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

Abstract

IMPORTANCE Calcitonin gene-related peptide (CGRP) antagonists have demonstrated tremendous promise in migraine management. However, these medications decrease reflex vasodilatory response, which may lead to exacerbation of microvascular disease in susceptible patients, such as patients with Raynaud phenomenon (RP). OBJECTIVE To investigate the microvascular complications of CGRP antagonists in patients with underlying RP. DESIGN, SETTING, AND PARTICIPANTS This retrospective cohort study was performed from May 18, 2018, to September 15, 2020, in Mayo Clinic Health System patients with Raynaud phenomenon while undergoing CGRP antagonist therapy to treat migraine. Inclusion criteria were age older than 18 years, history of migraine, past or current treatment with CGRP antagonists, and diagnosis of primary or secondary RP. EXPOSURE Treatment with CGRP antagonists. MAIN OUTCOMES AND MEASURES The main outcome measure was microvascular complications (eg, worsening RP, digital ulcerations, and gangrenous necrosis) after initiation of treatment with a CGRP antagonist. Patient demographic and clinical characteristics were compared between those who experienced complications and those who did not. RESULTS A total of 169 patients (163 [96.4%] female; 151 [89.3%] non-Hispanic White; mean [SD]age, 46 [13] years) were identified. Of the 169 patients, 9 (5.3%) exhibited microvascular complications, ranging from worsening RP to gangrene and autonecrosis that required distal digit amputation. Comparative analysis did not find statistically significant differences in demographic or clinical characteristics between the 2 cohorts. All 9 patients with complications were female (mean [SD] age, 40 [12] years). Five of the 9 patients (55.6%) had previously diagnosed RP; in 3 the RP was primary, and 2 it was secondary to scleroderma. The other 4 patients (44.4%) were newly diagnosed with RP. Eight of the 9 patients (88.9%) had chronic migraine; 4 had migraine with aura, 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). CONCLUSIONS AND RELEVANCEThe results of this study indicate that microvascular complications of CGRP antagonist use in patients with underlying RP are uncommon. The incidence of serious adverse events, although rare, warrant caution when considering the use of these agents in patients with RP.

Calcitonin gene-related peptide-targeting drugs and Raynaud’s phenomenon: a real-world potential safety signal from the WHO pharmacovigilance database

“…In fact, in 2019, three cases of Raynaud’s phenomenon induced or exacerbated by CGRP monoclonal antibodies have been reported [ 24 ]. In addition, the safety of CGRP-targeting drugs among patients with Raynaud’s phenomenon has recently been assessed [ 25 ]. Microvascular complications occurred in 9 of 169 patients (5.3%), ranging from worsening Raynaud’s phenomenon to gangrene, requiring distal digit amputation.…”

The evolving understanding of risk with calcitonin gene‐related peptide monoclonal antibodies based on real‐world data: A focus on hypertension and Raynaud phenomenon

“…Diminished CGRP activity has been shown to contribute to RP pathophysiology and CGRP infusions have been used to treat RP 9 . Given this, we conducted a retrospective cohort study of 169 adults with RP, both primary and secondary, on CGRP modulators (mAbs and small‐molecule receptor antagonists), examining the incidence of microvascular complications as the outcome measure 10 . The median age for the total cohort was 47 years (interquartile range [IQR] 21), 96% (163/169) were female, and 89% (151/169) were non‐Hispanic White.…”

Raynaud’s Secondary to Granulomatosis With Polyangiitis

“…Calcitonin gene-related peptide (CGRP) is a vasodilator and studies [17] show that there may be deficiency of CGRP in the digits resulting in vasoconstriction and RP attacks. The infusion of CGRP improved the blood flow to digits and reduced the digital ulceration.…”