A phase 1 trial of AP30663, a KCa2 channel inhibitor in development for conversion of atrial fibrillation.

AIMS: AP30663 is a novel compound under development for pharmacological conversion of atrial fibrillation by targeting the small conductance Ca2+ activated K+ (KCa2) channel. The aim of this extension phase 1 study was to test AP30663 at higher single doses compared to the first-in-human trial. METHODS: Sixteen healthy male volunteers were randomized into 2 cohorts: 6- and 8-mg/kg intravenous single-dose administration of AP30663 vs. placebo. Safety, pharmacokinetic and pharmacodynamic data were collected. RESULTS: AP30663 was associated with mild and transient infusion site reactions with no clustering of other adverse events but with an estimated maximum mean QTcF interval prolongation of 45.2 ms (95% confidence interval 31.5-58.9) in the 6 mg/kg dose level and 50.4 ms (95% confidence interval 36.7-64.0) with 8 mg/kg. Pharmacokinetics was dose proportional with terminal half-life of around 3 h. CONCLUSION: AP30663 in doses up to 8 mg/kg was associated with mild and transient infusion site reactions and an increase of the QTcF interval. Supporting Information support that the QTc effect may be explained by an off-target inhibition of the IKr channel.

One-Year Safety Evaluation of New Hyaluronic Acid Fillers (YYS Series): A Prospective, Multicenter, Observational Study.

BACKGROUND: With the continuous increasing availability of new filler products, each hyaluronic acid filler brand has distinctive pharmacokinetics, which may be associated with different complications. Therefore, the long-term safety of new generations of fillers should be evaluated. OBJECTIVE: This prospective, multicenter, observational, postmarketing study ( ClinicalTrials.gov identifier: NCT04738019) aimed to investigate the incidence of delayed-onset nodules and adverse reactions after the injection of new hyaluronic acid fillers (YYS series) into the facial skin. METHODS: Subjects scheduled to receive an injection YYS series filler were followed up for 52 weeks. The authors aimed to determine the incidence of a self-reported delayed-onset nodule-a visible or palpable nodule or mass at the injection site that was detected beyond the 14th day following the injection-during the 1-year follow-up period. RESULTS: Among the 1,022 subjects who received an injection of the YYS series, the incidences of delayed-onset nodules were 0% for YYS 360, YYS 540, and YYS 720. A 0.21% incidence (1 delayed hypersensitivity reaction) of a delayed-onset adverse reaction was noted for YYS 720, although none were reported for YYS 360 and YYS 540. CONCLUSION: In this study, a notably low frequency of adverse reactions associated with the YYS series was observed.

Treatment of Bullous Pemphigoid With Dupilumab: A Case Series of 30 Patients.

Bullous pemphigoid is often difficult to treat with the limited therapies available. Here, we describe clinical outcomes among 30 adults with bullous pemphigoid patients treated with dupilumab. We performed a multicenter, retrospective case series between March 2020 to August 2022. Patients received a loading dose of dupilumab 600 mg, followed by 300 mg maintenance dose with varying administration frequency tailored to individual patient response. All patients experienced at least some improvement in blister formation and pruritus, with 23 (76.7%) of patients demonstrating either complete clearance of blistering or marked response. Complete clearance of pruritus or marked response was noted in 25 (83.3%) of patients. Eight patients were effectively maintained solely on dupilumab. One (3.3%) patient reported an injection site reaction. Thirty patients represent a small sample, however, to our knowledge, this is the second largest group of BP treated with dupilumab. Furthermore, we provide an understandable framework for clinicians outside of academics to follow and assess treatment responses in their BP patients treated with dupilumab. Dupilumab should be considered as a therapeutic option in patients with bullous pemphigoid given its ability to induce sustained blistering and pruritus response in both typical and refractory cases while maintaining a favorable safety profile. J Drugs Dermatol. 2024;23(6):e144-e148. doi:10.36849/JDD.8258e.

Adverse Events Associated with Hyaluronic Acid Filler Injection for Non-surgical Facial Aesthetics: A Systematic Review of High Level of Evidence Studies.

BACKGROUND: Hyaluronic acid (HA) dermal fillers are widely used in aesthetic medicine. While generally safe, potential complications can arise. OBJECTIVE: This systematic review aims to identify and classify potential complications linked to the use of HA dermal fillers, as informed by high-quality, low-risk-of-bias studies. METHODS: This review follows the Cochrane review standards for clinical systematic reviews. This systematic review analyzed 48 high level of evidence studies on the use of hyaluronic acid (HA) dermal fillers in non-surgical facial aesthetics and the adverse events that occurred.The inclusion criteria were randomized control studies on HA dermal fillers and their complications. Excluded were case reports, case series, observational studies, and other non-randomized research due to their inability to provide generalized conclusions and their inherent publication bias. RESULTS: Adverse events were classified into three categories: expected reactions, product or technique-related adverse events, and severe adverse events. Most adverse events were short-lived injection site reactions, which resolved spontaneously. Specific HA fillers and injection techniques influenced the occurrence of adverse events, which generally resolved within weeks without treatment. Severe adverse events were rare, persisting for months and requiring active medical intervention. DISCUSSION: This classification system can enhance understanding, prevention, and treatment of HA filler complications, and support patient education. The common complications were injection site reactions, with persistent symptoms treated with topical steroids, NSAIDs, or hyaluronidase. Severe complications included severe edema, angioedema and others, often necessitating specific treatments. CONCLUSION: HA dermal fillers are generally safe and effective, with most adverse events being transient and mild to moderate in severity. Severe adverse events, although rare, do occur and are generally non-treatment related. Informed consent, patient education, and professional training are crucial for safe and successful outcomes. Level of Evidence II This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Prevention of nodules and enhancement of antibody response to genetically engineered recombinant vaccine against Human Chorionic Gonadotropin (hCG) for contraception.

OBJECTIVE: Human Chorionic Gonadotropin (hCG) plays a crucial role in embryo implantation and in maintenance of pregnancy. An immuno-contraceptive approach involves the use of a recombinant hCGß-LTB vaccine formulated with adjuvant Mycobacterium indicus pranii (MIP), to prevent pregnancy without disturbing ovulation, hormonal profiles, and menstrual cycles in women. The present work in mice was designed to address issues encountered in clinical trials conducted with hCGß-LTB vaccine, with focus on two primary concerns. Firstly, it aimed to determine the optimal vaccine dosage required to induce a high level of anti-hCG antibodies. Secondly, it aimed to assess the safety profile of the vaccine, specifically injection site reactions in the form of nodules, observed in some of the subjects. METHODS AND RESULTS: Studies undertaken indicate that a 2 µg dose of the protein version of the vaccine, administered in mice through the intramuscular route, can induce high anti-hCG titres. Furthermore, administering a booster dose enhances the antibody response. Our findings suggest that the concentration and frequency of administration of the adjuvant MIP can also be reduced without compromising vaccine efficacy. CONCLUSION: The issue of nodule formation at the injection site can be mitigated either by administering the vaccine along with MIP intramuscularly or injecting hCG vaccine and MIP at separate intradermal sites. Thus, protein vaccine administered at a 2µg dose via the intramuscular route addresses both efficacy and safety concerns.

The Phase I/II clinical trials initiated with the recombinant hCG vaccine in women revealed inadequate antibody titres in all subjects, alongside the development of nodules at the injection sites in some participants. Studies were undertaken in mice to propose potential strategies for mitigating injection site reactions and enhancing the antibody response. It was concluded that the optimum dose of the protein version of the vaccine to get high antibody titres, is 2 µg administered intramuscularly while upholding safety standards.

The Use of Facial Fillers in Clinical Practice: The Level of Patient Satisfaction and an Overview of Common Clinical Complications. / [Artículo traducido] Uso de rellenos faciales en la práctica clínica: nivel de satisfacción del paciente y visión general de las complicaciones clínicas comunes.

BACKGROUND: Patient esthetic satisfaction following facial fillers is an essential topic that should be studied as the number of individuals seeking treatment increases. The face is an essential component of the human body that is frequently associated with beauty, youthfulness, and health. Individuals may seek facial augmentation with fillers for a variety of reasons, such as congenital, acquired by means of aging or disease, or current aesthetic trends. OBJECTIVE: The aim is to assess patient's aesthetic satisfaction and description of common clinical complications in relation to the facial filler injections. METHOD: A cross sectional survey using a questionnaire derived from the global aesthetic improvement scale and WHO quality of life scale, convenience sampling was used to recruit patients attending cosmetic clinics, descriptive analysis and Chi-square methods were used to analyze the data. RESULTS: In the study, 500 female participants, with an average age of 28.48 years, were included. Over 90% reported improvement after filler treatment, ranging from improved to very much improved. A statistically significant correlation was observed between patient satisfaction and the number of filler treatments and the anatomical injection site. However, no statistically significant correlation was found when considering age groups. Local side effects, such as swelling and redness at the injection site, were common but generally mild and of short duration. CONCLUSION: Although the satisfaction level is currently high, practitioners in the field need to pay more attention to this important outcome, since understanding the patient's motivation and expectation before proceeding with the procedure is very important and can contribute significantly in determining patient satisfaction with the result.

Effect of Vupanorsen on Non-High-Density Lipoprotein Cholesterol Levels in Statin-Treated Patients With Elevated Cholesterol: TRANSLATE-TIMI 70.

BACKGROUND: Genetic loss-of-function variants in ANGPTL3 are associated with lower levels of plasma lipids. Vupanorsen is a hepatically targeted antisense oligonucleotide that inhibits Angiopoietin-like 3 (ANGPTL3) protein synthesis. METHODS: Adults with non-high-density lipoprotein cholesterol (non-HDL-C) ≥100 mg/dL and triglycerides 150 to 500 mg/dL on statin therapy were randomized in a double-blind fashion to placebo or 1 of 7 vupanorsen dose regimens (80, 120, or 160 mg SC every 4 weeks, or 60, 80, 120, or 160 mg SC every 2 weeks). The primary end point was placebo-adjusted percentage change from baseline in non-HDL-C at 24 weeks. Secondary end points included placebo-adjusted percentage changes from baseline in triglycerides, low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (ApoB), and ANGPTL3. RESULTS: Two hundred eighty-six subjects were randomized: 44 to placebo and 242 to vupanorsen. The median age was 64 (interquartile range, 58-69) years, 44% were female, the median non-HDL-C was 132.4 (interquartile range, 118.0-154.1) mg/dL, and the median triglycerides were 216.2 (interquartile range, 181.4-270.4) mg/dL. Vupanorsen resulted in significant decreases from baseline over placebo in non-HDL-C ranging from 22.0% in the 60 mg every 2 weeks arm to 27.7% in the 80 mg every 2 weeks arm (all P<0.001 for all doses). There were dose-dependent reductions in triglycerides that ranged from 41.3% to 56.8% (all P<0.001). The effects on LDL-C and ApoB were more modest (7.9%-16.0% and 6.0%-15.1%, respectively) and without a clear dose-response relationship' and only the higher reductions achieved statistical significance. ANGPTL3 levels were decreased in a dose-dependent manner by 69.9% to 95.2% (all P<0.001). There were no confirmed instances of significant decline in renal function or platelet count with vupanorsen. Injection site reactions and >3× elevations of alanine aminotransferase or aspartate aminotransferase were more common at higher total monthly doses (up to 33.3% and 44.4%, respectively), and there was a dose-dependent increase in hepatic fat fraction (up to 76%). CONCLUSIONS: Vupanorsen administered at monthly equivalent doses from 80 to 320 mg significantly reduced non-HDL-C and additional lipid parameters. Injection site reactions and liver enzyme elevations were more frequent at higher doses, and there was a dose-dependent increase in hepatic fat fraction. REGISTRATION: URL: https://clinicaltrials.gov; Unique identifier: NCT04516291.

Adverse Events and Serological Responses After SARS-CoV-2 Vaccination in Individuals With Inflammatory Bowel Disease.

INTRODUCTION: We determined adverse events after 4 doses of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccine in those with inflammatory bowel disease (IBD), associations between antibodies and injection site reactions (ISR), and risk of IBD flare. METHODS: Individuals with IBD were interviewed for adverse events to SARS-CoV-2 vaccine. Multivariable linear regression assessed the association between antibody titers and ISR. RESULTS: Severe adverse events occurred in 0.03%. ISR were significantly associated with antibody levels after the fourth dose (geometric mean ratio = 2.56; 95% confidence interval 1.18-5.57). No cases of IBD flare occurred. DISCUSSION: SARS-CoV-2 vaccines are safe for those with IBD. ISR after the fourth dose may indicate increased antibodies.

Injection site vaccinology of a recombinant vaccinia-based vector reveals diverse innate immune signatures.

Poxvirus systems have been extensively used as vaccine vectors. Herein a RNA-Seq analysis of intramuscular injection sites provided detailed insights into host innate immune responses, as well as expression of vector and recombinant immunogen genes, after vaccination with a new multiplication defective, vaccinia-based vector, Sementis Copenhagen Vector. Chikungunya and Zika virus immunogen mRNA and protein expression was associated with necrosing skeletal muscle cells surrounded by mixed cellular infiltrates. The multiple adjuvant signatures at 12 hours post-vaccination were dominated by TLR3, 4 and 9, STING, MAVS, PKR and the inflammasome. Th1 cytokine signatures were dominated by IFNγ, TNF and IL1ß, and chemokine signatures by CCL5 and CXCL12. Multiple signatures associated with dendritic cell stimulation were evident. By day seven, vaccine transcripts were absent, and cell death, neutrophil, macrophage and inflammation annotations had abated. No compelling arthritis signatures were identified. Such injection site vaccinology approaches should inform refinements in poxvirus-based vector design.

PD-L1 expression predicts efficacy in the phase II SPiReL trial with MVP-S, pembrolizumab, and low-dose CPA in R/R DLBCL.

BACKGROUND: Patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) have limited treatment options. METHODS: R/R DLBCL patients, who were mostly ineligible for ASCT due to age or comorbidities, were treated with maveropepimut-S (MVP-S, previously DPX-Survivac) a survivin directed T cell educating therapy, pembrolizumab, and intermittent low-dose cyclophosphamide. FINDINGS: We identified, using univariate analysis, a subset of patients with enhanced ORR, PFS and DOR. Patients with baseline CD20+/PD-L1 expression had an ORR of 46% (6/13) and the disease control rate was 10/13 (77%). The PFS and OS of the positive CD20+/PD-L1 patients were 7.1 months and 17.4 months, whereas in the intent-to-treat (ITT) population of 25 enrolled patients, the ORR was 28% (7/25), median PFS and OS were 4.2 months and 10.1 months respectively. A total of 6/7 clinical responders occurred in CD20+/PD-L1 patients. The regimen was well-tolerated, requiring only minor dose modifications and one discontinuation. Grade 1 or 2 injection site reactions occurred in 14/25, (56%). Statistically significant associations were also seen between PFS and; injection site reactions; and ELISpot response to survivin peptides, both identifying the mechanistic importance of specific immune responses to survivin. INTERPRETATION: This immunotherapy combination was found to be active and safe in this clinically challenging patient population.

Adverse reactions following MPox (monkeypox) vaccination: An overview from the Dutch and global adverse event reporting systems.

AIMS: The spreading of MPox (monkeypox) virus led to a vaccination campaign in the Netherlands for individuals at high risk of infection. This overview elucidates the characteristics of the reported adverse events following immunization (AEFI) following active immunization against monkeypox and thereby provides insight on the safety profile in daily practice. METHODS: Data were collected from the spontaneous reporting system of the Netherlands Pharmacovigilance Centre Lareb. Furthermore, the global database of the World Health Organization was consulted on globally reported AEFI following smallpox or monkeypox immunization in 2022. RESULTS: Until 15 November 2022, 148 unique individual case safety reports (ICSRs) regarding monkeypox vaccination were received at Lareb. Two ICSRs reported a serious outcome (1.4%). A total of 2205 ICSRs were received in the global database in 2022, of which 131 reports (5.9%) concerned a serious reaction. Reported AEFI in both databases mainly included injection site reactions and general systemic reactions commonly observed after vaccination. CONCLUSION: The pattern of reported AEFI for monkeypox vaccines both in the Dutch and global ICSR database is generally in accordance with the manufacturer's product information and consists largely of injection site reactions and nonserious AEFI related to systemic reactogenicity.

Real-world evidence of fremanezumab for treating migraine in Japan: a retrospective study.

BACKGROUND: There have been very few real-world studies reported in the literature solely focusing on fremanezumab in Asia. This study aimed to evaluate the efficacy and safety of fremanezumab in a real-world setting in Japan. METHOD: This single-centered, observational, retrospective study examined patients with migraines who received four doses of fremanezumab between December 2021 and August 2022 at Keio University Hospital. We assessed the changes in monthly migraine days, responder rates, and migraine-associated symptoms, as well as injection site reactions and adverse events. RESULT: Twenty-nine patients were enrolled, wherein 79.3% were women. Compared with those at baseline, the monthly migraine days decreased by 5.9 days at 4 months. The 50% responder rate was 55.2% at 4 months. A total of 57.9%, 47.8%, and 65.0% of patients showed improvement in the severity of photophobia, phonophobia, and nausea/vomiting, respectively. Moreover, injection site reactions were the most common adverse events (55.2%). CONCLUSION: Fremanezumab is effective and safe for migraine prevention in Japan. Fremanezumab also improved migraine-associated symptoms in half of the patients.

Metallothionein expression in feline injection site fibrosarcomas.

BACKGROUND: Feline injection site fibrosarcoma is an aggressive and infiltrative tumour arising in the background of chronic inflammation. The aim of this study was to evaluate the expression of metallothionein (I-II) in feline injection site fibrosarcomas and to assess its possible relationships with Ki67 index, inflammation score and tumour grade. The study included 40 feline fibrosarcomas, located in the common injection sites (i.e., interscapular area, thigh, flank), constituting archival diagnostic specimens collected between 2019-2020. Tumours were graded histologically according to the newly proposed soft-tissue sarcoma grading system in cats. Immunohistochemistry was performed to evaluate the expression of Ki67 and metallothionein in tumour cells. RESULTS: The cytoplasmic and sometimes nuclear expression of metallothionein was observed in all tumours grade I, 66.67% of tumours grade II and 55% of tumours grade III. The expression of metallothionein was negatively correlated with tumour grade and inflammation score, while the Ki67 index was positively correlated with tumour grade, inflammation score and necrosis score. CONCLUSION: The downregulation of MT expression in feline injection site fibrosarcomas seems to be connected with an increase in the inflammatory infiltration, hence tumour progression. This is the first study describing metallothionein expression in feline injection site fibrosarcomas.

Injection Site Reaction to Various Insulins as Type III Allergy With Urticarial Vasculitis in a Patient With Type I Diabetes Mellitus.

ABSTRACT: Injection site reactions are defined as skin reactions at the injection site to drugs administered subcutaneously. Pathophysiologically, these reactions are based on different immunological mechanisms. We report the case of a 49-year-old patient with type 1 diabetes mellitus (first diagnosis in 1994 at the age of 23 years). Continuous subcutaneous insulin infusion using an insulin pump has been used for many years. The patient presented to the department of dermatology with progressive symptoms in the area of the insulin injection sites on the lower abdomen, accompanied by pain, burning, erythema, tenderness, and the formation of subcutaneous nodules. Previous attempts to use different insulins and to change the injection sites did not improve his symptoms. Furthermore, the symptoms appeared within hours after the insulin pump was attached, so that the injection site has to be changed as soon as every 48 hours. No anaphylactic shock was reported at any time. Multiple histological specimens were obtained from an older lesion on the abdomen as well as from test sites after standard allergological tests (prick and intradermal tests) of various insulins. Histologically, these biopsies showed the image of an extensive deep-reaching small vessel vasculitis with the aspect of an urticarial vasculitis and confirmed the diagnosis of an injection-site reaction that can be characterized as a type III hypersensitivity reaction.

A Qualitative Study on Dupilumab's Impact on Atopic Dermatitis Among Adolescent and Adult Patients.

BACKGROUND: Atopic dermatitis (AD) is the most common inflammatory skin disease and dupilumab is US Food and Drug Administration-approved in both adult and pediatric AD patients. OBJECTIVE: To qualitatively assess the life experiences and impact of treatment in adult and adolescent patients with AD being treated with dupilumab. METHODS: Sixteen semi-structured interviews were conducted with adult (n=9) and adolescent (n=7) participants who had received a diagnosis of AD between 1/1/2017 and 1/1/2022 after they had received treatment with dupilumab. Results were analyzed using qualitative research methods. RESULTS: Most participants reported frustration with daily topical medications and starting dupilumab after exhausting other treatment options. Before treatment, participants described severe AD, social anxiety, and decreased self-esteem. Although most participants did not experience complete resolution of AD after treatment, all participants described a profound decrease in the physical and psychosocial burden of their disease. Participant satisfaction was high with dupilumab treatment. Injection-related pain was commonly reported as the most negative aspect of treatment. DISCUSSION: AD was physically and psychosocially debilitating in our cohort. Dupilumab offered an efficacious treatment for these patients and helped improve the physical and psychosocial burden of their disease. J Drugs Dermatol. 2023;22(2):148-153. doi:10.36849/JDD.7053.

A Systematic Review and Meta-Analysis of Injection Site Reactions in Randomized-Controlled Trials of Biologic Injections.

BACKGROUND: Biologic agents are emerging as an important treatment option for immune-mediated diseases. Injection site reactions following subcutaneous injection of biologic agents is not well described in the literature. OBJECTIVE: To summarize injection site reaction data in phase 3 trials of all biologic agents. METHODS: MEDLINE, Embase, and CENTRAL databases were systematically searched on February 8, 2022. Proportional meta-analysis was conducted to summarize injection site reaction prevalence for each biologic. RESULTS: There were 158 articles included in the review. The most common types of injection site reactions were erythema (42.8%), unspecified reaction (23.3%), pain (12.4%), and pruritus (5.7%). No patients discontinued their treatment due to injection site reactions in 39 of the 48 studies that reported on discontinuation data. There were 16 biologics included in meta-analysis across 80 eligible studies. The biologics with the highest point prevalence of patients reporting injection site reactions were Canakinumab (15.5%; 294 patients), Dupilumab (11.4%; 1888 patients), Etanercept (11.4%; 4363 patients), and Ixekizumab (11.2%; 2205 patients). The biologics with the lowest point prevalence of injection site reactions were Risankizumab (0.8%; 707 patients), Brodalumab (1.3%; 1365 patients), Guselkumab (1.3%; 1852 patients), Secukinumab (1.9%; 1277 patients). CONCLUSIONS: The prevalence of injection site reaction in response to biologics ranges from 0.08 to 15.5%. Canakinumab, Dupilumab, Etanercept, and Ixekizumab had the highest prevalence of injection site reactions. Risankizumab, Brodalumab, Guselkumab, and Secukinumab had the lowest prevalence of injection site reactions. Recommendations are made regarding the improvement of adverse event reporting to better understand the epidemiology of injection site reactions.

Adverse events following the first, second and third doses of a COVID-19 vaccine in hemodialysis patients.

BACKGROUND: This study aimed to identify adverse events following the first three doses of COVID-19 vaccines in hemodialysis (HD) patients. Risk factors associated with postvaccination adverse events were explored. METHODS: Postvaccination adverse events in 438 HD patients who received 3 doses of COVID-19 vaccines were prospectively assessed. The adverse events among three doses were compared using generalized linear mixed models. Factors associated with adverse events were assessed with multivariate analyses. RESULTS: The vast majority of participants received Oxford/AstraZeneca ChAdOx1 as their first two doses and Moderna mRNA-1273 as their third dose. Overall, 79%, 50% and 84% of the participants experienced at least one adverse event after their first, second, and third doses, respectively. These adverse events were mostly minor, short-lived and less than 5% reported daily activities being affected. Compared with the first dose, the second dose caused a lower rate of adverse events. Compared with the first dose, the third dose elicited a higher rate of injection site reactions and a lower rate of systemic reactions. Multivariate analyses showed that every 10-year increase of age (odds ratio 0.67, 95% confidence intervals 0.57-0.79) was associated with decreased risk of adverse events, while female sex (2.82, 1.90-4.18) and arteriovenous fistula (1.73, 1.05-2.84) were associated with increased risk of adverse events. Compared with Oxford/AstraZeneca ChAdOx1, Moderna mRNA-1273 was associated with an increased risk of injection site reactions. CONCLUSIONS: COVID-19 vaccination was well tolerated in HD patients. Age, sex, dialysis vascular access and vaccine types were associated with postvaccination adverse events.

Incidence and Characteristics of Delayed Injection Site Reaction to the mRNA-1273 Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Vaccine (Moderna) in a Cohort of Hospital Employees.

BACKGROUND: mRNA SARS-CoV-2 vaccines are administered to 2 million individuals per day in the United States under US Food and Drug Administration emergency use authorization. METHODS: Observational cohort study of hospital employees who received their first SARS-CoV-2 mRNA vaccination between 14 December 2020 and 8 January 2021, including employees who reported onset of an injection site reaction ≥48 hours after administration of their first or second dose to an employee hotline. RESULTS: Thirteen female employees who received the mRNA-1273 vaccine (Moderna) during the first 3 weeks of the SARS-CoV-2 vaccine rollout at San Francisco General Hospital reported a pruritic rash at the injection site appearing 3 -9 days after receipt of their initial dose. Five had milder or similar reactions with earlier onset after the second dose. One additional female employee reported this delayed reaction only after the second dose. None reported serious adverse events or had symptoms severe enough to seek medical attention. These cases represented 1.1% of the 1275 female employees who received their first mRNA-1273 dose and 2.0% of the 557 who were aged 31 -45 years during this initial vaccine rollout. None of 675 males who initiated mRNA-1273 or 3612 employees of any sex who initiated BNT162b (Pfizer) vaccination during this period reported delayed-onset reactions. CONCLUSIONS: These results suggest that delayed-onset, injection site pruritic rashes after mRNA-1273 SARS-CoV-2 vaccine administration, lasting up to 1 week, occur commonly in females, do not lead to serious sequela, and should not deter receipt of the second vaccine dose.

The comparative safety of human papillomavirus vaccines: A Bayesian network meta-analysis.

BACKGROUND AND AIMS: The safety of human papillomavirus (HPV) vaccines, one of the major challenges to public vaccination, has been controversial. This study assessed the adverse reactions of various HPV vaccines, including bivalent HPV (2vHPV), quadrivalent HPV (4vHPV), and 9-valent HPV (9vHPV) vaccines. METHODS: PubMed, Embase, and Central databases were searched for randomized controlled trials (RCTs) on the comparative safety of HPV vaccines. A network meta-analysis was performed based on the Bayesian framework random-effects model. RESULTS: This study included 23 RCTs. Analysis across these reports indicated that the 2vHPV vaccine was associated with significantly more systemic adverse events than the 4vHPV vaccine (risk ratio [RR]: 1.28, 95% credible interval [CrI]: 1.14-1.44), 9vHPV vaccine (RR: 1.25, 95% CrI: 1.06-1.49), and placebo (RR: 1.31, 95% CrI: 1.18-1.46). However, there were no statistically significant differences in serious adverse events between the vaccinated and placebo groups. For injection-site adverse events, there were substantial inconsistencies between the direct and indirect effects; therefore, the analysis results of the safety were presented only for systemic and serious adverse events. CONCLUSIONS: The 2vHPV vaccine resulted in more systemic adverse events than other vaccines and placebo. No significant differences in serious adverse events were observed. Further studies are needed to obtain more information regarding the safety of HPV vaccines.

Real world risk of infusion reactions and effectiveness of front-line obinutuzumab plus chlorambucil compared with other frontline treatments for chronic lymphocytic leukemia.

BACKGROUND: Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in North America. Previous studies have shown improved progression free survival (PFS) and response rates in unfit patients treated with obinutuzumab compared to other regimens. The aim of this study was to evaluate the obinutuzumab-chlorambucil regimen in the context of historical treatments and first-dose infusion reactions at CancerCare Manitoba (CCMB). METHODS: A retrospective chart review was conducted for patients treated with obinutuzumab from January 1, 2014 to December 31, 2017 at CCMB. A minimum data set was extracted for patients treated with other front-line therapies. Descriptive statistics were used to evaluate patient demographics, toxicity, duration and dosing of obinutuzumab treatment. Kaplan-Meier curves were used to evaluate time-to-next-treatment (TTNT), overall survival (OS) and PFS for patients treated with obinutuzumab. A multivariable logistic regression model was used to investigate associations between infusion related reactions (IRRs) and age at treatment, pre-treatment lymphocyte count, cumulative illness rating scale (CIRS) and receipt of prior chemotherapy. RESULTS: Forty seven percent of patients receiving frontline therapy received chlorambucil and obinutuzumab. Sixty-seven patients were treated with obinutuzumab and consisted of 36 males (53.7%) and 31 females (46.3%) with 29 patients (43.3%) over age 75 years. Rates of grade 3 and 4 obinutuzumab IRRs were lower (6%) compared to the CLL11 clinical trial (20%) due to local practices including slower infusion rates and using chlorambucil before starting obinutuzumab treatment. Many patients had difficulty tolerating the full dosage of chlorambucil. Only 26 patients (38.8%) had their dose of chlorambucil escalated to the full dose of 0.5 mg/kg. In addition, only 18 patients (26.9%) received all doses of obinutuzumab and all 12 doses of chlorambucil. CONCLUSIONS: In summary, first dose infusion reactions with obinutuzumab can be markedly reduced by using chlorambucil to decrease the lymphocyte count before obinutuzumab and by using a very slow initial obinutuzumab infusion rate. Modifications in chlorambucil dosing and obinutuzumab administration can improve tolerance without significant loss in efficacy.