Monoclonal antibodies blocking CGRP transmission: An update on their added value in migraine prevention.

The avenue of effective migraine therapies blocking calcitonin gene-related peptide (CGRP) transmission is the successful outcome of 35 years of translational research. Developed after short-acting, the small antagonists of the CGRP receptor (the "gepants"), the monoclonal antibodies blocking CGRP or its receptor (CGRP/rec mAbs) have changed the paradigm in migraine treatment. Contrary to the classical acute medications like triptans or nonsteroidal anti-inflammatory drugs (NSAIDs) with a transient effect, they act for long durations exclusively in the peripheral portion of the trigeminovascular system and can thus be assimilated to a durable attack treatment, unlike the classical preventives that chiefly act upstream on the central facets of migraine pathophysiology. Randomized controlled trials (RCT) of eptinezumab, erenumab, fremanezumab and galcanezumab have included collectively several thousands of patients, making them the most extensively studied class of preventive migraine treatments. Their results clearly indicate that CGRP/rec mAbs are significantly superior to placebo and have been comprehensively reviewed by Dodick [Cephalalgia 2019;39(3):445-458]. In this review we will briefly summarize the placebo-subtracted outcomes and number-needed-to-treat (NNT) of these pivotal RCTs and analyze new and post-hoc studies published afterwards focusing on effect size, effect onset and sustainability, response in subgroups of patients, safety and tolerability, and cost-effectiveness. We will also summarize our limited real-world experience with one of the CGRP/rec mAbs. Although methodological differences and lack of direct comparative trials preclude any reliable comparison, the overall impression is that there are only minor differences in efficacy and tolerability profiles between the four monoclonals: the average placebo-subtracted 50% responder rates for reduction in migraine headaches are 21.4% in episodic migraine (NNTs: 4-5), 17.4% in chronic migraine (NNTs: 4-8). Patients with an improvement exceeding 50% are rare, chronic migraineurs with continuous headache are unlikely to be responders and migraine auras are not improved. The effect starts within the first week after administration and is quasi maximal at one month. It is sustained for long time periods and may last for several months after treatment termination. CGRP/rec mAbs are effective even after prior preventive treatment failures and in patients with medication overuse, but the effect size might be smaller. They significantly reduce disability and health care resource utilization. The adverse effect profile of CGRP/rec mAbs is close to that of placebo with few minor exceptions and despite concerns related to the safeguarding role of CGRP in ischemia, no treatment-related vascular adverse events have been reported to date. Putting the CGRP/rec mAbs in perspective with available preventive migraine drug treatments, their major advantage seems not to be chiefly their superior efficacy but their unprecedented efficacy over adverse event ratio. Regarding cost-effectiveness, preliminary pharmaco-economic analyses of erenumab suggest that it is cost-effective for chronic migraine compared to no treatment or to onabotulinumtoxinA, but likely not for episodic migraine unless attack frequency is high, indirect costs are considered and its price is lowered.

IgE mediated sensitisation to aeroallergens in an asthmatic cohort: relationship with inflammatory phenotypes and disease severity.

BACKGROUND: Atopy is known to play an important role in the asthmatic disease. The main objective of this study was to evaluate the frequency of sensitisation to common aeroallergens in a cohort of asthmatics with different inflammatory phenotypes and disease severity. METHODS: We have conducted a retrospective cross-sectional study including 772 asthmatics recruited between 2003 and 2014 in our Asthma Clinic. The patients were defined as asthmatics on the basis of respiratory symptoms together with a positive methacholine test (PC20M) < 16 mg/ml and/or a reversibility to short-acting ß2-agonists (salbutamol) ≥ 12% and 200 ml. Sensitisation to house dust mites, grass and birch pollens, cats, dogs and moulds was assessed by RAST and a specific immunoglobulin E (IgE) > 0.35 kU/l was considered as significant. Inflammatory phenotypes were subdivided between pauci-granulocytic (n = 309) (40%), eosinophilic (n = 311) (40%), neutrophilic (N = 134) (17%) and mixed-granulocytic (N = 18) (3%) asthmatics. Severe asthmatics (n = 118) were defined according to the American Thoracic Society (ATS 2000) criteria and compared with mild-to-moderate asthmatics (N = 654). RESULTS: The eosinophilic phenotype was associated with higher levels of total serum IgE compared with neutrophilic and pauci-granulocytic asthma (p < 0.001 for both). Sensitisation rate to dogs and cats was higher in eosinophilic asthmatics (31% and 37%, respectively, p < 0.01 both) compared with neutrophilic (18% and 23% respectively) and pauci-granulocytic asthmatics (20% and 24%, respectively), while sensitisation rate to house dust mites and moulds were rather similar between the groups (ranging from 33% to 40% and from 10% to 16%, respectively). Severe asthmatics had slightly increased total serum IgE compared with mild-to-moderate asthmatics (p < 0.05) without any difference in the sensitisation rate to common aeroallergens. CONCLUSION: Eosinophilic asthma exhibits higher total serum IgE and sensitisation rate towards animal dander while clinical severity, though also associated with higher total IgE, did not preferentially relate to any type of common aeroallergens.

[Asthma-COPD overlap syndrome among patients with stable COPD]. / Étude du phénotype mixte BPCO-asthme dans une série de patients BPCO en état stable.

The purpose of this research was to describe the frequency and characteristics of the overlap syndrome among stable COPD patients (stage 2 to 4 according to GOLD). Material and method: We studied 46 patients with stable COPD recruited from the outpatient clinic of the CHU of Liege from May 2013 to April 2014. Definition of the overlap syndrome was based on the coexistence of post-bronchodilation FEV1/FVC < 70% and, either, an asthmatic history before the age of 40, or, at least, two functional and immune-inflammatory asthmatic traits : 1) significant FEV1 reversibility to inhaled bronchodilator (FEVI change >/= 200 ml and >/= 12% after bronchodilation), 2) eosinophilic inflammation : sputum eosinophils ≥ 3%,blood eosinophils ≥ 400/µl, or FENO ≥ 45 ppb, 3) clinical history of airway allergy, or total serum IgE ≥ 113 KU/l, or RAST ≥ 0,35 KU/l against major aeroallergens. 37% patients had the COPD-asthma overlap syndrome and this group had a higher CAT score reflecting more severe symptoms (24,6 ± 8,1 vs 19,4 ± 8, p < 0,05) despite similar level of airway obstruction. The transfer coefficient DLCO/VA was preserved in the overlap group (97 ± 24%), but altered in the pure COPD group (80 ± 20%), p < 0,05. Approximately one third of COPD patients present with the overlap syndrome and they are more symptomatic without any evidence of more severe airway obstruction.

Heterogeneity of phenotypes in severe asthmatics. The Belgian Severe Asthma Registry (BSAR).

UNLABELLED: The Belgian severe asthma registry is a web-based registry encompassing demographic, clinical, functional and inflammatory data of severe asthmatics (SA), aiming at improving awareness, knowledge on its natural history and subphenotypes, and offering tools to optimize care of this asthma population. METHODS: The cross-sectional analyses of this registry included 350 SA as defined by the ATS (2000) from 9 Belgian centres, with at least one year follow up. RESULTS: Mean age was 55 ± 14 yrs. SA were more frequently female (57%) and atopic (70%). Late-onset asthma (≥40 yr) was observed in 31% of SA. Current smokers represented 12% while 31% were ex-smokers. In addition to high doses ICS + LABA, 65% of patients were receiving LTRA, 27% anti-IgE and 24% maintenance oral corticosteroids (8 mg (Interquartile range-IQR:4-8) methylprednisolone). Despite impaired airflow (median FEV1:67%; IQR: 52-81) only 65% had a post-bronchodilator FEV1/FVC ratio <70%. The median blood eosinophil count was 240/mm³. The median FENO was 26 ppb (IQR: 15-43) and 22% of SA had FENO ≥ 50 ppb. Induced sputum was successful in 86 patients. Eosinophilic asthma (sputum Eos ≥ 3%) was the predominant phenotype (55%) while neutrophilic (sputum Neu ≥ 76%) and paucigranulocytic asthma accounted for 22% and 17% respectively. Comorbidities included rhinitis and chronic rhinosinusitis (49%), nasal polyposis (19%), oesophageal reflux (36%), overweight and obesity (47%) and depression (19%). In addition, 8% had aspirin-induced asthma and 3% ABPA. Asthma was not well-controlled in 83% according to ACT < 20 and 77% with ACQ > 1.5. CONCLUSION: In this cohort of patients with severe asthma, the majority displayed indices of persistent airflow limitation and eosinophilic inflammation despite high-dose corticosteroids, suggesting potential for eosinophil-targeted biotherapies.

Is FENO50 useful diagnostic tool in suspected asthma?

BACKGROUND: Asthma diagnosis is based on the presence of symptoms and the demonstration of airflow variability. Airway inflammation measured by fractional exhaled nitric oxide, measured at a flow rate of 50 ml/s (FE(NO50)) remains a controversial diagnostic tool. AIM: To assess the ability of FE(NO50) to identify bronchial hyperresponsiveness (BHR) to methacholine (provocative concentration of methacholine causing a 20% fall in FEV(1); PC20M ≤ 16 mg/ml) and to establish whether or not symptoms relate to FE(NO50) and PC20M in patients with no demonstrated reversibility to ß(2) -agonist. METHODS: We conducted a prospective study on 174 steroid naive patients with respiratory symptoms, forced expiratory volume in 1 s (FEV(1) ) ≥ 70% predicted and no demonstrated reversibility to ß(2) -agonist. Patients answered to a standardised symptom questionnaire and underwent FE(NO50) and methacholine challenge. Receiver-operating characteristic (ROC) curve and logistic regression analysis assessed the relationship between PC20M and FE(NO50) , taking into account covariates (smoking, atopy, age, gender and FEV(1)). RESULTS: A total of 82 patients had a PC20M ≤ 16 mg/ml and had significantly higher FE(NO50) (19 ppb vs. 15 ppb; p < 0.05). By constructing ROC curve, we found that FE(NO50) cut-off value of 34 ppb was able to identify not only BHR with high specificity (95%) and positive predictive value (88%) but low sensitivity (35%) and negative predictive value (62%). When combining all variables into the logistic model, FE(NO50) (p = 0.0011) and FEV(1) (p < 0.0001) were independent predictors of BHR whereas age, gender, smoking and atopy had no influence. The presence of diurnal and nocturnal wheezing was associated with raised FE(NO50) (p < 0.001 and p < 0.05, respectively). CONCLUSION: The value of FE(NO50) > 34 ppb has high predictive value of PC20M < 16 in patients with suspected asthma in whom bronchodilating test failed to demonstrate reversibility or was not indicated. However, FE(NO50) ≤ 34 ppb does not rule out BHR and should prompt the clinician to ask for a methacholine challenge.

Disturbed cytokine production at the systemic level in difficult-to-control atopic asthma: evidence for raised interleukin-4 and decreased interferon-γ release following lipopolysaccharide stimulation.

BACKGROUND: Disturbed cytokine production is thought to govern inflammation in asthma, which, in its turn, may lead to uncontrolled disease. The aim of this study was to assess the relationship between cytokine production from blood leucocytes and the level of asthma control. METHODS: We compared the production of interleukin (IL)-4, IL-6, IL-10, interferon (IFN)-γ and tumour necrosis factor-α from peripheral blood leucocytes in non-atopic healthy subjects (n = 22), atopic non-asthmatics (n = 10), well-controlled asthmatics [Juniper asthma control questionnaire (ACQ) score <1.5; n = 20] and patients with uncontrolled asthma despite inhaled or oral corticoids (ACQ score ≥1.5; n = 20). Fifty microlitres of peripheral blood was incubated for 24 h with RPMIc, lipopolysaccharide (LPS; 1 ng/ml) or phytohaemagglutinin (1 µg/ml), and cytokines were measured by immunotrapping (ELISA). RESULTS: Both controlled and uncontrolled asthmatics as well as atopic non-asthmatics spontaneously produced more IL-4 than non-atopic healthy subjects (p < 0.001). IL-4 production induced by LPS was significantly greater (p < 0.05) in both asthma groups compared to atopic non-asthmatics and non-atopic healthy subjects. By contrast, IFN-γ release induced by LPS was lower in uncontrolled asthmatics than in non-atopic healthy subjects (p < 0.05) and controlled asthmatics (p < 0.05). IL-10 release after LPS was greater in uncontrolled asthmatics than in atopic non-asthmatics (p < 0.05). No difference was observed regarding other cytokines. CONCLUSION: Blood cells from patients with difficult-to-control atopic asthma display highly skewed Th2 cytokine release following LPS stimulation.

Local and systemic cellular inflammation and cytokine release in chronic obstructive pulmonary disease.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a chronic airway inflammatory disease caused by repeated exposure to noxious gases or particles. It is now recognized that the disease also features systemic inflammation. The purpose of our study was to compare airway and systemic inflammation in COPD to that seen in healthy subjects and to relate the inflammation with the disease severity. METHODS: Ninety-five COPD patients, encompassing the whole severity spectrum of the disease, were recruited from our outpatient clinic and rehabilitation center and compared to 33 healthy subjects. Induced sputum and blood samples were obtained for measurement of inflammatory cell count. Interleukin (IL)-4, IL-6, IL-10, TNF-α and IFN-γ produced by 24h sputum and blood cell cultures were measured. RESULTS: Compared to healthy subjects, COPD exhibited a prominent airway neutrophilic inflammation associated with a marked IL-10, IL-6 and TNF-α release deficiency that contrasted with a raised IFN-γ production. Neutrophilic inflammation was also prominent at blood level together with raised production of IFN-γ, IL-10 and TNF-α. Furthermore, sputum neutrophilia correlated with disease severity assessed by GOLD stages. Likewise the extent of TNF-α release from blood cells also positively correlated with the disease severity but negatively with that of sputum cell culture. Blood release of TNF-α and IL-6 negatively correlated with body mass index. Altogether, our results showed a significant relationship between cellular marker in blood and sputum but poor relationship between local and systemic release of cytokines. CONCLUSIONS: COPD is characterized by prominent neutrophilic inflammation and raised IFN-γ production at both bronchial and systemic level. Overproduction of TNF-α at systemic level correlates with disease severity and inversely with body mass index.

[Inertia and adherence as factors influencing asthma control]. / Inertie et observance thérapeutiques en tant que facteurs influençant le contrôle de l'asthme.

Asthma is a chronic inflammatory disease which can be most often adequately controlled by current medications as demonstrated by multiple randomised clinical trials. Yet most of the recent surveys conducted in the real life setting point to an inadequate control in the majority of asthmatics. In addition to factors linked to the hygiene of life, clinician's inertia and patient's lack of adherence to the treatment certainly contribute to poor asthma control.

Cytokine production from sputum cells and blood leukocytes in asthmatics according to disease severity.

BACKGROUND: Although mild to moderate asthma is known to be Th2 driven, cytokines produced in refractory asthma might not fit the classical Th2 pattern. METHODS: The aim of our study was to assess the cytokine production by sputum and blood cells from 15 refractory asthmatics (American Thoracic Society Criteria) compared to 15 mild untreated and 17 moderate treated asthmatics and 22 healthy subjects. Spontaneous production of interleukin (IL)-4, IL-6, IL-10, interferon-gamma, and tumor necrosis factor alpha was measured by immunotrapping after 24 h sputum or blood cell culture. RESULTS: Moderate and refractory asthmatics were both characterized by a lower production of IL-6 from their airway cells compared to healthy subjects. However, the difference was no longer significant when expressing the results per gram of sputum. No significant difference between the three groups was found regarding other cytokines. As for cytokine production from blood, the three groups of asthmatics exhibited raised production of IL-4 when compared to healthy subjects, and this was true when results were expressed per blood volume or after normalization for total leukocyte cell count. Moderate asthmatics exhibited greater production of IL-10 when compared to refractory asthmatics and healthy subjects when results were normalized for total leukocyte cell count. CONCLUSIONS: Sputum cells from moderate and refractory asthmatics release less IL-6. While the systemic overproduction of IL-4 was observed through the all spectrum of asthma severity, moderate asthmatics exhibited greater systemic IL-10 production compared to refractory asthmatics.

[Omralizumab (Xolair) in severe persistent allergic asthma]. / L'omalizumab (Xolair) dans le traitement de l'asthme allergique persistant sévère.

Asthma is a chronic inflammatory airways disease. The inflammatory process is in many patients driven by an immunoglobulin E (IgE)-dependent process. Patients with severe asthma are at high risk of serious exacerbations and death and have few therapeutic options available. Omalizumab is a humanized monoclonal antibody that acts by binding to and inhibiting the effects of IgE, thereby interfering with one aspect of the asthma cascade. In addition to decreasing exacerbations, it has a steroid sparing role and many beneficial effects in asthma. As suggested by the new asthma GINA 2006 guidelines, this biological agent is indicated in severe persistent allergic asthma.

[Refractory asthma: underlying mechanisms, diagnosis and new therapeutic approach]. / Asthme réfractaire: mécanismes sous-jacents, diagnostics et nouvelles approches thérapeutiques.

There has been a recent increase in the prevalence of asthma worldwide. Most cases can be satisfactorily managed with a combination of inhaled corticoids and bronchodilators. However, some 10% of patients remain symptomatic despite high doses of inhaled corticosteroids and long-acting beta-2 agonists. They represent a heterogeneous group consisting of those who are either undertreated, or really refractory to current available treatment.