Breakthrough Attacks Research Articles

Real-world effectiveness, satisfaction, and optimization of ubrogepant for the acute treatment of migraine in combination with onabotulinumtoxinA: results from the COURAGE Study

BackgroundIndividuals using onabotulinumtoxinA as a preventive migraine treatment often use acute treatments for breakthrough attacks. Data on real-world effectiveness of the small-molecule calcitonin gene–related peptide (CGRP) receptor antagonist ubrogepant in combination with onabotulinumtoxinA are limited.MethodsCOURAGE, a prospective, multiple attack, observational study, evaluated the real-world effectiveness of ubrogepant (50 or 100 mg) for acute treatment of migraine in people receiving onabotulinumtoxinA, an anti-CGRP monoclonal antibody (mAb), or both. This analysis focused only on onabotulinumtoxinA users. The Migraine Buddy app was used to identify eligible participants and track response to treated attacks. For each ubrogepant-treated attack, meaningful pain relief (MPR) and return to normal function (RNF) at 2 and 4 h post-dose over 30 days was assessed. MPR was defined as a level of relief that is meaningful to the participant, usually occurring before the pain is all gone. After 30 days, satisfaction was reported on a 7-point scale and overall acute treatment optimization was evaluated using the migraine Treatment Optimization Questionnaire-4 (mTOQ-4).ResultsThis analysis included 122 participants who received ubrogepant and onabotulinumtoxinA and reported on 599 ubrogepant-treated attacks. Following the first ubrogepant-treated attack, MPR was achieved in 53.3% of participants 2 h post-dose and in 76.2% of participants 4 h post-dose. RNF was achieved in 25.4% of participants 2 h post-dose and in 45.9% of participants 4 h post-dose. MPR and RNF results were similar across up to 10 ubrogepant-treated attacks. After 30 days, satisfaction with ubrogepant in combination with onabotulinumtoxinA was reported by 69.8% of participants and acute treatment optimization (defined as mTOQ-4 score ≥ 4) was achieved in 77.6%.ConclusionsIn this prospective real-world effectiveness study, ubrogepant treatment in onabotulinumtoxinA users with self-identified migraine was associated with high rates of MPR and RNF at 2 and 4 h as well as satisfaction and acute treatment optimization. Although the lack of a contemporaneous control group limits causal inference, these findings demonstrate the feasibility of using a novel, app-based design to evaluate the real-world effectiveness and satisfaction of treatments.Graphical

Observational Analysis of the Costs Associated with Acute Treatment of Breakthrough Migraine Attacks in Medicaid Patients Using Preventive Therapies.

Medications for preventive treatment of migraine reduce migraine frequency, usually measured by a reduction in monthly migraine days (MMD), but generally do not eliminate the need for acute treatment. To assess the economic impact of treatment-related reductions in frequency, methodological guidance recommends capturing cost differences along the spectrum of MMD. Characterize monthly migraine medication costs along the spectrum of MMD for patients using calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs) for prevention. Medicaid State Drug Utilization Data (SDUD) were used to identify formulations and per-unit costs for oral, intranasal, and parenteral migraine-specific medications for acute and preventive treatment used by fee-for-service (FFS) Medicaid enrollees in 2020. National drug codes of relevant therapies were used to match SDUD to formulation characteristics including substance, route of administration, and branded/generic marketing status. Mean per-unit cost and the formulation's share of total prescriptions were estimated. Monthly medication costs were modeled based on formulations' per-unit costs and frequency of acute medication use during clinical trials of CGRP mAbs. In the SDUD, there were 563,338 prescriptions for migraine-specific acute medications; triptans accounted for 97.37%. Triptan formulations prescribed were 83.78% oral tablet, 10.89% orally disintegrating tablet, 2.60% intranasal, and 2.73% parenteral. Dihydroergotamine accounted for < 1% of total prescriptions and had the highest per-unit cost ($443.50, branded intranasal). There were 97,119 prescriptions for CGRP mAbs, the majority for erenumab (45.73%) or galcanezumab (45.24%). Modeled monthly acute and preventive medication costs ranged from approximately $550 in patients with the fewest MMD treated with oral triptans to > $1500 in patients with the most MMD treated with dihydroergotamine. In consideration of the migraine-specific acute medications used in FFS Medicaid 2020, for patients using CGRP mAbs for prevention, medication costs may vary significantly with the number of breakthrough attacks treated per month and the type of migraine-specific acute therapy used.

Interventions for the long-term prevention of hereditary angioedema attacks.

Hereditary angioedema (HAE) is a serious and potentially life-threatening condition that causes acute attacks of swelling, pain and reduced quality of life. People with Type I HAE (approximately 80% of all HAE cases) have insufficient amounts of C1 esterase inhibitor (C1-INH) protein; people with Type II HAE (approximately 20% of all cases) may have normal C1-INH concentrations, but, due to genetic mutations, these do not function properly. A few people, predominantly females, experience HAE despite having normal C1-INH levels and C1-INH function (rare Type III HAE). Several new drugs have been developed to treat acute attacks and prevent recurrence of attacks. There is currently no systematic review and meta-analysis that included all preventive medications for HAE. To assess the benefits and harms of interventions for the long-term prevention of HAE attacks in people with Type I, Type II or Type III HAE. We used standard, extensive Cochrane search methods. The latest search date was 3 August 2021. We included randomised controlled trials in children or adults with HAE that used medications to prevent HAE attacks. The comparators could be placebo or active comparator, or both; approved and experimental drug trials were eligible for inclusion. There were no restrictions on dose, frequency or intensity of treatment. The minimum length of four weeks of treatment was required for inclusion; this criterion excluded the acute treatment of HAE attacks. We used standard Cochrane methods. Our primary outcomes were 1. HAE attacks (number of attacks per person, per population) and change in number of HAE attacks; 2. mortality and 3. serious adverse events (e.g. hepatic dysfunction, hepatic toxicity and deleterious changes in blood tests). Our secondary outcomes were 4. quality of life; 5. severity of breakthrough attacks; 6. disability and 7. adverse events (e.g. weight gain, mild psychological changes and body hair). We used GRADE to assess certainty of evidence for each outcome. We identified 15 studies (912 participants) that met the inclusion criteria. The studies included people with Type I and II HAE. The studies investigated avoralstat, berotralstat, subcutaneous C1-INH, plasma-derived C1-INH, nanofiltered C1-INH, recombinant human C1-INH, danazol, and lanadelumab for the prevention of HAE attacks. We did not find any studies on the use of tranexamic acid for prevention of HAE attacks. All drugs except avoralstat reduced the number of HAE attacks compared with placebo. For breakthrough attacks that occurred despite prophylactic treatment, intravenous and subcutaneous forms of C1-INH and lanadelumab reduced attack severity. It is not known whether other drugs have a similar effect, as the severity of breakthrough attacks in people taking drugs other than C1-INH and lanadelumab was not reported. For quality of life, avoralstat, berotralstat, C1-INH (all forms) and lanadelumab increased quality of life compared with placebo; there were no data for danazol. Four studies reported on changes in disability during treatment with C1-INH, berotralstat and lanadelumab; all three drugs decreased disability compared with placebo. Adverse events, including serious adverse events, did not occur at a rate higher than placebo. However, serious adverse event data and other adverse event data were not available for danazol, which prevented us from drawing conclusions about the absolute or relative safety of this drug. No deaths were reported in the included studies. The analysis was limited by the small number of studies, the small number of participants in each study and the lack of data on older drugs, therefore the certainty of the evidence is low. Given the rarity of HAE, it is not surprising that drugs were rarely directly compared, which does not allow conclusions on the comparative efficacy of the various drugs for people with HAE. Finally, we did not identify any studies that included people with Type III HAE. Therefore, we cannot draw any conclusions about the efficacy or safety of any drug in people with this form of HAE. The available data suggest that berotralstat, C1-INH (subcutaneous, plasma-derived, nanofiltered and recombinant), danazol and lanadelumab are effective in lowering the risk or incidence (or both) of HAE attacks. In addition, C1-INH and lanadelumab decrease the severity of breakthrough attacks (data for other drugs were not available). Avoralstat, berotralstat, C1-INH (all forms) and lanadelumab increase quality of life and do not increase the risk of adverse events, including serious adverse events. It is possible that danazol, subcutaneous C1-INH and recombinant human C1-INH are more effective than berotralstat and lanadelumab in reducing the risk of breakthrough attacks, but the small number of studies and the small size of the studies means that the certainty of the evidence is low. This and the lack of head-to-head trials prevented us from drawing firm conclusions on the relative efficacy of the drugs.

IMPACT OF HEREDITARY ANGIOEDEMA (HAE) ATTACKS ON QUALITY OF LIFE AND ACTIVITIES OF DAILY LIVING

<h3>Introduction</h3> HAE is characterized by recurrent and unpredictable episodes of subcutaneous or submucosal swelling affecting the abdomen, extremities, genitals, face, and larynx. This study characterized the impact of HAE attacks on patients' quality of life and activities of daily living. <h3>Methods</h3> Between November 2021 and March 2022 the US HAE Association (HAEA) and HAE International (HAEi) invited patients with HAE to participate in a 2-hour focus group. Participants provided informed consent and completed pre- and post- focus group surveys. <h3>Results</h3> A total of 32 respondents (mean age 33yrs [range 15-72, ‘adolescent, 15-18yrs', n=7; ‘adult, 19+yrs', n=25]) reported a mean of 33 attacks annually (median 18, range 0-170). Attack management included on-demand therapy only (65% overall, [50% adolescent/68% adult]) or prophylaxis treatment with on-demand therapy for breakthrough attacks (35% overall, [50% adolescent/32% adult]). Overall, 67% (68% adolescent/67% adult; 65% on-demand/78% prophylaxis) reported that an untreated attack resulted in a change of daily plans and 58% (70% on-demand/36% prophylaxis) stated they could not participate in important events or activities. The unpredictability of attacks caused anxiety and negatively impacted mental health in 39% of participants (17% adolescent/44% adult; 36% on-demand/45% prophylaxis) and nearly half (28% adolescent/54% adult) reported feeling ‘less than 100% themselves' due to HAE. <h3>Conclusion</h3> HAE attacks produce a significant disease burden on mental health, daily activities, and overall quality of life in patients. Despite significant advances in treatment options, there remains an opportunity to improve the lives of those with HAE.

Treatment of hereditary angioedema-single or multiple pathways to the rescue.

Hereditary angioedema (HAE) is a rare disease caused by mutations in the SERPING1 gene. This results in deficient or dysfunctional C1 esterase inhibitor (C1-INH) and affects multiple proteases involved in the complement, contact-system, coagulation, and fibrinolytic pathways. Current options for the treatment and prevention of HAE attacks include treating all affected pathways via direct C1-INH replacement therapy; or specifically targeting components of the contact activation system, in particular by blocking the bradykinin B2 receptor (B2R) or inhibiting plasma kallikrein, to prevent bradykinin generation. Intravenously administered plasma-derived C1-INH (pdC1-INH) and recombinant human C1-INH have demonstrated efficacy and safety for treatment of HAE attacks, although time to onset of symptom relief varied among trials, specific agents, and dosing regimens. Data from retrospective and observational analyses support that short-term prophylaxis with intravenous C1-INH products can help prevent HAE attacks in patients undergoing medical or dental procedures. Long-term prophylaxis with intravenous or subcutaneous pdC1-INH significantly decreased the HAE attack rate vs. placebo, although breakthrough attacks were observed. Pathway-specific therapies for the management of HAE include the B2R antagonist icatibant and plasma kallikrein inhibitors ecallantide, lanadelumab, and berotralstat. Icatibant, administered for treatment of angioedema attacks, reduced B2R-mediated vascular permeability and, compared with placebo, reduced the time to initial symptom improvement. Plasma kallikrein inhibitors, such as ecallantide, block the binding site of kallikrein to prevent cleavage of high molecular weight kininogen and subsequent bradykinin generation. Ecallantide was shown to be efficacious for HAE attacks and is licensed for this indication in the United States, but the labeling recommends that only health care providers administer treatment because of the risk of anaphylaxis. In addition to C1-INH replacement therapy, the plasma kallikrein inhibitors lanadelumab and berotralstat are recommended as first-line options for long-term prophylaxis and have demonstrated marked reductions in HAE attack rates. Investigational therapies, including the activated factor XII inhibitor garadacimab and an antisense oligonucleotide targeting plasma prekallikrein messenger RNA (donidalorsen), have shown promise as long-term prophylaxis. Given the requirement of lifelong management for HAE, further research is needed to determine how best to individualize optimal treatments for each patient.

Real-World experience of interictal burden and treatment in migraine: a qualitative interview study.

BackgroundThe debilitating nature of migraine attacks is widely established; however, less is known about how the interictal burden (i.e., how patients are affected in-between migraine episodes) of migraine impacts on patients’ health-related quality of life (HRQL). Acute and preventive treatments may lift the burden of the disease, but they often have unwanted side effects and limited effectiveness. The objective of this study was to understand the interictal burden of migraines, from the patient perspective, and to explore patient experience with migraine treatments.MethodsParticipants (n=35) with a self-reported diagnosis of migraine were recruited in the US, UK and Canada, including a subgroup of patients who had taken calcitonin gene-related peptide monoclonal antibody (CGRP mAb) treatment for at least three months. Participants completed a background questionnaire, followed by a semi-structured interview via telephone or video call. The interviews explored patients’ migraine symptoms, perception of interictal burden and treatment experience. The interview transcripts were analysed using thematic analysis.ResultsThe most reported migraine symptom was migraine pain, followed by aura, sensory sensitivity and nausea. Most participants reported interictal impact on HRQL, lifestyle changes they made to avoid triggers or in anticipation of an attack, impacts on work, career, daily activities and relationships. Emotional impacts were reported by all participants, including anger, depression, anxiety and hopelessness. Many participants who took preventive treatments reported improvements in HRQL and functioning but still experienced breakthrough attacks. Among patients who took CGRP mAbs, participants noted varying consistency of treatment effectiveness between treatment administrations.ConclusionThis study detailed the additional HRQL impact of migraine in-between migraine attacks and described the unmet need for effective treatment options to prevent and mitigate migraine attacks.Supplementary InformationThe online version contains supplementary material available at 10.1186/s10194-022-01429-5.

Clinical profile and treatment outcomes in patients with hereditary angioedema with normal C1 esterase inhibitor

BackgroundHereditary angioedema (HAE) is often caused by low serum levels or functional deficiency in C1 inhibitor (C1-INH); however, in some cases, C1-INH serum level and function are measured as normal (HAE-nl-C1INH). Management of HAE-nl-C1INH is similar to management of HAE with C1-INH deficiency, including on-demand therapy for angioedema attacks and, potentially, prophylaxis. Recombinant human C1 esterase inhibitor (rhC1-INH) is indicated for treatment of acute HAE attacks. This study assessed the clinical profile and treatment outcomes in an HAE-nl-C1INH population with a history of rhC1-INH treatment. MethodsMedical records containing patient-reported outcomes from ten US treatment centers were analyzed retrospectively for medical history, angioedema attack characteristics, attack treatments, and clinical outcomes. ResultsTwenty-three patients were included, with wide US geographic representation. Most patients (87.0%) were female; median age was 36.0 years (range, 19–67 years). Of 20 patients with available data, 4 had their first angioedema attack during childhood (aged <12 years), 3 during adolescence (aged 12–17 years), and 13 during adulthood (aged 18–29 years, n = 7; aged ≥30 years, n = 6). Median age at HAE-nl-C1INH diagnosis was 31.5 years (range, 9–59 years). Previous failed treatments included high-dose antihistamines (n = 20) and corticosteroids (n = 20). Use of US Food and Drug Administration (FDA)–approved HAE therapy positively impacted patient-reported assessments of angioedema attacks. Most patients were taking rhC1-INH or lanadelumab as prophylaxis and icatibant or rhC1-INH for acute management. Most patients reported improved disease control with these therapies, including reductions in angioedema attack frequency and severity. Although most patients were receiving prophylactic therapy, availability of treatment for breakthrough attacks was important. ConclusionFindings from this retrospective study support use of FDA-approved HAE medications for prophylaxis and acute treatment of HAE attacks in patients with HAE-nl-C1INH. Individualized HAE treatment regimens were needed to optimize therapeutic outcomes.

Ubrogepant Is Safe and Efficacious in Participants Taking Concomitant Preventive Medication for Migraine: A Pooled Analysis of Phase3 Trials.

IntroductionUbrogepant is a calcitonin gene-related peptide receptor antagonist indicated for acute treatment of migraine that can be used to treat breakthrough attacks in individuals taking preventive treatment for migraine. We evaluated the impact of preventive medication use on the efficacy and safety of ubrogepant for the acute treatment of migraine.MethodsThis was an analysis of pooled efficacy data from the ACHIEVE I and ACHIEVE II phase 3 trials, in which efficacy of ubrogepant was assessed at 2 h after taking study medication for pain freedom, absence of most bothersome symptom (MBS), and pain relief. In addition, a long-term safety (LTS) extension trial was completed where safety was assessed on the basis of incidence and severity of treatment-emergent adverse events (TEAEs). Outcomes were compared between participants with or without prior (within 6 months) preventive medication use (anticonvulsants, beta blockers, antidepressants, or onabotulinumtoxinA). For efficacy analyses, data were pooled across ACHIEVE trials for the 50 mg and placebo groups; for safety analyses, data for all dose groups (50 mg and 100 mg) in the LTS trial were pooled.ResultsPreventive treatments were used by 417 of 2247 (18.6%) participants analyzed in the ACHIEVE trials and by 143 of 813 (17.5%) participants in the LTS trial. Responder rates for all outcomes were similar between participants with or without preventive treatment within each dose group (p > 0.05). No significant differences were noted across the different preventive medications. Rates and types of TEAEs were similar between participants with or without preventive treatment. No serious treatment-related adverse events were reported.ConclusionEfficacy and safety of ubrogepant for the acute treatment of migraine were similar between participants with or without prior or current use of concomitant preventive medication.Trial RegistrationClinicalTrials.gov identifiers: NCT02828020 (ACHIEVE I), NCT02867709 (ACHIEVE II), and NCT02873221 (long-term safety trial).Supplementary InformationThe online version contains supplementary material available at 10.1007/s12325-021-01923-3.

Inebilizumab for treatment of neuromyelitis optica spectrum disorder in patients with prior rituximab use from the N-MOmentum Study

Background: The B-cell–depleting agent rituximab (anti-CD20) was historically used to prevent attacks in neuromyelitis optica spectrum disorder (NMOSD). Inebilizumab, which targets and depletes CD19-expressing B cells, plasmablasts, and some plasma cells, received approval from the US Food and Drug Administration for treatment of NMOSD based on results from the randomized, placebo-controlled, phase 2/3 N-MOmentum trial. Because of their closely related mechanisms of action, consideration as to whether inebilizumab may be a suitable treatment option for patients with prior rituximab experience is important. This post hoc analysis of data from N-MOmentum assessed inebilizumab efficacy and tolerability in participants previously treated with rituximab.Methods: Adjudicated attacks, secondary efficacy outcomes, and treatment-emergent adverse events were assessed by prior rituximab use during a 6-month randomized control period and open-label period.Results: Seventeen participants in N-MOmentum had prior rituximab use, of whom 13 were randomly assigned to the inebilizumab treatment group. Seven of these participants had breakthrough attacks prior to enrollment (annualized attack rate, 0.78 attacks/person-year) despite rituximab use. While they were receiving inebilizumab in the randomized control period, 1 of 13 participants with prior rituximab use had an attack (hazard ratio vs all placebo, 0.16; 95% confidence interval: 0.02 1.20; p = 0.07). Two additional participants with prior rituximab use experienced attacks on inebilizumab during the open-label period, with an overall annualized attack rate of 0.08 (95% confidence interval: 0.02 0.34) attacks/person-year. This annualized attack rate was similar to that of participants without prior rituximab use (0.10 [95% confidence interval: 0.07 0.15]). None of the 7 participants who experienced attacks while taking rituximab experienced an attack while receiving inebilizumab. Two (12%) participants with prior rituximab use experienced serious treatment-emergent adverse events related to inebilizumab, with serious or grade ≥3 infections occurring in 3 (18%) participants each. No deaths or opportunistic infections were reported in this cohort.Conclusions: These findings support the efficacy of inebilizumab in participants with NMOSD who had previously been treated with rituximab. Infections occurred in nearly all study participants with prior rituximab exposure, highlighting a need for clinical vigilance in such individuals. Further studies are necessary to determine potential safety concerns of inebilizumab, including risk of infection, in rituximab-experienced patients.ClinicalTrials.gov identifier: NCT02200770

Despite Prophylactic Treatments, Break-through Attacks Continue among Patients with Hereditary Angioedema

There are several FDA-approved medications for prophylactic treatment of Hereditary Angioedema (HAE). Despite increased use of these therapies, patients continue to experience HAE attacks. We sought to evaluate attack frequency in patients receiving prophylactic treatment.

Risk Factors for Poor Asthma Control and Breakthrough Attacks

Asthma is one of the most common chronic diseases worldwide with an estimated 300 million affected individuals. Prevalence is increasing in many countries, especially in children. Asthma is a major cause of school and work absence. Health care expenditure on asthma is very high. Asthma1 symptoms may be triggered by factors which are well known such as viral infections, allergens, tobacco smoke, exercise and stress.

The use of tranexamic acid for on‐demand and prophylactic treatment of hereditary angioedema—A systematic review

AbstractHereditary angioedema (HAE), caused by inherited deficiency of C1 esterase inhibitor (C1‐INH), is characterized by recurring subcutaneous and/or submucosal edema. Although its efficacy remains controversial, tranexamic acid (TXA) is used to treat HAE in some countries. We analyzed TXA as an on‐demand and prophylactic treatment in patients with HAE. Published data were systematically sourced from PubMed and Embase. All retained articles underwent grading/bias assessment using the “SIGN” grading system, and the quality of retained studies was determined following assessment of design and methodology. Of 353 studies identified, 31 were included. On‐demand treatment and prophylactic treatment were assessed in five (N = 103) and 28 studies (N = 231), respectively. The majority of studies (80%) demonstrated that on‐demand TXA was ineffective for skin, abdominal, or laryngeal swellings. In a single randomized controlled trial, the median time to relief of symptoms was 2 and 12 hours for icatibant and TXA, respectively (P &lt; 0.001). For prophylaxis, while ~50% of case series, case reports, and observational studies reported beneficial effects of TXA, newer therapies, for example, icatibant and pdC1‐INH, were more effective. One study found that breakthrough attacks during TXA prophylaxis lasted significantly longer compared with C1‐INH (median time to resolution; 7 vs 3 hours, P = 0.016). Many studies failed to report safety data (16/31, 52%); however, pruritus, vomiting, and diarrhea were noted in some patients. There is no evidence for on‐demand use of TXA in HAE and limited evidence for prophylaxis. While TXA may be more beneficial than no treatment, newer, more effective therapies should be used when available.

Optimum Use of Acute Treatments for Hereditary Angioedema: Evidence-Based Expert Consensus

Acute treatment of hereditary angioedema due to C1 inhibitor deficiency has become available in the last 10 years and has greatly improved patients’ quality of life. Two plasma-derived C1 inhibitors (Berinert and Cinryze), a recombinant C1 inhibitor (Ruconest/Conestat alpha), a kallikrein inhibitor (Ecallantide), and a bradykinin B2 receptor inhibitor (Icatibant) are all effective. Durably good response is maintained over repeated treatments and several years. All currently available prophylactic agents are associated with breakthrough attacks, therefore an acute treatment plan is essential for every patient. Experience has shown that higher doses of C1 inhibitor than previously recommended may be desirable, although only recombinant C1 inhibitor has been subject to full dose–response evaluation. Treatment of early symptoms of an attack, with any licensed therapy, results in milder symptoms, more rapid resolution and shorter duration of attack, compared with later treatment. All therapies have been shown to be well-tolerated, with low risk of serious adverse events. Plasma-derived C1 inhibitors have a reassuring safety record regarding lack of transmission of virus or other infection. Thrombosis has been reported in association with plasma-derived C1 inhibitor in some case series. Ruconest was associated with anaphylaxis in a single rabbit-allergic volunteer, but no further anaphylaxis has been reported in those not allergic to rabbits despite, in a few cases, prior IgE sensitization to rabbit or milk protein. Icatibant is associated with high incidence of local reactions but not with systemic effects. Ecallantide may cause anaphylactoid reactions and is given under supervision. For children and pregnant women, plasma-derived C1 inhibitor has the best evidence of safety and currently remains first-line treatment.

An open-label study to evaluate the long-term safety and efficacy of lanadelumab for prevention of attacks in hereditary angioedema: design of the HELP study extension

BackgroundHereditary angioedema (HAE) is characterized by recurrent attacks of subcutaneous or submucosal edema. Attacks are unpredictable, debilitating, and have a significant impact on quality of life. Patients may be prescribed prophylactic therapy to prevent angioedema attacks. Current prophylactic treatments may be difficult to administer (i.e., intravenously), require frequent administrations or are not well tolerated, and breakthrough attacks may still occur frequently. Lanadelumab is a subcutaneously-administered monoclonal antibody inhibitor of plasma kallikrein in clinical development for prophylaxis of hereditary angioedema attacks. A Phase 1b study supported its efficacy in preventing attacks. A Phase 3, randomized, double-blind, placebo-controlled, parallel-arm study has been completed and an open-label extension is currently ongoing.Methods/designThe primary objective of the open-label extension is to evaluate the long-term safety of repeated subcutaneous administrations of lanadelumab in patients with type I/II HAE. Secondary objectives include evaluation of efficacy and time to first angioedema attack to determine outer bounds of the dosing interval. The study will also evaluate immunogenicity, pharmacokinetics/pharmacodynamics, quality of life, characteristics of breakthrough attacks, ease of self-administration, and safety/efficacy in patients who switch to lanadelumab from another prophylactic therapy. The open-label extension will enroll patients who completed the double-blind study (“rollover patients”) and those who did not participate in the double-blind study (“non-rollover patients”), which includes patients who may or may not be currently using another prophylactic therapy. Rollover patients will receive a single 300 mg dose of lanadelumab on Day 0 and the second dose after the patient’s first confirmed angioedema attack. Thereafter, lanadelumab will be administered every 2 weeks. Non-rollover patients will receive 300 mg lanadelumab every 2 weeks regardless of the first attack. All patients will receive their last dose on Day 350 (maximum of 26 doses), and will then undergo a 4-week follow-up.DiscussionPrevention of attacks can reduce the burden of illness associated with HAE. Prophylactic therapy requires extended, repeated dosing and the results of this study will provide important data on the long-term safety and efficacy of lanadelumab, a monoclonal antibody inhibitor of plasma kallikrein for subcutaneous administration for the treatment of HAE.Trial registration NCT02741596

Breakthrough attacks in patients with hereditary angioedema receiving long-term prophylaxis are responsive to icatibant: findings from the Icatibant Outcome Survey

BackgroundPatients with hereditary angioedema (HAE) due to C1-inhibitor deficiency (C1-INH-HAE) experience recurrent attacks of cutaneous or submucosal edema that may be frequent and severe; prophylactic treatments can be prescribed to prevent attacks. However, despite the use of long-term prophylaxis (LTP), breakthrough attacks are known to occur. We used data from the Icatibant Outcome Survey (IOS) to evaluate the characteristics of breakthrough attacks and the effectiveness of icatibant as a treatment option.MethodsData on LTP use, attacks, and treatments were recorded. Attack characteristics, treatment characteristics, and outcomes (time to treatment, time to resolution, and duration of attack) were compared for attacks that occurred with versus without LTP.ResultsData on 3228 icatibant-treated attacks from 448 patients with C1-INH-HAE were analyzed; 30.1% of attacks occurred while patients were using LTP. Attack rate, attack severity, and the distribution of attack sites were similar across all types of LTP used, and were comparable to the results found in patients who did not receive LTP. Attacks were successfully treated with icatibant; 82.5% of all breakthrough attacks were treated with a single icatibant injection without C1-INH rescue medication. Treatment outcomes were comparable for breakthrough attacks across all LTP types, and for attacks without LTP.ConclusionsPatients who use LTP should be aware that breakthrough attacks can occur, and such attacks can be severe. Thus, patients with C1-INH-HAE using LTP should have emergency treatment readily available. Data from IOS show that icatibant is effective for the treatment of breakthrough attacks. Trial Registration NCT01034969

MOG-IgG in NMO and related disorders: a multicenter study of 50 patients. Part 2: Epidemiology, clinical presentation, radiological and laboratory features, treatment responses, and long-term outcome.

BackgroundA subset of patients with neuromyelitis optica spectrum disorders (NMOSD) has been shown to be seropositive for myelin oligodendrocyte glycoprotein antibodies (MOG-IgG).ObjectiveTo describe the epidemiological, clinical, radiological, cerebrospinal fluid (CSF), and electrophysiological features of a large cohort of MOG-IgG-positive patients with optic neuritis (ON) and/or myelitis (n = 50) as well as attack and long-term treatment outcomes.MethodsRetrospective multicenter study.ResultsThe sex ratio was 1:2.8 (m:f). Median age at onset was 31 years (range 6-70). The disease followed a multiphasic course in 80 % (median time-to-first-relapse 5 months; annualized relapse rate 0.92) and resulted in significant disability in 40 % (mean follow-up 75 ± 46.5 months), with severe visual impairment or functional blindness (36 %) and markedly impaired ambulation due to paresis or ataxia (25 %) as the most common long-term sequelae. Functional blindess in one or both eyes was noted during at least one ON attack in around 70 %. Perioptic enhancement was present in several patients. Besides acute tetra-/paraparesis, dysesthesia and pain were common in acute myelitis (70 %). Longitudinally extensive spinal cord lesions were frequent, but short lesions occurred at least once in 44 %. Fourty-one percent had a history of simultaneous ON and myelitis. Clinical or radiological involvement of the brain, brainstem, or cerebellum was present in 50 %; extra-opticospinal symptoms included intractable nausea and vomiting and respiratory insufficiency (fatal in one). CSF pleocytosis (partly neutrophilic) was present in 70 %, oligoclonal bands in only 13 %, and blood-CSF-barrier dysfunction in 32 %. Intravenous methylprednisolone (IVMP) and long-term immunosuppression were often effective; however, treatment failure leading to rapid accumulation of disability was noted in many patients as well as flare-ups after steroid withdrawal. Full recovery was achieved by plasma exchange in some cases, including after IVMP failure. Breakthrough attacks under azathioprine were linked to the drug-specific latency period and a lack of cotreatment with oral steroids. Methotrexate was effective in 5/6 patients. Interferon-beta was associated with ongoing or increasing disease activity. Rituximab and ofatumumab were effective in some patients. However, treatment with rituximab was followed by early relapses in several cases; end-of-dose relapses occurred 9-12 months after the first infusion. Coexisting autoimmunity was rare (9 %). Wingerchuk’s 2006 and 2015 criteria for NMO(SD) and Barkhof and McDonald criteria for multiple sclerosis (MS) were met by 28 %, 32 %, 15 %, 33 %, respectively; MS had been suspected in 36 %. Disease onset or relapses were preceded by infection, vaccination, or pregnancy/delivery in several cases.ConclusionOur findings from a predominantly Caucasian cohort strongly argue against the concept of MOG-IgG denoting a mild and usually monophasic variant of NMOSD. The predominantly relapsing and often severe disease course and the short median time to second attack support the use of prophylactic long-term treatments in patients with MOG-IgG-positive ON and/or myelitis.

Symptom monitoring and quality of life in children with asthma: Scope for self-management in routine care

Objectives: To observe correlation between parental and child reporting of change in asthma symptoms and objective parameters of lung function over time. Design: Prospective cohort study. Materials and Methods: Children (n = 125) were divided into two age groups (6-10 years and 11-15 years) and were classified into intermittent, mild persistent, and moderate persistent grades of severity. Parental and child reporting of quality of life (QoL) scores were recorded on a pretested questionnaire on the initial visit and at 4 and 8 weeks. At each session, appropriate counseling regarding the disease and its primary management at home was done. The change in scores from first and second follow-up visits was statistically correlated with changes in symptom score recorded on symptom diary, peak expiratory flow rates (PEFR), and spirometry. Results : There was significant improvement in the subjective and objective parameters compared at the two follow-up visits. The magnitude of improvement in parental global rating of QOL was similar to improvement in objective measures of pulmonary function in children 6-10 years of age, whereas both parental and child rating correlated well with objective parameters in children 11-15 years of age. Also, symptom score emerged as a stronger predictor of acute exacerbation in PEFR in candidate children who had breakthrough attacks. Conclusion: Improvement in QoL score is a sensitive measure of functional improvement in asthmatic children on treatment and may complement objective measurements. Health education has a positive impact on treatment outcome. Self monitoring of symptoms at home fosters more patient involvement and promotes better management at all levels of care.

Role of Interleukin‐1 Inhibitors in the Management of Gout

Interleukin-1 (IL-1) inhibitors potentially have a role as antiinflammatory agents in refractory gout or for patients who are unable to tolerate conventional therapy, such as nonsteroidal antiinflammatory drugs (NSAIDs), colchicine, or glucocorticoids, for acute attacks. Additionally, IL-1 inhibitors may also help patients with polyarticular and tophaceous gout by making them less vulnerable to breakthrough attacks during initiation of chronic urate-lowering treatment, the mainstay of gout therapy. Because evidence highlights the role of proinflammatory cytokine IL-1 in the inflammation process during an acute gouty attack, IL-1 inhibitors are used to modulate the pathogenesis of a variety of autoinflammatory diseases, providing support for its potential role in the inflammatory process of gout. After NSAIDs, colchicine, and steroids, IL-1 inhibitors are beneficial as fourth-line therapy for acute gout attacks due to their high cost and limited clinical experience. The IL-1 inhibitors used in gout are anakinra, canakinumab, and rilonacept. Based on published evidence, anakinra has limited support in the form of anecdotal case reports to justify its use for treating gout. Canakinumab's toxic profile in clinical trials precludes its use in treating patients for gout, and rilonacept shows promise with a few well-designed studies to support its use in gout patients initiating urate-lowering treatment. When combined with current traditional therapies, these newer agents present clinicians and patients with more potential treatment options in the difficult-to-treat gout population.

Simple office-based behavioral approach to patients with chronic belching

Chronic belching can be a difficult and socially disabling symptom often attributed to reflux with poor response to therapy. In patients where aerophagia is identified as a clear cause, treatment with baclofen may not be tolerated, and biofeedback therapy is time-intensive and may still not be effective. In this pilot study, an office-based easy-to-perform method based on sustained glottal opening was used in five patients with chronic belching, in whom reflux and other causes had been excluded. Treatment consisted of having the patient breathe slowly and diaphragmatically with his or her mouth open during supine, then sitting periods to prevent belching. When this was successful, patients were then counseled on continuing this breathing with mouth slightly ajar as an outpatient using this persistently. Wide mouth opening was used for rescue therapy of belching attacks. All five patients responded to the office-based therapy with complete cessation of belching during the visit. At 1-month follow up, four patients remained asymptomatic. One patient was asymptomatic but for two breakthrough attacks easily managed with the protocol. A simple office-based procedure based on complete glottal opening can be curative for a subset of patients with chronic eructation secondary to repetitive air swallowing.

Recombinant human C1 inhibitor for the prophylaxis of hereditary angioedema attacks: a pilot study

Hereditary angioedema (HAE) is a disease characterized by recurrent tissue swelling affecting various body locations. Recent literature shows that patients with frequent attacks may benefit from long-term prophylaxis. This study evaluated the safety and prophylactic effect of weekly administrations of recombinant C1INH (rhC1INH). Patients with a history of HAE attacks occurring ≥every 2weeks received a once weekly administration of 50U/kg rhC1INH. Hereditary angioedema attack history was collected at screening. Breakthrough attacks during the study were recorded at each visit. Following a 2-week run-in period, HAE patients received 8 weekly rhC1INH administrations and were followed-up for an additional 6weeks. Efficacy was evaluated by comparing the HAE attack incidence during the treatment period to the historical attacks over the previous 2years. Safety evaluation was based on clinical laboratory and adverse events (AEs) reports. The 25 participants reported a mean of 0.9attacks/week over the past 2years. The mean breakthrough attack rate during the treatment period was 0.4attacks/week (95% CI 0.28-0.56). A total of 30 treatment-emergent-AEs were reported in 13 patients, all mild to moderate. One patient died from a laryngeal attack 25days after last study drug administration. The only possible drug related AEs reported were dry mouth, dizziness and anxiety in one patient and hypotension in another. There were no allergic AEs and no neutralizing antibodies observed. Weekly administrations of 50U/kg rhC1INH appeared to reduce the frequency of HAE attacks and were generally safe and well tolerated.