 %. It’s not clear if the various monoclonal antibodies have similar risk or not. Most reports have been with erenumab (1158), followed by galcanezumab (554), fremanezumab (175), eptinezumab (23), rimegepant (26), ubrogepant (4), and atogepant (3). A key message here is that the gepants have fewer eports of hair loss to date. They are also the newest drugs so there has not been the same amount of time to accumulate information.

In 2022, a study by Dr Woods suggested these CRGP monoclonal antibody drugs come with a 12 times higher risk of hair loss compared to the triptans. Woods suggested that the order of risk may be: fremanezumab (PRR 5.42; 95% CI 4.66-6.29), erenumab (PRR 4.29; 95% CI 4.05-4.54), galcanezumab (PRR 4.11; 95% CI 3.78-4.48), and eptinezumab (PRR 2.06; 95% CI 1.25-3.40) so it could be that some drugs in the class have a higher risk of hair loss than others. For example, this data suggests that fremanezumab would be more likely to cause hair loss than eptinezumab.

Overall, mores studies are needed to understand the precise risk of hair loss.

Most hair loss from patients using these drugs is felt to be a telogen effluvium. Other forms of hair loss are much less common. Alopecia areata has been reported with use of these drugs… but it’s not clear if this is a true risk or just a coincidence. After all, alopecia areata can occur in the population anyways so a certain proportion of patients are likely to develop alopecia areata in any study. For example, in the phase 3 studies of galcanezumab, alopecia areata occurred in 0.01 % to 0.1% of study patients. This is really not too different from the expected rate of alopecia areata in any population so it’s not enough yet to say these drugs are implicated in the development of alopecia areata.

b) Alopecia areata and CGRP signaling

From a molecular and genetic point of view, it’s not completely unreasonable to postulate that blocking CRGP signaling with drugs like CGRP monoclonal antibodies and CGRP receptor antagonists can favour the development of alopecia areata. In 1997, Rossi et al showed that in biopsies of patients with alopecia areata there was a reduction of skin levels of CGRP (and substance P). In 2003, Meyronet D et al showed similar findings namely that CGRP levels are lower in alopecia areata. In 2012, work by Dr Paus and colleagues (Kindori et al 2012) suggested that having high CGRP may help protect the “immune privilege” of hair follicles and prevent collapse of immune privilege in response to interferon-γ-(IFN-γ).

Despite the limited studies that suggest a reduction in CGRP signals in hair follicle might be a ‘bad’ thing - the reality is that in the world of clinical medicine —- we aren’t really seeing this phenomenon.

c) The Relationship between Alopecia Areata and Migraines

A 2021 study really changed how I think about the relationship between alopecia areata and migraines. I discussed the study in the past but will cover it again here. The study was a population based cohort study from Taiwan and showed that patients with alopecia areata were more likely to develop migraine headaches. Surprisingly, the data from the study also suggest that patients who experience migraine headaches are more likely to develop alopecia areata. This data suggested a ‘bidirectional’ relationship between migraine and alopecia areata. Patients with alopecia areata are at increased risk to develop migraines and patients with migraines are at increased risk to develop alopecia areata. A link to the 2021 article is found below.

There is certainly more and more evidence accumulating that suggests that there is some sort of immune dysfunction taking place in the pathways leading to migraine headaches.

This data opens the door to the possibility that properly and fully treating migraine headaches in patients with alopecia could be a good thing. Now, we don’t yet have good data to support this. But there is at least a possibility that the pathways that favour the development of migraine headaches are not so good for alopecia areata.

d) Summary about what we know in 2023 about using CGRP Blocking Drugs in patients with Alopecia Areata.

We need to be very clear about what we know and what we don’t know in 2023. It seems that these CGRP blocking drugs slightly increase the risk of hair loss. But this hair loss is mainly in the form of a temporary telogen effluvium. 2-3 % of patients might get this side effect - but 97-98% of patients will not get any sort of hair loss with use of these drugs. It’s not clear if CGRP monoclonal antibodies come with a greater risk of hair loss than the gepants - but it sure seems this way so far. We need to keep in mind we have way more data with the monoclonal antibodies than the gepants. More studies are needed as we get more experience with using gepants in the real world.

Let’s face the facts - we don’t have any good data that suggests either the monoclonal antibodies or the gepants increase the risk of developing alopecia areata. We certainly have zero data to suggest that using these drugs in someone with alopecia areata worsen outcomes in patients with alopecia areata. We have zero data to suggest that using a gepants would potentially worsen outcomes of patients with AA who are already doing quite well on baricitinib and oral minoxidil.

All this data is relatively new and I’ll be following its evolution. 5 years ago, I would have thought there was enough information to make me worried about these migraine drugs for my patients with alopecia areata. The reality is that as more and more data pours in over the past few years, I have no reason to continue to feel worried. There is really nothing that rises up as any kind of signal to suggest that gepants would increase the risk of a flare in a patient with alopecia areata who is regrowing on baricinitib.

We don’t have all the data yet and clearly this field is in its infancy. I would encourage you to review all these studies with your doctors. I’ll place the studies in the references. Together with your doctors, you can decide if you feel comfortable with the data we have so far in 2023. I have followed several patients of my own with alopecia areata on these drugs without evidence of disease worsening. We need more data over time but it’s looking encouraging so far.

REFERENCE

Kinori M, Bertolini M, Funk W, et al. Calcitonin gene-related peptide (CGRP) may award relative protection from interferon-γ-induced collapse of human hair follicle immune privilege. Exp Dermatol 2012; 21: 223–226
Evers S and Wald S. Effluvium and alopecia associated with monoclonal calcitonin gene-related peptide antibody use. Headache. 2023 Jan;63(1):165-167.

Meyronet D et al. Decreased CGRP staining in alopecia areata. Br J Dermatol. 2003 Aug;149(2):422-4.

Rossi R, Del Bianco E, Isolani D, et al. Possible involvement of neuropeptidergic sensory nerves in alopecia areata. Neuroreport 1997; 8: 1135–1138.

Ruiz M et al. Alopecia as an emerging adverse event to CGRP monoclonal antibodies: Cases Series, evaluation of FAERS, and literature review. Cephalalgia. 2023 Feb;43(2):3331024221143538.

Woods RH. Alopecia signals associated with calcitonin gene-related peptide inhibitors in the treatment or prophylaxis of migraine: A pharmacovigilance study. Pharmacotherapy. 2022 Oct;42(10):758-767.