Evaluation of the Safety of Calcitonin Gene-Related Peptide Antagonists for Migraine Treatment Among Adults With Raynaud Phenomenon

Key Points Question In patients with Raynaud phenomenon, what is the microvascular complication risk of calcitonin gene-related peptide (CGRP) antagonist use? Findings In this cohort study of 169 adults with Raynaud phenomenon, 9 patients had microvascular complications after CGRP antagonist use. Two of the 9 patients had severe adverse events, including digital autonecrosis that required distal amputation. Meaning This study suggests that microvascular complications are uncommon in patients with Raynaud phenomenon who are taking CGRP antagonists; however, the incidence of adverse microvascular events with high morbidity warrants caution in prescribing CGRP antagonists in these patients.


Introduction
A new class of medications known as calcitonin gene-related peptide (CGRP) inhibitors has been recently approved for the treatment of episodic and chronic migraine. There are 2 types of available CGRP inhibitors: (1) monoclonal antibodies that bind the CGRP receptor or ligand and (2) smallmolecule CGRP receptor antagonists. These medications suppress activity of CGRP, a neuropeptide located in the peripheral and central nervous system that is involved in pain modulation, particularly in the trigeminovascular system.
In addition to its role in the nervous system, CGRP confers potent vasodilatory effects, which may clinically manifest as flushing. 1 Deficiency of CGRP may play a crucial role in the pathophysiology of scleroderma and Raynaud phenomenon (RP). In scleroderma, there are fewer CGRP-supplying nerves, and in RP, there may be CGRP deficiency in the distal or acral skin. 2,3 Cutaneous blood flow increases in these patients after CGRP infusion. 3,4 A previous study 5 examined the effects of systemic therapy with calcitonin in patients with scleroderma, finding a reduction of digital ulceration and improvement in pulmonary function after infusion. In another study, the use of CGRP antagonists was associated with digital ulceration in 2 patients with underlying RP. 6 Microvascular complications of migraine therapies predate the advent of CGRP modulators, as evidenced by worsening RP documented in the use of vasoactive medications, such as ergot alkaloids, triptans, and β-blockers. With the emergence of CGRP antagonists as a mainstay in prophylactic and rescue migraine therapy, it is crucial to identify patients at risk for complications to develop appropriate and safe prescribing guidelines. In this study, we identified patients with primary or secondary RP while taking CGRP antagonists for migraine therapy and assessed for cutaneous microvascular complications.  Table 2, along with other pertinent demographic and clinical characteristics. The complications ranged from worsening RP (characterized by more frequent episodes of pain and discoloration elicited by cold temperature exposure) to worsening facial telangiectasias (Figure 1) to digital gangrene and autonecrosis that required distal digit amputation (Figure 2). Five of the 9 patients (55.6%) had previously diagnosed RP; in 3 patients, RP was primary, and in 2 it was secondary to scleroderma. The other 4 patients (44.4%) were newly diagnosed with RP after administration of CGRP antagonists. These patients did not undergo any immunologic testing or evaluation with a rheumatologist for RP. Eight of 9 patients (88.9%) had chronic migraine; 4 had migraine with aura (mostly visual), and 5 had migraine without aura. The CGRP antagonist agents temporally associated with the microvascular complications included galcanezumab (in 3 patients), erenumab (in 5 patients), and fremanezumab (in 1 patient).
Several important confounders were identified, including coincident administration of potential exacerbating medication (β-blockers 7 ), hematoma overlying the digit associated with RPs, and symptomatic worsening during wintertime. The mean time from CGRP antagonist induction to microvascular complication noted in the patients' medical records was 163 days (range, 26-365 days).

Discussion
In this cohort study, 5.3% of patients with migraine with underlying or undiagnosed RP who were prescribed CGRP modulators experienced microvascular complications. Comparative analysis of the 2 cohorts of patients (those with complications and those without) did not yield statistically significant differences in demographic characteristics, migraine characteristics, rheumatologic history, RP risk factor history, or CGRP antagonist use ( Table 1).
The natural history of primary RP is poorly characterized in the literature, precluding comparison of this study's complication rate to the historical rates of RP progression to ulceration or infarction. There is no evidence of digital ischemic injury in primary RP. 8,9 One study 10 followed up 78 patients with primary RP for 14 years, noting no associated morbidity or progression to scleroderma or other secondary rheumatologic conditions, and concluding that primary RP most commonly remains a benign condition. However, secondary RP frequently leads to vasculopathic damage, including ulceration and infarction. 11 Approximately 50% of patients with systemic sclerosis will experience digital ulceration at some point in the disease course. 12 In the patient cohorts in this study, the duration of RP before CGRP antagonist exposure was not correlated with progression to complications because approximately half of the patients with complications (4 of 9 patients) were  In addition, the co-occurrence of migraine and RP is well established. 14-16 One case-control study 14 in patients with migraines found that 25% had RP. Another study 17 reported that 32% of patients with scleroderma had comorbid migraine. Among 9 individuals with RP taking CGRP antagonists who exhibited microvascular complications, 4 (44%) had migraine with aura, which is nearly double the known prevalence of aura in patients with migraine (25%). 18 Migraine with aura is an established risk factor for cerebrovascular and cardiovascular ischemia, particularly in women. 19 Further studies are needed to evaluate the microvascular complication in individuals with migraine with aura who are taking CGRP antagonists.

JAMA Network Open | Pharmacy and Clinical Pharmacology
In the current study, 2 patients (1.2%) with RP who were taking CGRP antagonists experienced devastating sequelae. The first patient with serious complications had a history of secondary RP attributable to scleroderma and experienced sudden profusion of facial telangiectasias and accelerated, radiographically demonstrated, digital acro-osteolysis with subcutaneous digital calcinosis ( Figure 1). This finding highlights that vasoactive effects of CGRP antagonists may present in diverse ways in the context of scleroderma, which has additional vascular features beyond RP, including telangiectasias. The second patient with severe complications had no preexisting history of RP and experienced digital autonecrosis that required amputation ( Figure 2). Digital ulcerations or  it cannot be excluded that the lack of statistically significant differences among demographic or clinical characteristics between the 2 cohorts is attributable to limitations arising from the small sample size. In addition, from our experience, patients with severe or medication-refractory migraine were more likely to be prescribed the novel CGRP antagonists, which may limit generalizability of the findings. In addition, RP is a commonly overdiagnosed condition, often deliberately so, to ensure timely identification of patients with early-stage rheumatologic disease. 21 Potential erroneous inclusion of patients without RP in this analysis could underestimate the microvascular complication rate in patients with true RP who are taking CGRP antagonists. Finally, although temporal associations are drawn between CGRP exposure and RP exacerbations, the observational nature of the study cannot be used to determine causality.

Conclusions
The results of this study indicate that microvascular complications of CGRP antagonist use in patients with underlying RP are uncommon. No statistically significant differences were found in demographic or clinical characteristics between the 2 patient cohorts (patients taking CGRP antagonists with complications vs those without complications). Specifically, no statistically significant differences were found in risk factors for RP, migraine history, or specific CGRP antagonist medication. Nonetheless, the rare incidence of serious adverse events, including infarction that requires amputation, warrants caution when considering the use of these agents in patients with RP.
Future directions include conduction of a retrospective cohort study that examines the microvascular complication rates in patients with and without RP who are taking CGRP antagonists.
A hazard ratio extracted from this data would inform the risk profile of CGRP antagonists in this subpopulation.