ABSTRACT
Physical activity can worsen migraine, leading to reduced activity levels in adults with chronic migraine. This study investigated the change in average steps per day, as a surrogate marker of physical activity, in adults with chronic migraine successfully treated with monoclonal antibodies against calcitonin gene-related peptide or its receptor. Data were obtained from adults with chronic migraine, who were classified as responders to preventive treatment with monoclonal antibodies. The primary endpoint was the difference in a mean number of steps per day between the 3 months prior to treatment initiation and the first 3 months after treatment initiation. The secondary endpoint was the correlation between the change in steps per day and the change in monthly migraine days. Twenty-two (20 females) participants with a median age of 48.5 years were enrolled. The median number of steps per day increased from 4421 at baseline to 5241 after treatment (P = 0.039). We found a positive correlation between the increase in steps per day and the treatment response (P = 0.013). In conclusion, an increase in physical activity, based on steps per day, positively correlated with treatment response to monoclonal antibodies. Automatically registered daily step count data might be used to monitor physical activity as a response to preventive treatment in adults with chronic migraine.
Subject(s)
Antibodies, Monoclonal , Calcitonin Gene-Related Peptide , Migraine Disorders , Humans , Migraine Disorders/drug therapy , Migraine Disorders/immunology , Female , Male , Middle Aged , Pilot Projects , Calcitonin Gene-Related Peptide/immunology , Adult , Antibodies, Monoclonal/therapeutic use , Chronic Disease , Treatment Outcome , Biomarkers , ExerciseABSTRACT
Migraine, a primary headache disorder whose mechanism remains incompletely understood, appears to involve the activation of the trigeminovascular system (TS) during attacks. Research suggests that inflammatory processes mediated by the immune system may play a role in migraine pathophysiology. Neuroinflammation is often associated with migraine attacks, with cytokines serving as crucial mediators in the process. Elevated levels of pro-inflammatory cytokines, such as interleukin-1 beta (IL-1ß), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α), have been observed in the blood and cerebrospinal fluid of individuals experiencing migraine attacks. These cytokines have the capacity to sensitize pain pathways in the brain, thereby increasing sensitivity to pain stimuli. This phenomenon, known as central sensitization, is believed to contribute to the intensity and persistence of migraine pain. Kynurenines, endogenous mediators of glutamatergic mechanisms, can significantly influence the pathophysiology of primary headache disorders. The kynurenine system is collectively known as the kynurenine pathway (KP), which can act on multiple receptors, such as glutamate receptors, aryl hydrocarbon receptors (AhRs), G protein-coupled receptors 35 (GPR35), and α-7 nicotinic acetylcholine (α7 nACh) receptors. These receptors are also found on various cells of the immune system, so the role of the KP in the pathomechanism of primary headaches may also be mediated through them. In this review, our goal is to show a possible link between the receptors of the KP and immune system in the context of inflammation and migraine. Migraine research in recent years has focused on neuropeptides, such as calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating polypeptide (PACAP) as potential pathogenic factors and possible therapeutic approaches. These peptides share many similarities in their characteristics and roles. For instance, they exhibit potent vasodilation, occur in both the peripheral and central nervous systems, and play a role in transmitting nociception and neurogenic inflammation. The investigation of potential connections between the aforementioned neuropeptides and the kynurenine pathway could play a significant role in uncovering the pathomechanism of migraine and identifying new drug candidates.
Subject(s)
Kynurenine , Migraine Disorders , Humans , Migraine Disorders/immunology , Migraine Disorders/physiopathology , Migraine Disorders/metabolism , Kynurenine/metabolism , Animals , Neuroimmunomodulation/physiology , Neuroinflammatory Diseases/immunology , Neuroinflammatory Diseases/physiopathologyABSTRACT
BACKGROUND: Monoclonal antibodies (mAbs) targeting the calcitonin gene-related peptide (CGRP) pathway have shown good efficacy in migraine prophylaxis. However, a subset of patients does not respond to the first mAb treatment and switches among the available mAbs. The goal of this study is to characterize the switching pattern of migraine patients treated with anti-CGRP(-receptor, -R) mAbs, and to describe the headache burden of those who did not switch, switched once, and switched twice. METHODS: This study used real world data from the NeuroTransData Cohort, a registry of migraine patients treated at outpatient neurology clinics across Germany. Patients who had received at least one anti-CGRP(-R) mAb were included. Headache diaries were collected at baseline and during treatment, along with quality of life measures every three months. Results were summarized for the subgroups of patients who did not switch and those with one and two switches. RESULTS: Of the 655 eligible patients, 479 did not switch, 135 switched once, 35 twice, and 6 three or more times. The ≥ 50% response rates for monthly migraine days were 64.7%, 50.7%, and 25.0% for the no switch, one switch, and two switches groups in their last treatment cycles, respectively. Quality of life measures improved for the no switch and one switch groups, but not for the two switches group. CONCLUSION: Patients who switched among anti-CGRP(-R) mAbs during the course of their treatment still benefited overall but to a lesser extent than those who did not switch. Treatment response in patients who switched twice was markedly lower compared to the no switch and one switch subgroup.
Subject(s)
Antibodies, Monoclonal , Calcitonin Gene-Related Peptide , Migraine Disorders , Registries , Humans , Migraine Disorders/drug therapy , Migraine Disorders/immunology , Female , Male , Antibodies, Monoclonal/therapeutic use , Germany/epidemiology , Middle Aged , Adult , Calcitonin Gene-Related Peptide/immunology , Calcitonin Gene-Related Peptide Receptor Antagonists/therapeutic use , Calcitonin Gene-Related Peptide Receptor Antagonists/administration & dosage , Quality of Life , Drug Substitution/statistics & numerical data , Cost of Illness , Receptors, Calcitonin Gene-Related Peptide/immunology , Receptors, Calcitonin Gene-Related Peptide/metabolismABSTRACT
BACKGROUND: The pathogenesis of migraine remains unclear; however, a large body of evidence supports the hypothesis that immunological mechanisms play a key role. Therefore, we aimed to review current studies on altered immunity in individuals with migraine during and outside attacks. METHODS: We searched the PubMed database to investigate immunological changes in patients with migraine. We then added other relevant articles on altered immunity in migraine to our search. RESULTS: Database screening identified 1,102 articles, of which 41 were selected. We added another 104 relevant articles. We found studies reporting elevated interictal levels of some proinflammatory cytokines, including IL-6 and TNF-α. Anti-inflammatory cytokines showed various findings, such as increased TGF-ß and decreased IL-10. Other changes in humoral immunity included increased levels of chemokines, adhesion molecules, and matrix metalloproteinases; activation of the complement system; and increased IgM and IgA. Changes in cellular immunity included an increase in T helper cells, decreased cytotoxic T cells, decreased regulatory T cells, and an increase in a subset of natural killer cells. A significant comorbidity of autoimmune and allergic diseases with migraine was observed. CONCLUSIONS: Our review summarizes the findings regarding altered humoral and cellular immunological findings in human migraine. We highlight the possible involvement of immunological mechanisms in the pathogenesis of migraine. However, further studies are needed to expand our knowledge of the exact role of immunological mechanisms in migraine pathogenesis.
Subject(s)
Migraine Disorders , Humans , Migraine Disorders/immunology , Cytokines/immunology , Immunity, Cellular/immunology , Immunity, Humoral/immunologyABSTRACT
OBJECTIVE: The objective of this systematic review and meta-analysis was to determine whether patients with episodic (EM) or chronic migraine (CM), who were treated with anti-CGRP antibodies, showed a reversal from medication overuse (MO) or medication overuse headache (MOH) status at their baseline to non-overuse status. Furthermore, this study aimed to establish which acute headache medication (AHM) categories responded more effectively to anti-CGRP antibodies. METHODS: A systematic search was conducted in the PubMed database for relevant studies from January 2013 to September 2023. We included phase three randomized controlled trials to examine the role of anti-CGRP antibodies in patients with EM or CM and their MO status. A meta-analysis was conducted to find the association between anti-CGRP antibodies and the number of EM and CM patients with MO or MOH at baseline that reverted to non-MO status or below the MOH threshold. RESULTS: The initial search yielded a total of 345 studies. After removing duplicates and screening with inclusion criteria, 5 studies fulfilled our conditions. Each study reviewed the response to changes in the MO status of patients after receiving anti-CGRP antibodies, including eptinezumab, fremanezumab, galcanezumab, and erenumab, compared to placebo. Our study analyzed three AHM categories: triptans, simple analgesics, and multiple drugs. The overall relative risk (RR) was 1.44 (95% CI, 1.31 to 1.59; p < 0.001). The RRs for triptans, simple analgesics, and multi-drug groups were 1.71 (95% CI, 1.53 to 1.91; p < 0.001), 1.10 (95% CI, 0.83 to 1.47; p = 0.5), and 1.29 (95%CI 1.14 to 1.46; p < 0.001) respectively. CONCLUSION: The meta-analysis has shown that anti-CGRP antibodies were statistically significant in transitioning from MO or MOH status to non-MO status or below the MOH threshold (RR = 1.44) for all included studies and all AHM categories except for simple analgesics. Patients from the triptan group had the highest RR of 1.71 with a p-value < 0.001, while the simple analgesics group had an RR of 1.10, however, with a p-value > 0.05. Interestingly, this analysis can be interpreted as that anti-CGRP antibodies might not be effective in reducing simple analgesics use in EM or CM patients. Further studies are needed to investigate these matters.
Subject(s)
Headache Disorders, Secondary , Migraine Disorders , Randomized Controlled Trials as Topic , Humans , Migraine Disorders/drug therapy , Migraine Disorders/immunology , Headache Disorders, Secondary/drug therapy , Headache Disorders, Secondary/immunology , Clinical Trials, Phase III as Topic , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal/administration & dosage , Calcitonin Gene-Related Peptide/immunology , Calcitonin Gene-Related Peptide/antagonists & inhibitors , Analgesics/therapeutic use , Calcitonin Gene-Related Peptide Receptor Antagonists/therapeutic use , Calcitonin Gene-Related Peptide Receptor Antagonists/administration & dosageABSTRACT
BACKGROUND: Many patients with chronic migraine do not achieve clinically meaningful improvement in their headache frequency with monotherapy. The burden associated with chronic migraine calls for a multifaceted treatment approach targeting multiple aspects of migraine pathophysiology. OBJECTIVE: The aim of this study was to evaluate the effect of concurrent anti-calcitonin gene-related peptide (CGRP) monoclonal antibody (mAb) and onabotulinumtoxinA (onabot) treatment on median monthly migraine days (MMD) in patients with chronic migraine, through a retrospective study. METHODS: The electronic medical records of Cleveland Clinic patients either concurrently (dual therapy) or consecutively (monotherapy) treated with anti-CGRP mAbs and onabot between June 2018 and November 2021 were extracted. Only adult patients (≥ 18 years of age) were included in this study. MMDs for 194 concurrently treated (86.6% female and a median [interquartile range] age of 51 [41-61] years) and 229 consecutively treated (88.2% female and median age of 47 [IQR 39-57] years) patients were examined at baseline, after first therapy of either anti-CGRP mAb or onabot, and following dual therapy for 3 consecutive months. The reduction of MMDs for each treatment group were compared. The same approach was utilized to compare consecutive monotherapy at separate times (n = 229) and dual-therapy groups. RESULTS: The initial treatment of the dual-therapy group reduced the median (IQR) MMDs from 30 (30-30) to 15 (12-30) [p < 0.0001]. After initiation of dual therapy, the median MMDs was further decreased from 15 (12-30) to 8 (3-22) [p < 0.0001]. A majority [132/194 (68.0%)] of the dual-therapy patients reported a ≥ 50% reduction in MMD and 90/194 (46.4%) reported a ≥ 75% reduction. For the consecutive monotherapy group, median MMDs changed from a baseline of 30 (25-30) to 15 (8-25) from onabot monotherapy and decreased from 25 (15-30) to 12 (4-25) after anti-CGRP mAb monotherapy. Almost half (113/229 [49.3%] from onabot, and 104/229 [45.4%] from anti-CGRP mAb) of these patients achieved a ≥ 50% reduction in MMDs and a minority (38/229 [16.6%] from onabot, and 45/229 [19.7%] from anti-CGRP mAb) achieved a reduction of ≥ 75%. Additionally, dual therapy showed significant improvement in MMDs compared with monotherapy of either treatment (p < 0.0001). CONCLUSION: Dual therapy of anti-CGRP mAbs and onabot may be more efficacious than monotherapy, possibly due to their synergistic mechanisms of action.
Subject(s)
Botulinum Toxins, Type A , Calcitonin Gene-Related Peptide , Migraine Disorders , Humans , Botulinum Toxins, Type A/administration & dosage , Botulinum Toxins, Type A/pharmacology , Retrospective Studies , Female , Migraine Disorders/drug therapy , Migraine Disorders/immunology , Male , Middle Aged , Adult , Calcitonin Gene-Related Peptide/immunology , Calcitonin Gene-Related Peptide/antagonists & inhibitors , Chronic Disease , Antibodies, Monoclonal/pharmacology , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/therapeutic use , Drug Therapy, Combination , Drug Synergism , Treatment OutcomeABSTRACT
BACKGROUND: Chronic migraine (CM) is a disabling and hard-to-treat condition, associated with high disability and high cost. Among the preventive treatments, botulinum toxin A (BoNT-a) and monoclonal antibodies against the calcitonin gene-related protein (anti-CGRP mAbs) are the only disease-specific ones. The assessment of the disease burden is complex, and among others, tools such as the allodynia symptoms checklist (ASC-12) and headache impact test (HIT-6) are very useful. This exploratory study analysed the impact of these two therapies on migraine burden. METHODS: The RAMO study was a multicentre, observational, retrospective investigation conducted in two headache centres: the Fondazione IRCCS Istituto Neurologico Carlo Besta (Milan) and the Fondazione Policlinico Campus Bio-Medico (Rome). This study involved patients with chronic migraine treated with mAbs or BoNT-A. We conducted a subgroup exploratory analysis on HIT-6 and ASC-12 scores in the two groups. The Wilcoxon rank-sum test, Fisher's exact test, and ANOVA were performed. RESULTS: Of 126 patients, 36 on mAbs and 90 on BoNT-A had at least one available follow-up. mAbs resulted in a mean reduction of -11.1 and -11.4 points, respectively, in the HIT-6 at 6 and 12 months, while BoNT-A was reduced -3.2 and -3.6 points, respectively; the mAbs arm resulted in mean reductions in ASC-12 at 6 and 12 months of follow-up of -5.2 and -6.0 points, respectively, while BoNT-A showed lesser mean changes of -0.5 and -0.9 points, respectively. The adjusted analysis confirmed our results. CONCLUSIONS: In this exploratory analysis, anti-CGRP mAbs showed superior effectiveness for HIT-6 and ASC12 compared to BoNT-A. Reductions in terms of month headache days (MHD), migraine disability assessment test (MIDAS), and migraine acute medications (MAM) were clinically relevant for both treatments.
Subject(s)
Antibodies, Monoclonal , Botulinum Toxins, Type A , Hyperalgesia , Migraine Disorders , Botulinum Toxins, Type A/therapeutic use , Botulinum Toxins, Type A/immunology , Humans , Migraine Disorders/drug therapy , Migraine Disorders/immunology , Female , Male , Adult , Retrospective Studies , Middle Aged , Antibodies, Monoclonal/therapeutic use , Hyperalgesia/drug therapy , Calcitonin Gene-Related Peptide/antagonists & inhibitors , Calcitonin Gene-Related Peptide/immunology , Chronic Disease , Treatment OutcomeABSTRACT
OBJECTIVES: While a single 12-month treatment cycle (TrC) with anti-CGRP mAbs is not disease-modifying for most patients, there is limited understanding of the effects of multiple TrCs on migraine course. We evaluated whether a second TrC might modify the migraine course by comparing the occurrence of migraine relapse after discontinuation of the second TrC to that following the cessation of the first TrC. METHODS: In a real-life, multicenter, prospective study we considered all consecutive patients diagnosed with high-frequency episodic migraine (HFEM) or chronic migraine (CM) with > 3 treatment failures and treated with any anti-CGRP mAbs for ≥ 2 consecutive 12-month TrCs who were responders at week 12. The primary endpoint was the change in monthly migraine days (MMD) for HFEM or monthly headache days (MHD) for CM at the first month of treatment discontinuation after the second TrC (D2) compared to the first TrC (D1). Secondary endpoints included variations in monthly analgesic medications (MAM), Numeric Rating Scale (NRS), and Headache Impact Test (HIT-6) scores, ≥ 50%, ≥ 75%, and 100% response rates, and relapse from episodic migraine to CM and from no-medication overuse (MO) to MO at D2 vs. D1. RESULTS: One-hundred-seventy-eight patients completed two 12-month TrCs with anti-CGRP mAbs. At D2, patients experienced a significant reduction in MMD (- 0.6, p = 0.028), MHD (- 2.6, p < 0.001), monthly analgesic medications (- 2.0, p < 0.001), and HIT-6 score (- 2.2, p < 0.001) compared to D1, indicating improved effectiveness. The ≥ 50% response rate at weeks 45-48 during the first TrC was 95.5%, while at weeks 45-48 of the second TrC was 99.4%. Corresponding rates at D1 was 20.2% whereas at D2 was 51.6% (p < 0.0001). No statistical difference emerged in ≥ 75% and 100% responders. The relapse rate from episodic migraine to CM at D2 was lower than at D1 (12.3% vs 30.4%; p = 0.0002) Fewer patients experienced relapse from no-MO to MO at D2 compared to D1 (29.5% vs 68.7%; p = 0.00001). DISCUSSION: A second TrC with anti-CGRP mAbs demonstrated clinical improvements compared to the first one, as indicated by a milder migraine relapse at D2 compared to D1. Multiple TrCs with anti-CGRP mAbs could progressively modify migraine evolution by reducing CGRP-dependent neuroinflammatory nociceptive inputs to the brain.
Subject(s)
Antibodies, Monoclonal , Migraine Disorders , Humans , Migraine Disorders/drug therapy , Migraine Disorders/immunology , Male , Female , Adult , Middle Aged , Antibodies, Monoclonal/administration & dosage , Prospective Studies , Treatment Outcome , Recurrence , Calcitonin Gene-Related Peptide/immunology , Calcitonin Gene-Related Peptide/antagonists & inhibitorsABSTRACT
OBJECTIVE: Nearly 60% of migraine patients treated with monoclonal antibodies (mAbs) targeting the calcitonin gene-related peptide (CGRP) pathway experience a ≥ 50% reduction in monthly migraine days (MMD) at 12 weeks compared to baseline (responders). However, approximately half of the patients not responding to anti-CGRP mAbs ≤ 12 weeks do respond ≤ 24 weeks (late responders). We assessed frequency and characteristics of patients responding to anti-CGRP mAbs only > 24 weeks (ultra-late responders). METHODS: In this multicenter (n = 16), prospective, observational, real-life study, we enrolled all consecutive adults affected by high-frequency episodic migraine (HFEM: ≥ 8 days/month) or chronic migraine (CM), with ≥ 3 prior therapeutic failures, treated with any anti-CGRP mAbs for ≥ 48 weeks. We defined responders patients with a ≥ 50% response rate ≤ 12 weeks, late responders those with a ≥ 50% response rate ≤ 24 weeks, and ultra-late responders those achieving a ≥ 50% response only > 24 weeks. RESULTS: A total of 572 migraine patients completed ≥ 48 weeks of anti-CGRP mAbs treatment. Responders accounted for 60.5% (346/572), late responders for 15% (86/572), and ultra-late responders for 15.7% (90/572). Among ultra-late responders, 7.3% (42/572) maintained the ≥ 50% response rate across all subsequent time intervals (weeks 28, 32, 36, 40, 44, and 48) and were considered persistent ultra-late responders, while 8.4% (48/572) missed the ≥ 50% response rate at ≥ 1 subsequent time interval and were classified as fluctuating ultra-late responders. Fifty patients (8.7%) did not respond at any time interval ≤ 48 weeks. Ultra-late responders differed from responders for higher BMI (p = 0.033), longer duration of medication overuse (p < 0.001), lower NRS (p = 0.017) and HIT-6 scores (p = 0.002), higher frequency of dopaminergic symptoms (p = 0.002), less common unilateral pain-either alone (p = 0.010) or in combination with UAS (p = 0.023), allodynia (p = 0.043), or UAS and allodynia (p = 0.012)-a higher number of comorbidities (p = 0.012), psychiatric comorbidities (p = 0.010) and a higher proportion of patients with ≥ 1 comorbidity (p = 0.020). CONCLUSION: Two-thirds of patients not responding to anti-CGRP mAbs ≤ 24 weeks do respond later, while non-responders ≤ 48 weeks are quite rare (8.7%). These findings suggest to rethink the duration of migraine prophylaxis and the definition of resistant and refractory migraine, currently based on the response after 2-3 months of treatment.
Subject(s)
Antibodies, Monoclonal , Calcitonin Gene-Related Peptide , Migraine Disorders , Humans , Migraine Disorders/immunology , Migraine Disorders/drug therapy , Male , Female , Adult , Middle Aged , Antibodies, Monoclonal/administration & dosage , Calcitonin Gene-Related Peptide/immunology , Prospective Studies , Treatment Outcome , Time FactorsABSTRACT
Calcitonin gene-related peptide (CGRP), a 37 amino-acid neuropeptide found mostly in peptidergic sensory C-fibers, has been suggested to be implicated in the pathogenesis of migraine, which is one of the most common neurological disorders seen in medical practice, affecting almost 16% of the US population. While previously thought to be a vascular condition, migraine attacks are the result of neurogenic inflammation and peripheral/central sensitization through dysfunctional activation of the trigeminovascular system. To date, two classes of therapeutic agents have been developed to interrupt the function of CGRP: CGRP-targeted monoclonal antibodies (mAbs) and small-molecule antagonists (gepants). There are currently four CGRP-targeted mAbs and three gepants that are US Food and Drug Administration (FDA) approved for the treatment of migraine. Multiple phase II and III studies have established the efficacies and tolerability of these treatments. Previously, we reviewed the fundamental role of CGRP in migraine pathogenesis. Here, we discuss in depth the clinical evidence (randomized controlled trials and real-world studies), safety, and tolerability of CGRP-targeted mAbs and gepants for treating migraine.
Subject(s)
Antibodies, Monoclonal , Antineoplastic Agents, Immunological , Calcitonin Gene-Related Peptide Receptor Antagonists , Migraine Disorders , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/pharmacology , Antibodies, Monoclonal/therapeutic use , Antineoplastic Agents, Immunological/pharmacology , Antineoplastic Agents, Immunological/therapeutic use , Calcitonin Gene-Related Peptide , Calcitonin Gene-Related Peptide Receptor Antagonists/immunology , Calcitonin Gene-Related Peptide Receptor Antagonists/pharmacology , Calcitonin Gene-Related Peptide Receptor Antagonists/therapeutic use , Humans , Migraine Disorders/drug therapy , Migraine Disorders/immunology , Randomized Controlled Trials as Topic , Receptors, Calcitonin Gene-Related Peptide/immunologyABSTRACT
Background: Eptinezumab is a humanized monoclonal antibody that selectively binds calcitonin gene-related peptide and is indicated for the preventive treatment of migraine in adults. This analysis characterizes the immunogenic profile of eptinezumab using data from clinical trials of eptinezumab for migraine prevention. Methods: Immunogenicity data were collected from five studies that included 2076 patients with episodic or chronic migraine treated with eptinezumab at dose levels ranging from 10 to 1000 mg, administered intravenously for up to 4 doses at 12-week intervals. Anti-drug antibody (ADA) results were available from 2074 of these patients. Four studies were randomized, double-blind, placebo-controlled trials with ADA monitoring for up to 56 weeks; one was a 2-year, open-label, phase 3 safety study with ADA monitoring for 104 weeks. Patients who had a confirmed ADA-positive result at the end-of-study visit were monitored for up to 6 additional months. Development of ADA and neutralizing antibodies (NAbs) were evaluated to explore three key areas of potential impact: pharmacokinetic exposure profile (eptinezumab trough plasma concentrations), efficacy (change in monthly migraine days), and safety (rates of treatment-emergent adverse events). These studies included methods designed to capture the dynamics of a potential humoral immune response to eptinezumab treatment, and descriptive analyses were applied to interpret the relationship of ADA signals to drug exposure, efficacy, and safety. Results: Pooled across the five clinical trials, treatment-emergent ADAs and NAbs occurred in 15.8 and 6.2% of eptinezumab-treated patients, respectively. Highly consistent profiles were observed across all studies, with initial onset of detectable ADA observed at the week 8 measurement and maximal ADA frequency and titer observed at week 24, regardless of eptinezumab dose level or number of doses. After 24 weeks, the ADA and NAb titers steadily declined despite additional doses of eptinezumab. Interpretation: Collectively, these integrated analyses did not demonstrate any clinically meaningful impact from ADA occurring after treatment with eptinezumab. The ADA profiles were low titer and transient, with the incidence and magnitude of ADA or NAb responses declining after week 24. Development of ADAs and NAbs did not impact the efficacy and safety profiles of eptinezumab.
Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies/blood , Calcitonin Gene-Related Peptide/antagonists & inhibitors , Migraine Disorders/prevention & control , Antibodies/immunology , Antibodies, Monoclonal, Humanized/adverse effects , Antibodies, Monoclonal, Humanized/blood , Antibodies, Monoclonal, Humanized/pharmacokinetics , Double-Blind Method , Humans , Migraine Disorders/blood , Migraine Disorders/immunology , Migraine Disorders/metabolism , Treatment OutcomeABSTRACT
Migraine is a prevalent medical condition and the second most disabling neurological disorder. Regarding its pathophysiology, calcitonin gene-related peptide (CGRP) plays a key role, and, consequently, specific antimigraine pharmacotherapy has been designed to target this system. Hence, apart from the gepants, the recently developed monoclonal antibodies (mAbs) are a novel approach to treat this disorder. In this review we consider the current knowledge on the mechanisms of action, specificity, safety, and efficacy of the above mAbs as prophylactic antimigraine agents, and examine the possible adverse events that these agents may trigger. Antimigraine mAbs act as direct scavengers of CGRP (galcanezumab, fremanezumab, and eptinezumab) or against the CGRP receptor (erenumab). Due to their long half-lives, these molecules have revolutionized the prophylactic treatment of this neurovascular disorder. Moreover, because of their physicochemical properties, these agents are hepato-friendly and do not cross the blood-brain barrier (highlighting the relevance of peripheral mechanisms in migraine). Nevertheless, apart from potential cardiovascular side effects, the interaction with AMY1 receptors and immunogenicity induced by autoantibodies against mAbs could be a concern for the safety of long-term treatment with these molecules.
Subject(s)
Antibodies, Monoclonal/pharmacology , Calcitonin Gene-Related Peptide/immunology , Migraine Disorders/drug therapy , Animals , Antibodies, Monoclonal/adverse effects , Autoantibodies/immunology , Blood-Brain Barrier/metabolism , Cardiovascular Diseases/chemically induced , Humans , Migraine Disorders/immunology , Migraine Disorders/physiopathology , Receptors, Calcitonin Gene-Related Peptide/immunologyABSTRACT
The exact etiology of migraine has not yet been fully understood. There is no specific diagnostic test for migraine and is often misdiagnosed like all other types of headaches. The lack of a diagnostic test is also a significant impediment to migraine management. In previous clinical studies, the author and his team found decreased levels of CD4+CD25+ Regulatory T cells (Treg) in migraine patients. These reductions were significant in the ictal phase of migraine, regardless of the subtype of migraines. Interestingly, the recent preclinical study demonstrated a significant improvement in nitroglycerine induced headache by activating Treg cells. Therefore, the author argued that peripheral Treg cell levels can be a therapeutically relevant biomarker for migraine.
Subject(s)
Migraine Disorders/immunology , T-Lymphocytes, Regulatory/immunology , Biomarkers , HumansABSTRACT
BACKGROUND & OBJECTIVE: To conduct a systematic review and network meta-analysis of all randomized trials investigating effects of anti-calcitonin gene related peptide monoclonal antibodies (anti-CGRP mAbs) on adult patients with chronic migraine. METHODS: MEDLINE, Embase and Cochrane Central Register of Controlled Trials searched from inception to July 2020; and clinical trial registries. The network meta-analysis was conducted in Bayesian framework using OpenBUGS and R, with the random effects model selected to allow for apparent heterogeneity between studies in the treatment comparison effects. RESULTS: Overall 38 studies (5164 chronic migraineurs in seven randomized trials) were included with treatment course of at least 12 weeks. Fremanezumab 675 + 225 + 225 mg QM (SC) injections were numerically more effective in lowering migraine days with lower MDs compared to eptinezumab 10 mg (IV) (MD: -1.52, 95% CrIs: -4.24, 0.99), eptinezumab 30 mg (IV) (MD: -0.33, 95% CrIs: -3.02, 2.16), eptinezumab 100 mg (IV) (MD: -0.59, 95% CrIs: -2.80, 1.42), eptinezumab 300 mg (IV) (MD: -0.02, 95% CrIs: -2.29, 1.98), erenumab 70 mg QM (SC) (MD: -0.17, 95% CrIs: -2.84, 2.25), erenumab 140 mg QM (SC) (MD: -0.18, 95% CrIs: -2.87, 2.26), fremanezumab 675 mg (SC) (MD: -0.30, 95% CrIs: -1.81, 1.14), galcanezumab 120 mg QM (SC) (MD: -0.71, 95% CrIs: -3.44, 1.55) and galcanezumab 240 mg QM (SC) (MD: -0.58, 95% CrIs: -3.09, 1.89), however the results were non-significant. Similarly, the anti-CGRP mAbs were also observed to have comparable safety and immunogenicity with no significant differences. CONCLUSIONS: Although all doses of anti-CGRP mAbs have comparable efficacy, safety and tolerability based on uncertainties in indirect comparisons for all outcomes, the calculated effect estimates numerically favored high doses of subcutaneous fremanezumab and intravenous eptinezumab as the effective therapy with acceptable safety and tolerability for short term prevention of chronic migraine.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Calcitonin Gene-Related Peptide/immunology , Migraine Disorders/drug therapy , Humans , Migraine Disorders/immunology , Network Meta-Analysis , Treatment OutcomeABSTRACT
Objectives: Migraine is a primary headache disorder with unknown pathophysiology. Recently, many studies have suggested the role of immune dysfunction in the pathophysiology of this disorder. In this study, we investigated the percentage of regulatory T cells (Treg cells) in different migraine categories.Methods: Peripheral blood samples of 40 newly diagnosed cases of migraine and 33 healthy individuals were collected for Treg cell analysis by flow cytometry.Results: The percentage of Treg cells in migraine patients with all subgroups including patients with or without auras and patients with chronic or episodic migraine was significantly lower than that of the control group. Also, a significant increase in the CD25 means fluorescence intensity (MFI) was observed in migraine without aura and chronic migraine groups, compared to the normal group.Conclusions: In this study, the number of Treg cells significantly decreased in new cases of migraine, which suggests that migraine is a result of an impairment in the immunological system or an autoimmune disease. Also, the insignificant difference in the number of Treg cells between the two categories of migraine suggests that there is no link between the reduced number of Treg cells and the emergence of aura symptoms or duration of the disease.
Subject(s)
Migraine Disorders/blood , Migraine Disorders/immunology , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism , Adult , Cross-Sectional Studies , Female , Flow Cytometry/methods , Humans , Male , Migraine Disorders/diagnosisABSTRACT
OBJECTIVE: It has been reported that patients with antiphospholipid antibodies (aPL) and refractory migraine may experience symptomatic improvement with antithrombotic therapy, but this phenomenon has not been well studied. This study was undertaken to detail the response to trials of antithrombotic therapy in these patients. METHODS: This is a retrospective study of 75 patients with refractory migraine and aPL who were given a 2-4 week trial of aspirin, clopidogrel and/or anticoagulation. Major response was defined as 50-100% improvement in frequency and/or severity of migraine; minor response: 25-49% improvement; no response: <25% improvement. RESULTS: 66 patients were given a trial of aspirin: 47% responded (21% major); 60 patients were given a trial of clopidogrel: 83% responded (67% major); and 34 patients were given a trial of anticoagulation (usually apixaban): 94% responded (85% major). The response rate to any anti-thrombotic therapy was 89% (83% major). Many patients also noted improvement in non-headache symptoms. No patient experienced stroke. There was no major bleeding during any 2-4 week treatment trial and only 3 of 69 patients maintained on an antithrombotic regimen for a median follow up of 29.9 months (5-100) experienced major bleeding. CONCLUSIONS: There was a high rate of symptomatic response to antithrombotic therapy in this context and long-term follow up suggested an individualized symptom-derived antithrombotic regimen may be associated with a low bleeding risk. Our data support consideration of a 2-4 week trial of antithrombotic therapy, usually starting with antiplatelet therapy, in aPL-positive patients with refractory migraine, particularly if other treatment options have been exhausted. As a retrospective study, our data provide only Class IV level of evidence, but they suggest randomized controlled trials are warranted to validate these encouraging findings.
Subject(s)
Antibodies, Antiphospholipid/blood , Fibrinolytic Agents/therapeutic use , Migraine Disorders/drug therapy , Pyrazoles/therapeutic use , Pyridones/therapeutic use , Adolescent , Adult , Aged , Antiphospholipid Syndrome/complications , Antiphospholipid Syndrome/diagnosis , Antiphospholipid Syndrome/immunology , Aspirin/administration & dosage , Aspirin/therapeutic use , Child , Clopidogrel/administration & dosage , Clopidogrel/therapeutic use , Cyclooxygenase Inhibitors/administration & dosage , Cyclooxygenase Inhibitors/therapeutic use , Female , Fibrinolytic Agents/administration & dosage , Hemorrhage/chemically induced , Hemorrhage/epidemiology , Humans , Male , Middle Aged , Migraine Disorders/immunology , Purinergic P2Y Receptor Antagonists/administration & dosage , Purinergic P2Y Receptor Antagonists/therapeutic use , Pyrazoles/administration & dosage , Pyridones/administration & dosage , Retrospective Studies , Severity of Illness Index , Stroke/chemically induced , Stroke/epidemiology , Treatment Outcome , Young AdultABSTRACT
Migraine is a debilitating neurological condition, with a global prevalence rate of 10.68% in men and 18.79% in women. Elucidation of the molecular mechanisms underlying migraines is of great importance for improving the quality of life of patients. The release of the neuropeptide calcitonin gene-related peptide (CGRP) from trigeminal nerve terminals is involved in the pathogenesis of migraine. Recent studies have shown that up-regulation of miR-34a-5p expression is associated with acute migraine attacks. Here, we investigated whether alteration of the expression of miR-34a-5p induces the release of the vasoactive peptide CGRP. We isolated primary rat trigeminal ganglion neurons and performed gain- and loss-of-function assays to alter the expression level of miR-34a-5p. Down-regulation of miR-34a-5p inhibited the expression of interleukin-1ß (IL-1ß)/cyclooxygenase 2 (COX2)/prostaglandin E2 (PGE2), decreased IL-1ß, PGE2 and CGRP release, and up-regulated the expression of silencing information regulator 1 (SIRT1) in trigeminal ganglion, whereas overexpression of miR-34a-5p enhanced the expression of IL-1ß/COX2/PGE2, increased the release of IL-1ß, PGE2 and CGRP, and decreased the expression of SIRT1 in trigeminal ganglion. In addition, overexpression of miR-34a-5p induced apoptosis in primary rat trigeminal neurons. In summary, these findings suggest that miR-34a-5p up-regulates the IL-1ß/COX2/PGE2 inflammation pathway, induces apoptosis and enhances release of CGRP via inhibition of SIRT1 expression in trigeminal ganglion neurons; thus, miR-34a-5p may have potential as a therapeutic target for the treatment of migraine.
Subject(s)
MicroRNAs/metabolism , Migraine Disorders/genetics , Sirtuin 1/genetics , Animals , Animals, Newborn , Apoptosis/genetics , Apoptosis/immunology , Calcitonin Gene-Related Peptide/metabolism , Cells, Cultured , Cyclooxygenase 2/metabolism , Dinoprostone/metabolism , Disease Models, Animal , Down-Regulation , Humans , Inflammation/genetics , Inflammation/immunology , Interleukin-1beta/metabolism , Migraine Disorders/immunology , Migraine Disorders/pathology , Neurons/metabolism , Primary Cell Culture , Rats , Signal Transduction/genetics , Signal Transduction/immunology , Sirtuin 1/metabolism , Trigeminal Ganglion/immunology , Trigeminal Ganglion/pathology , Up-Regulation/immunologyABSTRACT
INTRODUCTION: Interest is growing in the role of pituitary adenylate cyclase-activating polypeptide (PACAP) and its specific PAC1 receptor in migraine and in their antagonism as a strategy for migraine prevention. AREAS COVERED: We discuss and critically evaluate (i) the evidence of the role of PACAP in migraine pathophysiology and (ii) the first clinical trials in migraine prophylaxis with monoclonal antibodies AMG 301 and ALD1910 which act against PAC1 and PACAP38 respectively. We examined PubMed, Scopus, and ClinicalTrials.gov electronic databases to examine the relevant material. EXPERT OPINION: There is much proof of the ability of PACAP to cause migraine, but there is limited evidence that blocking PACAP or PAC1 receptor can prevent migraine. However, the potential of anti-PACAP antibodies in migraine prophylaxis is high. Theoretically, if these antibodies block the activation of the trigeminovascular system, they will prevent the onset of migraine attacks. There are still knowledge gaps in the role of PACAP in migraine and the risk/benefit ratio of anti-PACAP antibodies must be carefully studied.
Subject(s)
Antibodies, Monoclonal/administration & dosage , Migraine Disorders/prevention & control , Pituitary Adenylate Cyclase-Activating Polypeptide/immunology , Animals , Antibodies, Monoclonal/pharmacology , Humans , Migraine Disorders/immunology , Migraine Disorders/physiopathology , Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide/immunologyABSTRACT
Due to inconclusive findings of previous researches, we aimed to evaluate inflammatory state biomarkers in episodic and chronic migraineurs (EM and CM patients) compared to headache-free controls in the current study. Seventy-one migraine patients and 19 age-sex-matched controls were recruited. After obtaining demographic data and recording headache characteristics, blood samples were gathered and analyzed to evaluate the serum levels of C-reactive protein (CRP), tumor necrosis factor(TNF)-α and interleukin (IL)-6. Serum levels of IL-6, CRP and TNF-α were significantly higher among subjects with CM than the EM and controls. Further, positive correlations were noted for number of headache days/month and serum IL-6 (r=0.53, p<0.001), CRP (r=0.62, p<0.001), and TNF-α (r=0.58, p<0.001). In sum, according to current findings, a pro-inflammatory state was detected among chronic and episodic migraineurs compared to healthy control, as revealed by augmented concentrations of pro-inflammatory cytokines (e.g. IL6, CRP, and TNF-α). It was also underlined that with increasing levels of inflammatory factors, headaches tended to be more chronic. However, in order to confirm the hypothesis that neuroinflammation plays a role in migraine pain genesis, long-term cohort studies and well-designed experimental and randomized controlled trials are required.