Raynaud's Phenomenon Associated With Calcitonin Gene-Related Peptide Monoclonal Antibody Antagonists

Two cases are reported of migraineurs who reported Raynaud's phenomenon (RP) exacerbated while taking monoclonal antibodies to the calcitonin gene-related peptide (CGRP) ligand (fremanezumab and galcanezumab) and 1 case of new onset RP while taking the CGRP receptor antagonist (erenumab). The prevalence of primary and secondary RP, causes of secondary RP, co-morbidity with migraine, and medications which might induce or exacerbate RP are reviewed. The pathophysiology of how CGRP monoclonal antagonists might exacerbate or induce RP is discussed. The cases suggest but do not prove causation.     

影像技术在雷诺现象中的应用进展

雷诺现象是由于血管神经功能紊乱导致血管痉挛收缩、微循环障碍引起供血不足的一系列临床表现,是多种疾病的伴发症状,与疾病的进展及并发症有密切关系,是影响疾病预后及疗效的重要因素。随着技术的进步发展,越来越多的方法和技术被应用于雷诺现象的诊断及鉴别诊断。本文将影像技术在雷诺现象中的应用进展进行综述。     

The effect of sympathetic blockade and cooling in Raynaud's phenomenon

Summary. Nineteen patients with Raynaud's phenomenon (12 suffering from generalized scleroderma [GS] and seven from primary Raynaud's phenomenon [PR] and seven cold-tolerant healthy women underwent a cooling challenge with combined body and finger cooling. Finger systolic blood pressure was measured at 30 and 15°C, before and after nervous blockade at the finger-base with lidocain. Finger/arm blood pressure ratio (FBP/armBP) at 30°C was significantly lower in GS as compared to controls and PR, and it did not change after nervous blockade in any group. FBP/armBP at 15°C, decreased to zero in all patients with Raynaud's phenomenon and to median 0–67 in controls, prior to nervous blockade. After nervous blockade, in response to cooling, FBP/armBP at 15°C decreased significantly and was comparable in all groups. We conclude that the sympathetic nervous system seems to play an important part in provoking Raynaud's phenomenon in PR and most GS.     

Whole-body cooling increases plasma endothelin-1 levels in women with primary Raynaud's phenomenon

To understand better the role of endothelin-1 (ET-1) in the pathogenesis of primary Raynaud's phenomenon (PRP), we investigated the basal ET-1 plasma levels and changes after whole-body cooling in healthy women and those with PRP. The study was performed as an open parallel-group comparison during the month of February. The Raynaud group included 21 female patients (mean age 45·3 years, range 21–57 years) who had had disabling Raynaud's phenomenon for a mean period of 17 years (range 2–26 years). The control group consisted of 25 healthy women (mean age 43·6 years, range 27–56 years). Plasma levels of ET-1 were measured on two separate occasions: once after 30 min of rest at room temperature and after 40 min of whole-body cooling. There were no significant differences in baseline plasma ET-1 levels between the two groups of women. The plasma ET-1 levels increased significantly in the PRP group after cold exposure (mean difference 0·11 pmol l^?1, 95% CI 0·005–0·214, P = 0·012). In contrast, the levels of plasma ET-1 in the control group did not change significantly after cold provocation. In conclusion, no differences in plasma basal levels of ET-1 were observed between the two groups. However, women suffering from Raynaud's phenomenon responded with a slight but significant elevation in plasma levels of ET-1 after whole-body cooling, whereas the healthy control subjects did not. The results from the present study confirm previous observations that endothelial dysfunction may be of aetiological importance in PRP.     

Plasma exchange: a controlled study of the effect in patients with Raynaud's phenomenon and scleroderma

Six female patients with stage I and II vascular scleroderma and Raynaud's phenomenon were treated with plasma exchange and placebo plasma exchange. Placebo exchange consisted of the return of the patient's own separated plasma. No consistent long-term objective improvement was demonstrated in patients treated with either plasma exchange or placebo plasma exchange. Immediate increases in pulse volume, digital blood pressure, and skin temperature occurred in some patients with both procedures. Mechanisms of change remain unexplained, and further study is warranted.     

Magnesium sulphate infusion decreases circulating calcitonin gene-related peptide (CGRP) in women with primary Raynaud's phenomenon

Summary. The effects of two different vasodilating agents (MgSO₄ infusion and the calcium antagonist nifedipine) on circulating levels of calcitonin gene-related peptide (CGRP) were studied in 12 women with pronounced primary Raynaud's phenomenon (PRP) and in 12 healthy females. There were no significant differences with regard to basal levels of circulating CGRP between women with PRP and the control group; median 15–5 (range 10–48) vs. 14 (range 10–69) pmol 1^-1, respectively. However, treatment with MgSO₄ infusion significantly decreased circulating CGRP in women with PRP only from median 15–5 (range 10–48) to 10 (range 10–110) pmol l^-1) (P<0–05). On the other hand 14 days of treatment with nifedipine did not affect circulating CGRP in either of the investigated groups. Erythrocyte magnesium (ery-Mg) levels increased significantly after MgSO₄ infusion in women with PRP (2–43± 0–13 vs. 2–52 ± 0–15mmol 1^-1, P<0–05) but not in the controls (2–51 ± 0–24 vs. 2–57 ± 0–28 mmol l^-1, ns). In conclusion, the decrease of circulating CGRP after MgSO₄ infusion in women with PRP provides further evidence that magnesium plays a significant role in the pathophysiology of PRP.     

Limitation of finger systolic pressure measurement as a diagnostic test for primary Raynaud's phenomenon in a female population

Summary. The diagnostic value of measurement of the finger systolic pressure (FSP) was assessed during combined local and whole body cooling in a population-based sample of women with a medical history of primary Raynaud's phenomenon. Forty women had mild Raynaud's phenomenon and 40 had pronounced Raynaud's phenomenon. The results were compared with subjective assessments of complaints from Raynaud's phenomenon as indicated on a visual analogue scale (VAS) in the same group of women. The mean FSP at 10°C was significantly lower in the patients than in 24 age- and sex-matched controls, but there was a large overlap in individual responses. The sensitivity of the FSP method was only 51% for the whole group with primary Raynaud's phenomenon. There was no significant difference in FSP at 10°C between subjects with mild and those with pronounced Raynaud's phenomenon. The subjective severity of the symptoms as indicated on VAS was significantly higher in these two combined groups than in the controls. The mean VAS value was significantly higher in the group with pronounced Raynaud's phenomenon (P<0·01) than in that with the mild type. The low sensitivity of FSP measurement implies that this method is of limited value as a diagnostic test in subjects with primary Raynaud's phenomenon. Furthermore, there was no significant correlation between FSP and the VAS values (r= 0·23).     

Fremanezumab plus plasmapheresis in a patient with chronic migraine and myasthenia gravis: Case report of an effective treatment

A patient with chronic migraine and generalized myasthenia gravis was concurrently treated with fremanezumab and with therapeutic plasmapheresis (PEX). Fremanezumab was dosed right after a PEX session, or in the midpoint between sessions, and the efficacy of both treatments was maintained. This case broadens the drug's clinical applications and it helps in choosing the appropriate medical regimen in patients requiring both treatments.     

Reduction in acute migraine-specific and non-specific medication use in patients treated with erenumab: post-hoc analyses of episodic and chronic migraine clinical trials

BackgroundIn patients with migraine, overuse of acute medication, including migraine-specific medication (MSM) such as triptans and ergots, can lead to adverse health outcomes, including development of medication overuse headache. Here, we examined the effect of erenumab on reducing acute medication use, in particular MSM, in patients with episodic migraine (EM) and chronic migraine (CM).MethodsThe current post-hoc analyses were based on data from the double-blind treatment phase (DBTP) of two erenumab studies, a pivotal EM (N = 955) and a pivotal CM (N = 667) trial, and their respective extensions. Patients were administered subcutaneous placebo or erenumab (70 or 140 mg) once monthly. Daily acute headache medication use (including MSM and non-MSM) was recorded using an electronic diary during a 4-week pretreatment baseline period until the end of the treatment period. Outcome measures included change in monthly acute headache medication days (HMD) in acute headache medication users at baseline, and changes in monthly MSM days (MSMD) in MSM users at baseline and non-MSMD in non-MSM users at baseline.ResultsIn total, 60 and 78 % of patients (all acute headache medication users) with EM and CM used MSM at baseline, respectively. For acute headache medication users, the change in mean monthly acute HMD over Months 4, 5 and 6 compared with the pre-DBTP was 1.5, 2.5, and 3.0 for placebo, erenumab 70 mg and 140 mg, respectively for the EM study. The respective change in monthly MSMD in MSM users was 0.5, 2.1 and 2.8, and in monthly non-MSMD in non-MSM users was 2.3, 2.6, and 2.7. In the acute headache medication users at baseline, the change in monthly acute HMD at Month 3 compared with pre-DBTP was 3.4, 5.5, and 6.5 for placebo, erenumab 70 mg and 140 mg, respectively for the CM study. The respective change in monthly MSMD in MSM users was 2.1, 4.5, and 5.4, and in monthly non-MSMD in non-MSM users was 5.9, 6.4, and 6.6. Reductions in MSMD versus placebo were sustained in the extension periods of both studies. Erenumab was also associated with a higher proportion of MSM users achieving ≥ 50 %, ≥ 75 and 100 % reduction from baseline in monthly MSMD versus placebo in both EM and CM.ConclusionsIn both EM and CM, treatment with erenumab is associated with a significant and sustained reduction in the use of acute headache medication, in particular MSM.Trial registrations{"type":"clinical-trial","attrs":{"text":"NCT02456740","term_id":"NCT02456740"}}NCT02456740; {"type":"clinical-trial","attrs":{"text":"NCT02066415","term_id":"NCT02066415"}}NCT02066415; {"type":"clinical-trial","attrs":{"text":"NCT02174861","term_id":"NCT02174861"}}NCT02174861.     

Evaluation of vascular risk in patients with migraine with and without aura treated with erenumab: Post hoc analysis of pooled long-term clinical trial data

Objective

To assess cardiovascular (CV) safety of erenumab in clinical trial patients associated with degree of CV risk.

Background

Hypertension has been considered a theoretical risk associated with the inhibition of the calcitonin gene-related peptide pathway in migraine management, particularly in a patient population with pre-existing CV risk factors.

Methods

Data pooled from four double-blind, randomized trials were used to assess blood pressure (BP) changes and CV safety in patients grouped based on 10-year risk of cardiac, cerebrovascular, and peripheral artery disease as no-risk-factors, low-risk (>0% to ≤10%), moderate-risk (>10% to ≤20%), and high-risk (>20%) categories. CV safety was assessed as ischemic cardiovascular and cerebrovascular adverse events (ICCAE).

Results

There was no apparent difference between placebo- (N = 1032) and erenumab-treatment groups (70 mg, N = 885; 140 mg, N = 504) in clinical worsening of BP category from baseline to Months 1–3 (14% [143/1032] placebo vs. 13% [114/885] and 14% [71/504] for erenumab 70 and 140 mg, respectively) regardless of baseline BP category. The adverse event (AE) profile of erenumab was similar across CV risk categories throughout the long-term analysis. Erenumab-treated patients with high and moderate 10-year CV risk (N = 107) did not experience any ICCAEs during the double-blind treatment period; there was a single ICCAE (a cerebral dural venous sinus thrombosis) observed in the low-risk erenumab group (N = 273). There were no increases in AEs during the long-term extensions of up to 5 years (N = 2499; 3482 patient-years of exposure to erenumab) with exposure-adjusted incidence rates of cardio/cerebrovascular disorder AEs of 0.4, 0.5, 0.0, and 1.1 (per 100 patient-years) for no risk factor (N = 1805), low (N = 492), moderate (N = 121), and high (N = 81) 10-year CV risk groups, respectively.

Conclusions

Ischemic CV and cerebrovascular AEs were uncommon and the incidence rates were similar across the 10-year CV risk categories. This analysis helps provide more detail on the CV safety of erenumab.