Potential role of the intratumoral microbiota in colorectal cancer immunotherapy.

Colorectal cancer (CRC) has been one of the most common malignancies worldwide. Despite the advances in current therapies, the mortality rate of CRC remains high. Among them, immunotherapy has achieved satisfactory results in some CRC patients, however, how to expand the use of immunotherapy in CRC patients remains an urgent challenge. Surprisingly, the intratumoral microbiota has been found in multiple tumor tissues, including CRC. It has been demonstrated that the intratumoral microbiota is associated with the progression and treatment of CRC, and is able to enhance or decrease anti-tumor immune responses via different mechanisms as well as influence the immunotherapy efficacy, providing new potential therapeutic targets for CRC immunotherapy. In this review, we focus on the characteristics of the intratumoral microbiota, its roles in the genesis and development of CRC, its modulation of anti-tumor immune responses and immunotherapy, and propose potential applications of the intratumoral microbiota in CRC immunotherapy. Additionally, we propose possible directions for future research on the intratumoral microbiota related to CRC immunotherapy.

Microbes in the tumor microenvironment: New additions to break the tumor immunotherapy dilemma.

Immunotherapies currently used in clinical practice are unsatisfactory in terms of therapeutic response and toxic side effects, and therefore new immunotherapies need to be explored. Intratumoral microbiota (ITM) exists in the tumor environment (TME) and reacts with its components. On the one hand, ITM promotes antigen delivery to tumor cells or provides cross-antigens to promote immune cells to attack tumors. On the other hand, ITM affects the activity of immune cells and stromal cells. We also summarize the dialog pathways by which ITM crosstalks with components within the TME, particularly the interferon pathway. This interaction between ITM and TME provides new ideas for tumor immunotherapy. By analyzing the bidirectional role of ITM in TME and combining it with its experimental and clinical status, we summarized the adjuvant role of ITM in immunotherapy. We explored the potential applications of using ITM as tumor immunotherapy, such as a healthy diet, fecal transplantation, targeted ITM, antibiotics, and probiotics, to provide a new perspective on the use of ITM in tumor immunotherapy.

Development and biological characterization of an infectious cDNA clone of NADC34-like PRRSV.

Introduction: Porcine Reproductive and Respiratory Syndrome virus (PRRSV) causes high abortion rates in gestating sows and stillbirths, as well as high piglet mortality, seriously jeopardizing the pig industry in China and worldwide. Methods: In this study, an infectious clone containing the full-length genome of NADC34-like PRRSV was constructed for the first time using reverse genetic techniques. The gene was amplified segmentally onto a plasmid, transfected into BHK-21 cells, and the transfected supernatant was harvested and transfected into PAM cells, which showed classical cytopathic effects (CPE). Results: The virus rJS-KS/2021 was successfully rescued which could be demonstrated by Western Blot and indirect immunofluorescence assays. Its growth curve was similar to the original strain. Replace the 5'UTR and 3'UTR of rJS-KS/2021 with 5'UTR and 3'UTR of HP-PRRSV (strain SH1) also failed to propagate on MARC-145. Discussion: In this study, an infectious clone of NADC34-like was constructed by reverse genetics, replacing the UTR and changing the cellular tropism of the virus. These findings provide a solid foundation for studying the recombination of different PRRSVs and the adaption of PRRSVs on MARC-145 in the future.

Role of imbalanced gut microbiota in promoting CRC metastasis: from theory to clinical application.

Metastasis poses a major challenge in colorectal cancer (CRC) treatment and remains a primary cause of mortality among patients with CRC. Recent investigations have elucidated the involvement of disrupted gut microbiota homeostasis in various facets of CRC metastasis, exerting a pivotal influence in shaping the metastatic microenvironment, triggering epithelial-mesenchymal transition (EMT), and so on. Moreover, therapeutic interventions targeting the gut microbiota demonstrate promise in enhancing the efficacy of conventional treatments for metastatic CRC (mCRC), presenting novel avenues for mCRC clinical management. Grounded in the "seed and soil" hypothesis, this review consolidates insights into the mechanisms by which imbalanced gut microbiota promotes mCRC and highlights recent strides in leveraging gut microbiota modulation for the clinical prevention and treatment of mCRC. Emphasis is placed on the considerable potential of manipulating gut microbiota within clinical settings for managing mCRC.

The value of intratumoral microbiota in the diagnosis and prognosis of tumors.

Intratumoral microbiota (ITM) are microorganisms present in tumor cells. ITM participate in tumor development by affecting tumor cells directly and the tumor microenvironment (TME), indirectly. Alterations in ITM instigate changes in tumor DNA, activate oncogenic pathways, induce tumor inflammatory responses, disrupt normal immune activity, and facilitate the secretion of effectors leading to tumor progression, metastasis, or diminished therapeutic effects. ITM varies significantly in different types of cancer cells and disease states. The presence of certain ITM serves as a predictor of various disease states. Thus, ITM predicts tumorigenesis, tumor grade, treatment efficacy, and prognosis, making it a potential tumor biomarker. The present study aimed to determine the mechanisms by which ITM affects tumor development, especially through the TME; highlight the significant potential of ITM in enhancing tumor diagnosis and prognosis; and outline future directions for ITM research, with a focus on the development of innovative tumor markers.

Symbiotic microbial communities in various locations of the lung cancer respiratory tract along with potential host immunological processes affected.

Lung cancer has the highest mortality rate among all cancers worldwide. The 5-year overall survival rate for non-small cell lung cancer (NSCLC) is estimated at around 26%, whereas for small cell lung cancer (SCLC), the survival rate is only approximately 7%. This disease places a significant financial and psychological burden on individuals worldwide. The symbiotic microbiota in the human body has been significantly associated with the occurrence, progression, and prognosis of various diseases, such as asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis. Studies have demonstrated that respiratory symbiotic microorganisms and their metabolites play a crucial role in modulating immune function and contributing to the pathophysiology of lung cancer through their interactions with the host. In this review, we provide a comprehensive overview of the microbial characteristics associated with lung cancer, with a focus on the respiratory tract microbiota from different locations, including saliva, sputum, bronchoalveolar lavage fluid (BALF), bronchial brush samples, and tissue. We describe the respiratory tract microbiota's biodiversity characteristics by anatomical region, elucidating distinct pathological features, staging, metastasis, host chromosomal mutations, immune therapies, and the differentiated symbiotic microbiota under the influence of environmental factors. Our exploration investigates the intrinsic mechanisms linking the microbiota and its host. Furthermore, we have also provided a comprehensive review of the immune mechanisms by which microbiota are implicated in the development of lung cancer. Dysbiosis of the respiratory microbiota can promote or inhibit tumor progression through various mechanisms, including DNA damage and genomic instability, activation and regulation of the innate and adaptive immune systems, and stimulation of epithelial cells leading to the upregulation of carcinogenesis-related pathways.

Shift in dominant genotypes of Japanese encephalitis virus and its impact on current vaccination strategies.

Japanese encephalitis (JE) is a zoonotic ailment from the Japanese encephalitis virus (JEV). JEV belongs to the flavivirus genus and is categorized into a solitary serotype consisting of five genetically diverse genotypes (I, II, III, IV, and V). The JEV genotype III (GIII) was the prevailing strain responsible for multiple outbreaks in countries endemic to JEV until 1990. In recent years, significant improvements have occurred in the epidemiology of JE, encompassing the geographical expansion of the epidemic zone and the displacement of prevailing genotypes. The dominant genotype of the JEV has undergone a progressive shift from GIII to GI due to variations in its adaptability within avian populations. From 2021 to 2022, Australia encountered an epidemic of viral encephalitis resulting from infection with the GIV JEV pathogen. The current human viral encephalitis caused by GIV JEV is the initial outbreak since its initial discovery in Indonesia during the late 1970s. Furthermore, following a time frame of 50 years, the detection and isolation of GV JEV have been reported in Culex mosquitoes across China and South Korea. Evidence suggests that the prevalence of GIV and GV JEV epidemic regions may be on the rise, posing a significant threat to public safety and the sustainable growth of animal husbandry. The global approach to preventing and managing JE predominantly revolves around utilizing the GIII strain vaccine for vaccination purposes. Nevertheless, research has demonstrated that the antibodies generated by the GIII strain vaccine exhibit limited capacity to neutralize the GI and GV strains. Consequently, these antibodies cannot protect against JEV challenge caused by animal GI and GV strains. The limited cross-protective and neutralizing effects observed between various genotypes may be attributed to the low homology of the E protein with other genotypes. In addition, due to the GIV JEV outbreak in Australia, further experiments are needed to evaluate the protective efficiency of the current GIII based JE vaccine against GIV JEV. The alteration of the prevailing genotype of JEV and the subsequent enlargement of the geographical extent of the epidemic have presented novel obstacles in JE prevention and control. This paper examines the emerging features of the JE epidemic in recent years and the associated problems concerning prevention and control.

One-Year and 18-Month Outcomes in nAMD Patient Eyes Switched to Brolucizumab Alone versus to Brolucizumab Alternating with Other Anti-VEGF Agents.

Objective: Retrospective, real-world study to evaluate visual acuity (VA), anti-vascular endothelial growth factor (anti-VEGF) injection intervals, and central macular thickness (CMT) in neovascular age-related macular degeneration (nAMD) eyes switched to brolucizumab only or to brolucizumab alternating with another anti-VEGF. Methods: The overall study population comprised eyes that were given ≥1 brolucizumab injection between 1 October 2019 and 30 November 2021. The brolucizumab-only (BRO) cohort consisted of prior anti-VEGF-treated eyes treated exclusively with ≥3 brolucizumab injections over ≥12 or ≥18 months; the alternating brolucizumab (ALT) cohort comprised prior anti-VEGF-treated eyes treated with ≥2 brolucizumab injections and ≥1 other anti-VEGF over ≥12 or ≥18 months. Results: A total of 482 eyes received ≥1 brolucizumab injection during the study period. Mean VA changes from baseline were -1.1±15.1 letters (BRO cohort; n = 174) and 1.3±13.0 letters (ALT cohort; n = 47) at Month 12, and 0.0±13.5 letters (BRO cohort; n = 95) and -7.3±17.2 letters (ALT cohort; n = 29) at Month 18. Mean changes in injection intervals were +26.9±48.1 days (BRO cohort) and +11.1±17.3 days (ALT cohort) at Month 12 and +36.3±52.3 days (BRO cohort) and +14.0±19.9 days (ALT cohort) at Month 18. Mean changes in CMT were -35.2±108.1 µm (BRO cohort) and -31.5±91.2 µm (ALT cohort) at Month 12 and -38.9±75.0 µm (BRO cohort) and -9.0±59.9 µm (ALT cohort) at Month 18. Intraocular inflammation-related adverse events were recorded in 22/482 (4.6%) eyes. Conclusion: Treatment with either brolucizumab alone or brolucizumab alternating with another anti-VEGF can preserve vision, reduce CMT, and extend anti-VEGF injection intervals in patients with nAMD.

B602L-Fc fusion protein enhances the immunogenicity of the B602L protein of the African swine fever virus.

African swine fever (ASF) is an acute, highly contagious, and deadly infectious disease caused by the African swine fever virus (ASFV) and has a huge impact on the pig industry. A lack of vaccines and effective therapeutic drugs has brought great challenges to the prevention and control of ASF. In this study, insect baculovirus expression system was used to express ASFV B602L protein (B602L) alone and the IgG FC-fused B602L protein (B602L-Fc), and evaluate the immune effect of B602L-Fc in mice model. To be specific, the ASFV B602L protein and B602L-Fc fusion protein were successfully expressed by the insect baculovirus expression system. Then, Functional analysis in vitro revealed that the B602L-Fc fusion protein bound and interacted with the FcRI receptor of antigen-presenting cells and significantly promoted the expression of proteins involved in antigen presentation and various cytokines at mRNA levels in porcine alveolar macrophages. Additionally, immunization using B602L-Fc fusion protein remarkably promoted the Th1-biased cellular immune response and humoral immune response in mice. In conclusion, The B602L-Fc fusion protein could up-regulate the expression of molecules involved in antigen presentation in APCs and enhance the humoral and cellular immune responses in mice. These results suggest that ASFV B602L-Fc recombinant fusion protein may be a promising candidate for subunit vaccine. This study provided useful data for the development of subunit vaccines for ASF.

Mutated Toll-like receptor 9 increases Alzheimer's disease risk by compromising innate immunity protection.

The development of Alzheimer's disease (AD) involves central and peripheral immune deregulation. Gene identification and studies of AD genetic variants of peripheral immune components may aid understanding of peripheral-central immune crosstalk and facilitate new opportunities for therapeutic intervention. In this study, we have identified in a Flanders-Belgian family a novel variant p.E317D in the Toll-like receptor 9 gene (TLR9), co-segregating with EOAD in an autosomal dominant manner. In human, TLR9 is an essential innate and adaptive immune component predominantly expressed in peripheral immune cells. The p.E317D variant caused 50% reduction in TLR9 activation in the NF-κB luciferase assay suggesting that p.E317D is a loss-of-function mutation. Cytokine profiling of human PBMCs upon TLR9 activation revealed a predominantly anti-inflammatory response in contrast to the inflammatory responses from TLR7/8 activation. The cytokines released upon TLR9 activation suppressed inflammation and promoted phagocytosis of Aß42 oligomers in human iPSC-derived microglia. Transcriptome analysis identified upregulation of AXL, RUBICON and associated signaling pathways, which may underline the effects of TLR9 signaling-induced cytokines in regulating the inflammatory status and phagocytic property of microglia. Our data suggest a protective role of TLR9 signaling in AD pathogenesis, and we propose that TLR9 loss-of-function may disrupt a peripheral-central immune crosstalk that promotes dampening of inflammation and clearance of toxic protein species, leading to the build-up of neuroinflammation and pathogenic protein aggregates in AD development.

microRNA-132 regulates gene expression programs involved in microglial homeostasis.

microRNA-132 (miR-132), a known neuronal regulator, is one of the most robustly downregulated microRNAs (miRNAs) in the brain of Alzheimer's disease (AD) patients. Increasing miR-132 in AD mouse brain ameliorates amyloid and Tau pathologies, and also restores adult hippocampal neurogenesis and memory deficits. However, the functional pleiotropy of miRNAs requires in-depth analysis of the effects of miR-132 supplementation before it can be moved forward for AD therapy. We employ here miR-132 loss- and gain-of-function approaches using single-cell transcriptomics, proteomics, and in silico AGO-CLIP datasets to identify molecular pathways targeted by miR-132 in mouse hippocampus. We find that miR-132 modulation significantly affects the transition of microglia from a disease-associated to a homeostatic cell state. We confirm the regulatory role of miR-132 in shifting microglial cell states using human microglial cultures derived from induced pluripotent stem cells.

Switching to brolucizumab: injection intervals and visual, anatomical and safety outcomes at 12 and 18 months in real-world eyes with neovascular age-related macular degeneration.

BACKGROUND: The anti-vascular endothelial growth factor (anti-VEGF) injection interval influences treatment burden and compliance in neovascular age-related macular degeneration (nAMD). This real-world study investigates visual acuity (VA), injection-interval extension, central macular thickness (CMT) and safety in nAMD eyes switched to the anti-VEGF agent brolucizumab and followed for up to 18 months. METHODS: This retrospective study included patients with nAMD who were switched from other anti-VEGF agents to brolucizumab only. Patient eyes were grouped into three nested cohorts with the overall cohort receiving ≥ 1 brolucizumab injection, the second receiving ≥ 3 brolucizumab injections with a follow-up period of ≥ 12 months and the third cohort receiving ≥ 3 brolucizumab injections with a follow-up period of ≥ 18 months. Study endpoints included changes from baseline at 12 or 18 months in VA, injection intervals, and CMT. Sub-group analyses were conducted using baseline injection interval length or baseline VA as qualifiers. RESULTS: Overall, 482 eyes received ≥ 1 brolucizumab injection; 174 eyes received ≥ 3 brolucizumab injections with ≥ 12 months of follow-up, and 95 eyes received ≥ 3 brolucizumab injections with ≥ 18 months of follow-up. VA (mean [95% confidence intervals]) remained stable relative to baseline after 12 months (- 1.1 [- 3.7, 1.6] letters; p = 0.42) and 18 months (0.0 [- 3.1, 3.1] letters; p = 0.98) of brolucizumab treatment, respectively, and pre-switch injection intervals or baseline VA had no notable effect. Following the switch to brolucizumab, injection intervals were extended from baseline to month 12 by 26.9 (19.7, 34.0) days (p < 0.0001), and eyes with pre-switch injection intervals < 8 weeks were able to have their injection intervals extended by 23.6 days longer than eyes with pre-switch injection intervals ≥ 8 weeks. At 18 months, injection intervals were extended by 36.3 (25.6, 46.9) days (p < 0.0001) compared to baseline. Following switch to brolucizumab, CMT was reduced at both 12 and 18 months (12 months: - 35.2 (- 51.7, - 18.8) µm, p < 0.0001; 18 months: - 38.9 (- 54.3, - 22.0) µm, p < 0.0001). Intraocular inflammation-related adverse events were reported in 4.6% of brolucizumab-treated eyes. CONCLUSIONS: This real-world study demonstrates that injection intervals may be significantly extended with maintained vision and reduced CMT in nAMD eyes switching to brolucizumab therapy from other anti-VEGFs.

Progress of gut microbiome and its metabolomics in early screening of colorectal cancer.

Gut microbes are widely considered to be closely associated with colorectal cancer (CRC) development. The microbiota is regarded as a potential identifier of CRC, as several studies have found great significant changes in CRC patients' microbiota and metabolic groups. Changes in microbiota, like Fusobacterium nucleatum and Bacteroides fragilis, also alter the metabolic activity of the host, promoting CRC development. In contrast, the metabolome is an intuitive discriminative biomarker as a small molecular bridge to distinguish CRC from healthy individuals due to the direct action of microbes on the host. More diagnostic microbial markers have been found, and the potential discriminatory power of microorganisms in CRC has been investigated through the combined use of biomic genomic metabolomics, bringing new ideas for screening fecal microbial markers. In this paper, we discuss the potential of microorganisms and their metabolites as biomarkers in CRC screening, hoping to provide thoughts and references for non-invasive screening of CRC.

Genetic characterization of porcine reproductive and respiratory syndrome virus from Eastern China during 2017-2022.

Porcine reproductive and respiratory syndrome (PRRS) is an immunosuppressive disease caused by PRSS virus (PRRSV). PRRSV mainly causes reproductive disorders in pregnant sows and respiratory diseases in piglets. Recently, it has emerged as one of the most important diseases of the pig industry across the globe. In this study, we have collected 231 samples from differently sized pig farms in Eastern China from 2017 to 2022 to investigate the epidemic characteristics of the disease. All samples were screened by RT-PCR and analyzed further using Nsp2 and ORF5 genes. The result showed that the positive rate of PRRSV was 24% (54/231). Phylogenetic analysis (13 positive samples) revealed that all isolates belonged to genotype 2, and they were mainly distributed in four lineages (i.e., lineage 1, 3, 5, and 8). Nsp2 is the most variable protein among all PRRSV NSPs, several isolates from this study had amino acid deletions within Nsp2 compared to that of strain VR-2332. The major structural protein glycoprotein (GP5) protein is encoded by ORF5. Epitope analysis of the 13 isolated strains and additional reference strains revealed that all 13 strains had some mutations on the decoy epitope, the primary neutralizing epitope, T cell epitopes, and B cell epitopes. This study showed that the prevalent PRRSV strain in Eastern China was still HP-PRRSV, while the proportion of NADC30-like and NADC34-like strains have increased. This study further enriches the epidemiological data of PRRS in Eastern China and provides a theoretical basis for vaccine development and prevention and control of the disease across the region.

Single-cell RNA transcriptomic analysis identifies Creb5 and CD11b-DCs as regulator of asthma exacerbations.

Immune responses that result in asthma exacerbation are associated with allergen or viral exposure. Identification of common immune factors will be beneficial for the development of uniformed targeted therapy. We employed a House Dust Mite (HDM) mouse model of asthma and challenged allergic HDM mice with allergens (HDM, cockroach extract (CRE)) or respiratory syncytial virus (RSV). Purified lung immune cells underwent high-dimensional single-cell RNA deep sequencing (scRNA-seq) to generate an RNA transcriptome. Gene silencing with siRNA was employed to confirm the efficacy of scRNA-seq analysis. scRNA-seq UMAP analysis portrayed an array of cell markers within individual immune clusters. SCENIC R analysis showed an increase in regulon number and activity in CD11b- DC cells. Analysis of conserved regulon factors further identified Creb5 as a shared regulon between the exacerbation groups. Creb5 siRNAs attenuated HDM, CRE or RSV-induced asthma exacerbation. scRNA-seq multidimensional analysis of immune clusters identified gene pathways that were conserved between the exacerbation groups. We propose that these analyses provide a strong framework that could be used to identify specific therapeutic targets in multifaceted pathologies.

AAV-mediated delivery of an anti-BACE1 VHH alleviates pathology in an Alzheimer's disease model.

Single domain antibodies (VHHs) are potentially disruptive therapeutics, with important biological value for treatment of several diseases, including neurological disorders. However, VHHs have not been widely used in the central nervous system (CNS), largely because of their restricted blood-brain barrier (BBB) penetration. Here, we propose a gene transfer strategy based on BBB-crossing adeno-associated virus (AAV)-based vectors to deliver VHH directly into the CNS. As a proof-of-concept, we explored the potential of AAV-delivered VHH to inhibit BACE1, a well-characterized target in Alzheimer's disease. First, we generated a panel of VHHs targeting BACE1, one of which, VHH-B9, shows high selectivity for BACE1 and efficacy in lowering BACE1 activity in vitro. We further demonstrate that a single systemic dose of AAV-VHH-B9 produces positive long-term (12 months plus) effects on amyloid load, neuroinflammation, synaptic function, and cognitive performance, in the AppNL-G-F Alzheimer's mouse model. These results constitute a novel therapeutic approach for neurodegenerative diseases, which is applicable to a range of CNS disease targets.

Research progress of mesenchymal stem cell-derived exosomes on inflammatory response after ischemic stroke.

Ischemic stroke is characterized by cute onset and high mortality. The suppression of neuroinflammation is crucial in the treatment of ischemic stroke. Exosomes derived from mesenchymal stem cell (MSC) have attracted extensive research attention due to their wide origin, small size, and containing large number of active components. Recent studies have shown that MSC-derived exosomes can inhibit the proinflammatory activity of microglia and astrocytes and stimulate their neuroprotective activity; also can inhibit neuroinflammation by regulating immune cells and inflammatory mediators. This article reviews the roles and related mechanism of MSC-derived exosomes in neuroinflammation after ischemic stroke, hoping to provide ideas and references for the development of a novel approach for the treatment of ischemic stroke diseases.

The promise of microRNA-based therapies in Alzheimer's disease: challenges and perspectives.

Multi-pathway approaches for the treatment of complex polygenic disorders are emerging as alternatives to classical monotarget therapies and microRNAs are of particular interest in that regard. MicroRNA research has come a long way from their initial discovery to the cumulative appreciation of their regulatory potential in healthy and diseased brain. However, systematic interrogation of putative therapeutic or toxic effects of microRNAs in (models of) Alzheimer's disease is currently missing and fundamental research findings are yet to be translated into clinical applications. Here, we review the literature to summarize the knowledge on microRNA regulation in Alzheimer's pathophysiology and to critically discuss whether and to what extent these increasing insights can be exploited for the development of microRNA-based therapeutics in the clinic.

Health Care Utilization and Costs in Patients With Migraine Who Have Failed Previous Preventive Treatments.

OBJECTIVE: To characterize health care utilization (HCU) and associated costs among patients with migraine categorized by the number of preventive treatment failures (TFs; 1 TF, 2 TFs, and 3+ TFs) using real-world data. METHODS: This retrospective analysis identified adults with incident migraine diagnosis in the IBM MarketScan Commercial and Medicare Supplemental database between January 1, 2011, and June 30, 2015. TF was defined in the 2 years after the first migraine diagnosis period. One TF, 2 TFs, and 3+ TFs were defined as patients who had received only 2 preventive treatments (PTs), 3 PTs, and 4+ PTs in the 2-year period, respectively. A negative binomial model was used to analyze HCU data, and a 2-part model was used for cost data controlling for the preindex Deyo-Charlson Comorbidity Index. RESULTS: Overall, 24,282 patients with incident migraine who had failed at least 1 PT were included in the analysis. Of these, 72.7% (n = 17,653) had 1 TF, 20.2% (n = 4,900) had 2 TFs, and 7.1% (n = 1,729) had 3+ TFs. Adjusted annualized rates of all-cause and migraine-specific HCU increased with an increase in the number of TFs (1.4-4 times higher; all p < 0.0001 vs 1 TF). The mean total all-cause health care costs were higher by $3,732 (95% confidence interval [CI]: $2,708-$4,588) in patients with 2 TFs and by $8,912 (95% CI: $7,141-$10,822) in patients with 3+ TFs vs those with 1 TF. Outpatient costs were the key drivers of differences in health care costs. CONCLUSIONS: TF in patients with migraine was associated with a substantial resource and cost burden, which increased with the number of TFs.

Effectiveness of erenumab and onabotulinumtoxinA on acute medication usage and health care resource utilization as migraine prevention in the United States.

BACKGROUND: Migraine is a common neurological disease that can have a substantial impact on patients' lives and on society. Erenumab, a fully human monoclonal antibody that targets the calcitonin gene-related peptide receptor, was specifically developed for migraine prevention. The efficacy of erenumab has been established in several clinical trials; however, the real-world comparative effectiveness of erenumab has not been fully investigated. OBJECTIVE: To evaluate the real-world impact of erenumab and onabotulinumtoxinA on acute medication usage and health care resource utilization (HCRU) among patients with migraine in the United States. METHODS: This retrospective US claims analysis (Optum's deidentified Clinformatics Data Mart Database) evaluated patients aged at least 18 years diagnosed with migraine who initiated erenumab or onabotulinumtoxinA between May 1, 2018, and September 30, 2019 (index date: first erenumab/onabotulinumtoxinA claim). Cohorts were matched 1:1 using the propensity score (PS) method (greedy match with caliper = 0.1). Stratification was performed based on gender, chronic migraine without aura diagnosis, onabotulinumtoxinA use, and acute/preventive drug use. The impact of erenumab and onabotulinumtoxinA on acute medication usage and HCRU was assessed in the 6-month post-index period. An exploratory analysis assessed the impact of erenumab and onabotulinumtoxinA on a composite endpoint of: (1) outpatient visit with a migraine diagnosis and associated acute medication claim, (2) hospital admission with a primary migraine diagnosis, or (3) emergency department visit with a primary migraine diagnosis. PS-matched data were used for comparative analyses; logistic regression with covariate adjustment was used for dichotomous variables, and a negative binomial model was used for count variables, with odds ratios or rate ratios (RRs) and 95% CIs calculated. RESULTS: Following stratified PS matching, 1,338 patients were included in both cohorts. At 6 months, the adjusted average number of claims per person for any acute medication was significantly lower in the erenumab cohort (1.13 vs 1.29 in the onabotulinumtoxinA cohort; RR = 0.88; 95% CI = 0.80-0.96; P = 0.0069), although the difference in the number of claims for triptans and barbiturates was statistically nonsignificant. The adjusted average number of all-cause and migraine-specific visits per person to health care providers was generally lower in the erenumab cohort compared with the onabotulinumtoxinA cohort. Patients in the erenumab cohort had a significantly lower number of composite events (0.44 vs 0.69 in the onabotulinumtoxinA cohort; RR = 0.63; 95% CI = 0.56-0.71; P < 0.0001). Similarly, the adjusted proportion of patients with any of the 3 composite events was lower in the erenumab cohort (31.7% vs 44.3% in the onabotulinumtoxinA cohort; OR = 0.59; 95% CI = 0.49-0.70; P < 0.0001). CONCLUSIONS: In this retrospective claims analysis study, erenumab significantly reduced acute medication usage (opioids and nonsteroidal anti-inflammatory drugs; any acute medication when analyzed together) and HCRU to a greater extent than onabotulinumtoxinA. DISCLOSURES: This study was supported by Novartis Pharma AG. Novartis employees contributed to the study design, analysis of the data, and the decision to publish the results. Fang, Abdrabboh, Glassberg, Vo, and Ferraris are employed by Novartis. Zhou and Shen are employed by KMK Consulting, Inc., which received funding from Novartis to conduct the study. Tepper reports grants from Allergan, Amgen, ElectroCore, Eli Lilly, Lundbeck, Neurolief, Novartis, Satsuma, and Zosano, outside the submitted work; personal fees from Dartmouth-Hitchcock Medical Center, American Headache Society, Thomas Jefferson University, Aeon, Align Strategies, Allergan/AbbVie, Alphasights, Amgen, Aperture Venture Partners, Aralez Pharmaceuticals Canada, Axsome Therapeutics, Becker Pharmaceutical Consulting, BioDelivery Sciences International, Biohaven, ClearView Healthcare Partners, CoolTech, CRG, Currax, Decision Resources, DeepBench, DRG, Eli Lilly, Equinox, ExpertConnect, GLG, Guidepoint Global Healthcare Consultancy Group, Health Science Communications, HMP Communications, Impel, InteractiveForums, M3 Global Research, Magellan Rx Management, Medicxi, Navigant Consulting, Neurorelief, Nordic BioTech, Novartis, Pulmatrix, Reckner Healthcare, Relevale, SAI MedPartners, Satsuma, Slingshot Insights, Spherix Global Insights, Sudler and Hennessey, Synapse Medical Communications, System Analytic, Teva, Theranica, Thought Leader Select, Trinity Partners, XOC, Zosano, Krog and Partners, and Lundbeck, outside the submitted work; and CME honoraria from American Academy of Neurology, American Headache Society, Cleveland Clinic Foundation, Diamond Headache Clinic, Elsevier, Forefront Collaborative, Hamilton General Hospital, Ontario, Canada, Headache Cooperative of New England, Henry Ford Hospital, Detroit, Inova, Medical Learning Institute PeerView, Medical Education Speakers Network, Miller Medical Communications, North American Center for CME, Physicians' Education Resource, Rockpointe, ScientiaCME, WebMD/Medscape. The abstract and poster of these results were presented at The Migraine Trust Virtual Symposium (MTIS), October 3-9, 2020.