Real-world safety profile of eculizumab in patients with paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, or generalized myasthenia gravis: an integrated analysis of post-marketing surveillance in Japan.

Eculizumab is a C5 inhibitor approved for the treatment of paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), and anti-acetylcholine receptor antibody-positive generalized myasthenia gravis (AChR + gMG) in Japan. We report integrated safety data from post-marketing surveillance in these three indications, focusing on commonly occurring adverse events (AEs) and infection-related AEs. Of 1219 patients registered, 1055 (PNH: 780; aHUS: 192; AChR + gMG: 83) had available safety data. Total eculizumab exposure was 3977.361 patient-years. AEs were reported in 74.03% of patients. AEs with an incidence of  ≥ 1.0 per 100 patient-years included hemolysis, headache, nasopharyngitis, renal impairment, anemia, pneumonia, upper respiratory tract inflammation, influenza, condition aggravated, and infection. The incidence of infection-related AEs was 21.30 per 100 patient-years, the most frequent types (≥ 1.0 per 100 patient-years) being nasopharyngitis, pneumonia, influenza, and infection. Meningococcal infections were reported in four patients (0.10 per 100 patient-years). Two patients died from meningococcal sepsis, with a mortality rate of 0.05 per 100 patient-years. This is the largest safety dataset on eculizumab in Japan derived from more than 10 years of clinical experience. No new safety signals were observed and the safety profile of eculizumab was consistent with that in previous clinical trials and international real-world safety analyses.

Evaluating the risk of infections under interleukin 23 and interleukin 17 inhibitors relative to tumour necrosis factor inhibitors - A population-based study.

BACKGROUND: The risk of infections among patients with psoriasis undergoing interleukin (IL)-23 inhibitors (IL-23i) and IL-17 inhibitors (IL-17i) is yet to be exhaustively determined. OBJECTIVE: To assess the risk of infectious complications in patients with psoriasis managed by IL-23i and IL-17i with tumour necrosis factor inhibitors (TNFi) as a comparator. METHODS: A global cohort study comprised two distinct analyses comparing patients with psoriasis under different therapeutic modalities; (i) new users of IL-23i (n = 5272) versus TNFi (n = 5272) and (ii) new users of IL-17i (n = 15,160) versus TNFi (n = 15,160). Study groups were compared regarding the risk of 26 different infections. Propensity score matching was conducted to optimize between-group comparability. RESULTS: Patients under IL-23i had a lower risk of otitis media (HR, 0.66; 95% CI, 0.44-0.97), encephalitis (HR, 0.18; 95% CI, 0.04-0.78), herpes zoster (HZ; HR, 0.58; 95% CI, 0.41-0.82), hepatitis B virus (HBV) reactivation (HR, 0.24; 95% CI, 0.12-0.47), cytomegalovirus (HR, 0.25; 95% CI, 0.07-0.86), influenza (HR, 0.52; 95% CI, 0.38-0.71) and parasitic diseases (HR, 0.78; 95% CI, 0.64-0.95). IL-17i was associated with a decreased risk of pneumonia (HR, 0.76; 95% CI, 0.68-0.85), septicaemia (HR, 0.84; 95% CI, 0.72-0.97), upper respiratory tract infection (HR, 0.84; 95% CI, 0.77-0.92), HZ (HR, 0.79; 95% CI, 0.67-0.92), HBV (HR, 0.59; 95% CI, 0.46-0.76) and hepatitis C virus (HR, 0.71; 95% CI, 0.57-0.88) reactivation, cytomegalovirus (HR, 0.58; 95% CI, 0.36-0.93), Epstein-Barr virus (HR, 0.38; 95% CI, 0.19-0.75), influenza (HR, 0.70; 95% CI, 0.61-0.81) and parasitic diseases (HR, 0.80; 95% CI, 0.72-0.88). CONCLUSION: Compared with TNFi, IL-23i and IL-17i are associated with decreased risk of several infectious diseases. These agents might be preferred in patients with susceptibility to infections.

Association of Influenza Vaccination With Risk of Bell Palsy Among Older Adults in Taiwan.

Importance: Annual administration of the influenza vaccine (fluVc) is currently the most effective method of preventing the influenza virus in older adults. However, half of adults older than 65 years remain unvaccinated in Taiwan, possibly because of concern about adverse events, such as Bell palsy (BP). Currently, studies on the association between fluVc and risk of BP are inconsistent. Objective: To determine whether the incidence of BP increases following fluVc in older adults. Design, Setting, and Participants: A self-controlled case series study design was used. Days 1 through 7, days 8 through 14, days 15 through 30, and days 31 through 60 following fluVc were identified as risk intervals, and days 61 through 180 were considered the control interval. A total of 4367 vaccinated individuals aged 65 years or older who developed BP within 6 months following fluVc were enrolled. Population-based retrospective claims data were obtained between 2010 and 2017; data were analyzed from April 2022 through September 2022. Exposure: Government-funded seasonal fluVc. Main Outcomes and Measures: The outcome of interest was BP onset in risk intervals compared with control intervals. Three or more consecutive diagnoses of BP within 60 days following fluVc were used as the definition of a patient with BP. Poisson regression was used to analyze the incidence rate ratio (IRR) of risk intervals compared with control intervals. Results: In total, 13 261 521 patients who received the fluVc were extracted from the National Health Insurance Research Database in Taiwan from January 1, 2010, to December 31, 2017. Of those, 7 581 205 patients older than 65 years old met the inclusion criteria. The number of patients with BP diagnosed within 6 months following fluVc enrolled for risk analysis was 4367 (mean [SD] age, 74.19 [5.97] years; 2349 [53.79%] female patients). The incidence rate of BP among all observed fluVc older adults was 57.87 per 100 000 person-years. The IRRs for BP on days 1 through 7, days 8 through 14, and days 15 through 30 were 4.18 (95% CI, 3.82-4.59), 2.73 (95% CI, 2.45-3.05), and 1.67 (95% CI, 1.52-1.84), respectively. However, there was no increase during days 31 through 60 (IRR, 1.06; 95% CI, 0.97-1.16). The postvaccination risk of BP was consistent across all subgroups stratified by sex, age group, and baseline conditions. Conclusions and Relevance: The present self-controlled case series indicated that the risk of BP in individuals older than 65 years increased within the first month, especially within the first week, following fluVc. But overall, the adverse event rate of BP was low, and considering the morbidity and mortality of influenza infection, the benefits of fluVc still outweigh the risks.

Cutaneous Adverse Reactions Following Influenza Vaccination in Adults.

OBJECTIVE: To review the literature on cutaneous reactions to the influenza vaccine in adults. DATA SOURCES: Authors systematically searched three databases: PubMed, MEDLINE, and EMBASE. STUDY SELECTION: Case reports published between January 1, 1995 and December 31, 2020 that described a cutaneous reaction to any brand of the influenza vaccine in adults were included. Exclusion criteria included having the wrong study design, pediatric cases, publication prior to 1995, and lack of cutaneous reaction to the vaccine. DATA EXTRACTION: A total of 232 articles were identified. After duplicate removal, title and abstract screening, and full-text screening, 29 studies were included in the final review. Data extracted included patient sex, age, type of influenza vaccine received, time from vaccine administration to cutaneous reaction, duration of cutaneous reaction, description of cutaneous reactions, treatments used, and the outcome (eg, resolution, reoccurrence, complications). DATA SYNTHESIS: The mean age of participants was 43.7 years (range, 19-82 years), and 60% were women (n = 18). The most frequent cutaneous reaction that occurred following influenza vaccination included erythematous macules/papules/plaques (n = 17 [56.7%]), vasculitic and purpuric rashes (n = 5 [16.7%]), and maculopapular (morbilliform) rashes (n = 3 [10.0%]). All patients received treatment, and 96.7% (n = 29) of the cutaneous manifestations were resolved. Most studies did not report any further complications upon follow-up. CONCLUSIONS: Understanding and identifying the relationship between the influenza vaccine and possible cutaneous manifestations can help providers predict and anticipate these adverse effects.

Association between cold weather, influenza infection, and asthma exacerbation in adults in Hong Kong.

Despite a conspicuous exacerbation of asthma among patients hospitalized due to influenza infection, no study has attempted previously to elucidate the relationship between environmental factors, influenza activity, and asthma simultaneously in adults. In this study, we examined this relationship using population-based hospitalization records over 22 years. Daily numbers of hospitalizations due to asthma in adults of 41 public hospitals in Hong Kong during 1998-2019 were obtained. The data were matched with meteorological records and air pollutant concentrations. We used type-specific and all-type influenza-like illness plus (ILI+) rates as proxies for seasonal influenza activity. Quasi-Poisson generalized additive models together with distributed-lag non-linear models were used to examine the association. A total of 212,075 hospitalization episodes due to asthma were reported over 22 years. The cumulative adjusted relative risk (ARR) of asthma hospitalizations reached 1.15 (95 % confidence interval [CI], 1.12-1.18) when the ILI+ total rate increased from zero to 20.01 per 1000 consultations. Compared with the median temperature, a significantly increased risk of asthma hospitalization (cumulative ARR = 1.10, 95 % CI, 1.05-1.15) was observed at the 5th percentile of temperature (i.e., 14.6 °C). Of the air pollutants, oxidant gas was significantly associated with asthma, but only at its extreme level of concentrations. In conclusion, cold conditions and influenza activities are risk factors to asthma exacerbation in adult population. Influenza-related asthma exacerbation that appeared to be more common in the warm and hot season, is likely to be attributable to influenza A/H3N2. The heavy influence of both determinants on asthma activity implies that climate change may complicate the asthma burden.

Maternal vaccination-current status, challenges, and opportunities.

AIM: Maternal vaccination is a promising strategy for protecting pregnant women and newborns against severe infections. This review aims to describe the current status and challenges associated with maternal vaccination against seasonal influenza, tetanus-diphtheria-pertussis (Tdap/DTaP), and novel coronavirus disease of 2019 (COVID-19) in Japan and other countries, mainly the United States and the United Kingdom. METHODS: A literature search was conducted in PubMed and other public websites (e.g., Centers for Disease Control and Prevention) to obtain information on maternal vaccination. RESULTS: Inactivated vaccines are recommended for pregnant women by gynecologic societies in Japan, the United States, and the United Kingdom. Among pregnant Japanese women, the influenza and COVID-19 (two doses) vaccine coverage rates were 27.0%-53.5% (six studies) and 73.6% (one study), respectively; there are no studies on maternal vaccination with DTaP. Concerns regarding vaccine safety are a major barrier to maternal vaccination across countries. Maternal vaccination is effective in preventing severe disease in pregnant women and protecting infants aged <6 months, is generally safe, and does not increase the risk of adverse maternal and fetal outcomes. Providing accurate information regarding vaccination through healthcare providers and the government and government funding for vaccines may help improve maternal vaccination rates in Japan. CONCLUSION: Current coverage for maternal vaccination is still low globally mainly because of vaccine hesitancy among pregnant women. The government, drug-regulatory authorities, and healthcare professionals must educate pregnant women about the effectiveness and safety of maternal vaccines and encourage vaccination when the benefits outweigh the risks.

A Multicenter, Prospective, Randomized, Parallel-Group Trial on the Effects of Temporary Methotrexate Discontinuation for One Week Versus Two Weeks on Seasonal Influenza Vaccination in Patients With Rheumatoid Arthritis.

OBJECTIVE: This clinical trial was conducted to investigate whether discontinuing methotrexate (MTX) for 1 week after seasonal influenza vaccination is noninferior to discontinuing for 2 weeks after vaccination in patients with rheumatoid arthritis (RA). METHODS: In this multicenter, prospective, randomized, parallel-group noninferiority trial, RA patients receiving a stable dose of MTX were randomly assigned at a ratio of 1:1 to discontinue MTX for 1 week or for 2 weeks after they received the quadrivalent 2021-2022 seasonal influenza vaccine containing H1N1, H3N2, B/Yamagata, and B/Victoria strains. The primary outcome measure was the proportion of patients with a satisfactory vaccine response, which was defined as ≥4-fold increase in antibody titers, as determined with the hemagglutination inhibition assay, against ≥2 of the 4 vaccine strains at 4 weeks after vaccination. RESULTS: The modified intent-to-treat population included 90 patients in the 1-week MTX hold group and 88 patients in the 2-week MTX hold group. The mean ± SD MTX doses were 12.6 ± 3.4 mg/week in the 1-week MTX hold group and 12.9 ± 3.3 mg/week in the 2-week MTX hold group. The proportion of satisfactory vaccine responses did not differ between the groups (68.9% versus 75.0%; P = 0.364). The rate of seroprotection and the fold increase in antibody titers for each of the 4 influenza antigens were similar between the groups. CONCLUSION: A temporary discontinuation of MTX for 1 week after vaccination was noninferior to a discontinuation of MTX for 2 weeks after vaccination, regarding induction of a satisfactory vaccine response to a seasonal influenza vaccine in patients with RA receiving a stable dose of MTX.

The Hospital Recovery Scale: A clinically useful endpoint in patients hospitalized with influenza.

BACKGROUND: Currently, no single best primary endpoint exists for measuring the efficacy of treatments in seriously ill patients with respiratory infections, such as influenza, who require hospitalization. The Hospital Recovery Scale is an ordinal endpoint used to evaluate treatment outcomes in clinical studies of hospitalized patients infected with influenza. METHODS: To determine whether Hospital Recovery Scale outcomes correspond to those for other clinical endpoints in patients hospitalized due to influenza, data from the phase 3 randomized, double-blind ZORO clinical trial (NCT01231620) were analyzed. Randomized influenza-infected patients were divided into subgroups of interest based on prespecified baseline and infection-related characteristics, as well as randomized treatment arms (intravenous zanamivir 300 mg or 600 mg, or oral oseltamivir 75 mg). Clinical endpoints relevant to this population were included to analyze differences in outcomes between the subgroups, and correspondence of these endpoints and hospital recovery endpoint was evaluated. RESULTS: Data from 488 patients were analyzed. There were strong correlations (ρs > 0.8) between the Hospital Recovery Scale assessed on the day after completion of a 5-day antiviral therapy (Day 6) and both time to hospital discharge and time to intensive care unit discharge, and moderate to strong correlations (0.6 < ρs < 0.8) between the Hospital Recovery Scale on Day 6 and several other relevant clinical endpoints. CONCLUSIONS: The Hospital Recovery Scale is applicable as a primary endpoint in trials to evaluate new therapies for severely ill patients hospitalized due to influenza, and may have utility in other severe respiratory illnesses such as COVID-19.

Barriers and facilitators to vaccination for COVID-19, pertussis, and influenza during pregnancy: Protocol for an umbrella review.

Pregnant women are particularly vulnerable to infection. Furthermore, infection from pertussis, influenza and COVID-19 increases the likelihood of adverse consequences to the mother and developing baby such as stillbirth, ICU admission, and pre-term caesarean birth. Increased rates of transmission and risk of adverse consequences from infection justifies the provision of national maternal vaccination programmes. Additionally, maternal vaccination helps protect the infant until they are able to receive their own vaccinations; a time when they are most at risk of mortality from influenza and pertussis. Vaccination during pregnancy has been repeatedly demonstrated as safe and effective in reducing harm, although rates of uptake remain low compared to the general population. The current protocol describes the methodology for an umbrella review aiming to explore the barriers and facilitators of vaccination during pregnancy for pertussis, influenza, and COVID-19. Systematic reviews that investigate the barriers and facilitators of at least one of either pertussis, influenza, or COVID-19 will be included in this review. Multiple databases will be searched, and included reviews assessed for quality (using the Joanna Briggs Institute (JBI) quality assessment for systematic reviews) and degree of overlap of included primary studies. Included reviews will be analysed according to the WHO SAGE model of determinants of vaccine hesitancy and separated by whether these explore influenza and pertussis, or COVID-19. The outcomes of this review will help inform the development of interventions to increase uptake of vaccination during pregnancy, and on whether interventions need to be tailored depending on the infectious disease. The key findings will identify the specific barriers and facilitators of vaccination hesitancy by considering contextual influences (e.g. sociodemographic variables), individual/social group influences (e.g. trust in the institutions), and vaccine-specific issues (e.g. safety and recommendations).

Efficacy and safety of baricitinib in combination with topical corticosteroids in patients with moderate-to-severe atopic dermatitis with inadequate response, intolerance or contraindication to ciclosporin: results from a randomized, placebo-controlled, phase III clinical trial (BREEZE-AD4).

BACKGROUND: Baricitinib, an oral selective Janus kinase (JAK)1 and JAK 2 inhibitor, was shown to improve the signs and symptoms of moderate-to-severe atopic dermatitis (AD). OBJECTIVES: To evaluate the efficacy and safety of baricitinib with background topical corticosteroids (TCS) in patients with moderate-to-severe AD and inadequate response, intolerance or contraindication to ciclosporin A (CA). METHODS: In this double-blind, randomized, placebo-controlled, phase III study, patients were randomized 1: 1: 2: 1 to placebo (N = 93), baricitinib 1 mg (N = 93), 2 mg (N = 185) or 4 mg (N = 92) with background TCS. The primary endpoint was the proportion of patients receiving baricitinib 4 mg or 2 mg (+ TCS) vs. placebo + TCS who achieved ≥ 75% improvement from baseline in the Eczema Area and Severity Index (EASI 75) at week 16. RESULTS: Baricitinib 4 mg + TCS was superior to placebo + TCS for EASI 75 (4 mg: 32%, placebo: 17%, P = 0·031) at week 16 and for improvements in itch, skin pain and number of night-time awakenings owing to itch. Improvements were maintained through 52 weeks of treatment. Treatment-emergent adverse events (TEAEs) were more common with baricitinib than placebo (+ TCS); most were mild or moderate. The most frequent TEAEs with baricitinib 4 mg + TCS were nasopharyngitis, herpes simplex, influenza and headache. No deaths or deep vein thromboses were reported. CONCLUSIONS: Baricitinib 4 mg + TCS improved the signs and symptoms of moderate-to-severe AD through 52 weeks of treatment in patients with inadequate response, intolerance or contraindication to CA. The safety profile was consistent with previous studies of baricitinib in moderate-to-severe AD. What is already known about this topic? Ciclosporin A is indicated for the treatment of atopic dermatitis that is refractory to topical therapies. However, its use is limited by safety concerns and it may not provide adequate response for some patients. Baricitinib, an oral selective Janus kinase (JAK)1 and JAK2 inhibitor, has been shown to improve the signs and symptoms of moderate-to-severe atopic dermatitis as a monotherapy or in combination with topical corticosteroids. What does this study add? Baricitinib combined with background low- or moderate-potency topical corticosteroids provided improvements in the signs and symptoms of moderate-to-severe atopic dermatitis through 1 year of treatment in patients with a contraindication, intolerance or failure to respond to ciclosporin A. The most common treatment-emergent adverse events with baricitinib 4 mg were nasopharyngitis, herpes simplex, influenza and headache. The safety profile was consistent with previous studies in patients with moderate-to-severe atopic dermatitis.

Spinal corticosteroid injections are not associated with increased influenza risk.

BACKGROUND CONTEXT: Spinal corticosteroid injections (CSI) are often used to treat radicular and axial pain arising from the spine. Systemic corticosteroids are well known to cause immunosuppression, and locally injected spinal CSI are known to have some systemic absorption. However, it is unknown whether spinal CSI increases the risk of systemic viral infections, such as influenza. PURPOSE: To determine whether spinal CSI causes an increased risk for influenza infection and whether they reduce the protective effect of vaccination STUDY DESIGN/SETTING: A retrospective cohort study was performed at Kaiser Permanente Northern California, a large healthcare system with a diverse population. PATIENT SAMPLE: Adults (n=60,880) who received a spinal CSI during influenza seasons from 2016 to 2019. A comparison was made with 121,760 case-matched individuals who did not receive a spinal CSI. OUTCOME MEASURES: The primary outcome was odds of influenza diagnosis following spinal CSI compared with case-matched controls. Secondary analysis examined odds of influenza diagnosis based on vaccination status, multiple same-day injections, and epidural versus non-epidural route of injection. METHODS: The electronic health record and associated research databases were analyzed to identify patients who received a spinal CSI during three consecutive flu seasons, 2016 through 2019. Injections were stratified into epidural versus non-epidural CSI and single injections versus multiple same-day injections. Additionally, the rate of influenza in vaccinated versus non-vaccinated individuals was examined. Inpatient flu diagnosis was used as a proxy for severe disease. After case matching was completed, odds ratios for flu diagnosis were calculated using a logistical regression model. RESULTS: The odds of flu diagnosis following spinal CSI were not increased compared with controls (OR 0.93 [0.87-1.01, 95% Wald CL]). For epidural CSI the OR was 0.91 (0.83-1.00, 95% Wald CL), and non-epidural it was 1.00 (0.89-1.13, 95% Wald CL). There were similar findings for multiple same-day injections and when looking at inpatient flu diagnosis. For vaccinated individuals, the OR for flu following spinal CSI was 0.86 (0.80-0.92, 95% Wald CL), which indicates a protective effect in these patients. CONCLUSIONS: Spinal CSI did not increase the odds of subsequently receiving a diagnosis of influenza, regardless of vaccination status, location of injection, single versus multiple same-day injection, or co-morbidity. Vaccination had a protective effect against influenza, and this was not adversely affected by receiving spinal CSI during the flu season.

Spinal region corticosteroid injections are not associated with increased risk for influenza.

BACKGROUND CONTEXT: Spinal region corticosteroid injections (CSI) are intended to act locally to relieve radicular or axial back pain, however some systemic absorption occurs, potentially placing recipients at risk for immunosuppressive effects of corticosteroids. No previous studies examine whether patients undergoing spinal region CSI are at increased risk for viral infections, particularly influenza-a common viral illness with potentially serious consequences, especially for patients with multimorbidity. PURPOSE: To examine odds of influenza in patients who received spinal region CSI compared to matched controls. STUDY DESIGN: Retrospective cohort study. PATIENT SAMPLE: Adults (n=9,196) who received a spinal CSI (epidural, facet, sacroiliac, paravertebral block) during influenza seasons occurring from 2000 to 2020 were 1:1 matched to controls without spinal CSI. OUTCOME MEASURES: The primary outcome was odds of influenza diagnosis in spinal CSI patients compared to matched controls. Predetermined subgroup analyses examined odds of influenza diagnosis based on vaccination status and injection location. METHODS: An institutional database was queried to identify patients that received spinal CSI during influenza season (September 1 to April 30) from 2000 to 2020. Patients were matched by age, sex, and influenza vaccination status to controls without spinal CSI within the specified influenza season. Influenza diagnosis was ascertained using International Classification of Disease codes and data was analyzed using multiple logistic regression adjusted for comorbidities associated with increased risk for influenza. RESULTS: A total of 9,196 adults (mean age 60.8 years, 60.4% female) received a spinal CSI and were matched to a control. There were no increased odds of influenza for spinal CSI patients as compared to matched controls (OR 1.13, [95% CI, 0.86-1.48]). When subgroups were examined, there were also no increased odds of influenza for spinal CSI patients based on immunization status (unvaccinated or vaccinated) or spinal injection location (epidural or non-epidural). CONCLUSIONS: Spinal region CSI was not associated with increased odds of influenza or reduced vaccine efficacy. This is reassuring given the analgesic and functional restoration benefits of these injections. Assessing risk of viral infection associated with spinal CSI is particularly relevant in the era of the COVID-19 pandemic, and further work is needed to address this issue.

Vaccination Opportunities in Multiple Sclerosis Patients Treated with Cladribine Tablets.

COVID 19 pandemic and mass vaccination campaigns have revealed the situation of the most vulnerable patients. In this work, we focused our attention to patients who have Multiple Sclerosis (MS), particularly in treatment with cladribine tablets, trying to understand if and when it is possible to administer the vaccine successfully. In light of the novel topic, we studied the existing literature and analysed experiences with previous vaccinations, such as influenza and VZV, as well as data from countries where vaccination campaigns had already begun. Overall, we have taken into account the mechanism of action, the pharmacokinetic/pharmacodynamic of cladribine, and the changes in the immune system after its administration, together with the preliminary data about the humoral response to influenza, VZV, and SARS-CoV-2 vaccinations in cladribine treated patients. In conclusion, data showed that the use of cladribine tablets seems to permit flexibility regarding vaccination timing and we suggest that vaccination in those patients should be safe and effective. The current COVID 19 pandemic has re-ignited the interest in vaccines and vaccination procedures. The importance of including fragile individuals has increased as a result of mass vaccination. Millions of patients with multiple sclerosis (MS) around the world are debating whether they can safely receive their vaccine shot with the same efficacy despite receiving immune-modulating or immune-suppressive treatments. In the absence of conclusive empirical data, we will review and discuss the available evidence and the reasonable conclusions for one specific treatment, namely cladribine tablets (Mavenclad).

Long-term safety of brodalumab in Japanese patients with plaque psoriasis: An open-label extension study.

Brodalumab, an interleukin-17 receptor A inhibitor, demonstrated rapid and robust efficacy with a favorable safety profile in patients with moderate to severe plaque psoriasis. Here, we present data from a multicenter, open-label extension study in patients with plaque psoriasis with/without psoriatic arthritis who completed 64 weeks of treatment with brodalumab (140 or 210 mg, every 2 weeks [Q2W]). Patients were enrolled to evaluate the long-term safety and efficacy of a modified dose of brodalumab. Eligible patients were switched to a reduced dose of brodalumab (140 mg every 4 weeks on day 1) in the extension study; the dose and dosing interval were modified sequentially at the physician's discretion (minimum 140 mg every 8 weeks and maximum 210 mg Q2W) until drug approval, after which all patients were switched to 210 mg Q2W for postmarketing surveillance. Of the 129 patients enrolled, 107 (82.9%) completed the 108-week or more extension study. All patients had psoriasis that was well controlled with brodalumab treatment on day 1. Improvement in psoriasis-related symptoms, evaluated with the Psoriasis Area and Severity Index, Psoriasis Scalp Severity Index, Dermatology Life Quality Index, Nail Psoriasis Severity Index, and American College of Rheumatology 20, 50 and 70, was maintained during the 108-week extension study. Brodalumab treatment was well tolerated throughout, and no new safety signals were identified. The most commonly reported treatment-related adverse event was nasopharyngitis, followed by influenza and oral candidiasis. No cases of serious candida infection or Crohn's disease were observed in this study. Serious treatment-related adverse events, such as appendicitis, brain abscess, bacterial meningitis, colon cancer, immunoglobulin A nephropathy and tubulointerstitial nephritis, were reported in one patient each. No anti-brodalumab-binding antibodies or brodalumab-neutralizing antibodies were detected in any patient throughout the extension study. Overall, the long-term efficacy and safety of brodalumab were demonstrated over 108 weeks.

Impact of parental smoking on influenza and others respiratory infections in children.

BACKGROUND: The predisposition of cigarette smokers for the development of respiratory infections, including influenza, have been well documented. As well, those exposed to side stream smoke are prone to viral and bacterial infections of the respiratory tract. AIM: The study aimed to evaluate whether the prevalence of smoking parents is higher among children with respiratory tract infections, including influenza, in comparison to the general population. MATERIAL AND METHODS: Observational, cohort study. The authors surveyed a cohort of patients and their families, hospitalized in the Paediatric University Hospital in Warsaw during 2018 influenza season. Patients were diagnosed with influenza (using PCR) or other respiratory tract infections. A questionnaire on smoking habits was performed. RESULTS: Overall, 72 patients were included in the study, median age 2 years and 9 months (IQR: 1.4 - 7.2), influenza was diagnosed in 43% (n= 31) of patients. The percentage of regularly smoking parents in the whole cohort amounted to 33.3% (44 of 132) and was statistically significantly higher (p < 0.05) than in the general population (22.7%), whereas in the subgroup with influenza and non-influenza infections it reached 32.2% and 34.2%, respectively. CONCLUSIONS: The prevalence of smoking parents of children with acute respiratory tract infections is higher than in the general population: exposing children to tobacco smoke is one of the risk factors for acquiring influenza and others respiratory tract infections. Quitting smoking can decrease the risk of infectious diseases.

The DOT1L inhibitor Pinometostat decreases the host-response against infections: Considerations about its use in human therapy.

Patients with acute myeloid leukemia frequently present translocations of MLL gene. Rearrangements of MLL protein (MLL-r) in complexes that contain the histone methyltransferase DOT1L are common, which elicit abnormal methylation of lysine 79 of histone H3 at MLL target genes. Phase 1 clinical studies with pinometostat (EPZ-5676), an inhibitor of DOT1L activity, demonstrated the therapeutic potential for targeting DOT1L in MLL-r leukemia patients. We previously reported that down-regulation of DOT1L increases influenza and vesicular stomatitis virus replication and decreases the antiviral response. Here we show that DOT1L inhibition also reduces Sendai virus-induced innate response and its overexpression decreases influenza virus multiplication, reinforcing the notion of DOT1L controlling viral replication. Accordingly, genes involved in the host innate response against pathogens (RUBICON, TRIM25, BCL3) are deregulated in human lung epithelial cells treated with pinometostat. Concomitantly, deregulation of some of these genes together with that of the MicroRNA let-7B, may account for the beneficial effects of pinometostat treatment in patients with MLL-r involving DOT1L. These results support a possible increased vulnerability to infection in MLL-r leukemia patients undergoing pinometostat treatment. Close follow up of infection should be considered in pinometostat therapy to reduce some severe side effects during the treatment.

Potential effect of germanium exposure on the risk of influenza-like illness in housewives in Shanxi Province, China.

Few studies have examined the relationship between exposure to germanium (Ge) and the risk of influenza-like illness (ILI). Therefore, we investigated the association of Ge exposure and its interaction with single nucleotide polymorphisms (SNPs) related to Phase II metabolism on ILI risk among housewives in Shanxi Province, northern China. This cross-sectional study enrolled 373 housewives. Information on the housewives' characteristics and the frequency of ILI was collected by questionnaire. We analyzed the Ge concentrations in hair samples taken from near the scalp at the back of the head. Blood samples were used to identify SNPs related to Phase II metabolism. The results suggested that the hair Ge concentration was associated with ILI risk with an adjusted odds ratio and 95% confidence interval of 2.59 (1.61-4.19). A significant dose-response relationship was observed without or with adjusting for confounders. We did not observe any interaction effect between the hair Ge concentration and the SNPs on ILI risk. We found that high dietary consumption of meat and fried foods was positively correlated with the hair Ge concentration. Therefore, chronic Ge exposure may be a risk factor for an increased frequency of ILI in housewives.

First-in-Human Phase I Trial of a Tumor-Targeted Cytokine (NHS-IL12) in Subjects with Metastatic Solid Tumors.

PURPOSE: The NHS-IL12 immunocytokine is composed of two IL12 heterodimers fused to the NHS76 antibody. Preclinical studies have shown that this antibody targets IL12 to regions of tumor necrosis by binding histones on free DNA fragments in these areas, resulting in enhanced antitumor activity. The objectives of this phase I study were to determine the maximum tolerated dose (MTD) and pharmacokinetics of NHS-IL12 in subjects with advanced solid tumors. PATIENTS AND METHODS: Subjects (n = 59) were treated subcutaneously with NHS-IL12 in a single ascending-dose cohort followed by a multiple ascending-dose cohort (n = 37 with every 4-week dosing). RESULTS: The most frequently observed treatment-related adverse events (TRAE) included decreased circulating lymphocytes, increased liver transaminases, and flu-like symptoms. Of the grade ≥3 TRAEs, all were transient and only one was symptomatic (hyperhidrosis). The MTD is 16.8 µg/kg. A time-dependent rise in IFNγ and an associated rise in IL10 were observed following NHS-IL12. Of peripheral immune cell subsets evaluated, most noticeable were increases in frequencies of activated and mature natural killer (NK) cells and NKT cells. Based on T-cell receptor sequencing analysis, increases in T-cell receptor diversity and tumor-infiltrating lymphocyte density were observed after treatment where both biopsies and peripheral blood mononuclear cells were available. Although no objective tumor responses were observed, 5 subjects had durable stable disease (range, 6-30+ months). CONCLUSIONS: NHS-IL12 was well tolerated up to a dose of 16.8 µg/kg, which is the recommended phase II dose. Early clinical immune-related activity warrants further studies, including combination with immune checkpoint inhibitors.See related commentary by Lyerly et al., p. 9.

Management of flu-like syndrome with cetirizine in patients with relapsing-remitting multiple sclerosis during therapy with interferon beta: Results of a randomized, cross-over, placebo-controlled pilot study.

BACKGROUND: Flu-like syndrome (FLS) is a common adverse event experienced by patients with relapsing-remitting multiple sclerosis (RRMS) treated with interferon beta (IFNß). FLS can lead to poor treatment adherence and early IFNß discontinuation. The involvement of interleukin-6 (IL-6) in the occurrence of FLS has been suggested. We hypothesized that cetirizine, a second-generation histamine H1 receptor antagonist able to reduce the levels of IL-6, might improve IFNß-induced FLS. METHODS: We conducted a pilot, cross-over, randomized, placebo-controlled, double-blind study to evaluate the efficacy of cetirizine 10 mg added after each IFNß injection to the standard of care for FLS (acetaminophen or nonsteroidal anti-inflammatory drugs) on FLS in patients with RRMS treated with IFNß. Patients were randomized to two treatment sequences: 1) 4-week treatment with placebo added to the standard treatment for FLS, followed by 4-week treatment with cetirizine added to the standard of care, and 2) first addition of cetirizine, then of placebo. The primary efficacy endpoint was the mean change of FLS severity [11-point visual analog scale (VAS)] after 4 weeks of treatment within each sequence. RESULTS: Forty-five patients (71.1% female, mean age 39.1 years, mean time from RRMS diagnosis 5.8 years) were randomized to treatment sequences 1 and 2. The differences between cetirizine and placebo in the intensity of FLS were not statistically significant: total mean VAS scores at 4 hours from IFNß injection were 3.57 and 3.42 for cetirizine and placebo, respectively (difference -0.15; 95% confidence interval: from -0.74 to 0.44; p = 0.6029). The two treatments were similar also with regard to other efficacy measures considered and to the safety/tolerability profile. CONCLUSIONS: The addition of cetirizine to the standard of care for IFNß-induced FLS in patients with RRMS does not seem to provide significant benefits compared with placebo. Further effort is required to understand the mechanisms underlying IFNß-induced FLS. TRIAL REGISTRATION: EudraCT 2013-001055-12.

TRPV1 polymorphisms and risk of interferon ß-induced flu-like syndrome in patients with relapsing-remitting multiple sclerosis.

Interferon-ß (IFN-ß) is often discontinued in RRMS patients due to its most common side effect, the flu-like syndrome (FLS). The mechanisms underlying IFN ß-induced FLS symptoms are still unclear. The endocannabinoid system (ECS) is a key regulator of pain and inflammation. Thus we tested the hypothesis that the ECS could be involved in FLS severity by exploring the effect of genetic polymorphisms with functional impact on the ECS, on patient-reported FLS symptoms. GG-carriers of the transient-receptor-potential-vanilloid-1 (TRPV1) single nucleotide polymorphism rs222747 reported greater pain and weakness during FLS. This study suggests that the TRPV1 channel is involved in FLS severity.