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Respiratory Investigation Jan 2024Biologics are increasingly being used in patients with severe uncontrolled asthma. However, the trends in their use for treating severe asthma in Japan remain unclear.
BACKGROUND
Biologics are increasingly being used in patients with severe uncontrolled asthma. However, the trends in their use for treating severe asthma in Japan remain unclear.
METHODS
The number of patients with asthma prescribed omalizumab or mepolizumab between April 2017 and March 2018 was estimated according to sex, age, and geographical region using data from the National Database of Health Insurance Claims and Specific Health Checkups of Japan.
RESULTS
Overall, 5,014, 3,449 and 7,977 patients were prescribed omalizumab, mepolizumab, or either combination, respectively. The total number of patients prescribed biologics displayed a bimodal distribution with peaks in their early teens and seventies. Biologics were most commonly used by male and female patients in their seventies. Prescription was 1.24 times higher in males than in females up to the teenage years, whereas it was 1.95 times higher in females than in males from their twenties onwards. Omalizumab was prescribed 1.45 times more frequently than mepolizumab, especially in pediatric patients, and was prescribed 1.96 times more often to female patients than to male patients. Regional differences were observed in the proportion of patients prescribed biologics. Correlation analysis suggested a weak relationship (r = 0.3226, p = 0.0270) between the proportion of patients prescribed biologics and board-certified allergists according to the geographic region.
CONCLUSIONS
In Japan, biologics are prescribed more often to older patients with severe asthma compared to those in other countries. Thus, eliminating the regional disparities in asthma treatment by specialists is necessary to provide appropriate medical care to patients with severe asthma.
Topics: Adolescent; Humans; Male; Female; Child; Omalizumab; Anti-Asthmatic Agents; Japan; Cohort Studies; Asthma; Biological Products; Antibodies, Monoclonal, Humanized
PubMed: 38101278
DOI: 10.1016/j.resinv.2023.11.003 -
Frontiers in Immunology 2023MHC class II molecules are essential for appropriate immune responses against pathogens but are also implicated in pathological responses in autoimmune diseases and...
INTRODUCTION
MHC class II molecules are essential for appropriate immune responses against pathogens but are also implicated in pathological responses in autoimmune diseases and transplant rejection. Previous studies have shed light on the systemic contributions of MHC haplotypes to the development and severity of autoimmune diseases. In this study, we addressed the B cell intrinsic MHC haplotype impact on follicular inclusion, germinal center (GC) participation and plasma cell (PC) differentiation in the context of systemic lupus erythematosus (SLE).
METHODS
We leveraged the 564Igi mouse model which harbors a B cell receptor knock-in from an autoreactive B cell clone recognizing ribonuclear components, including double-stranded DNA (dsDNA). This model recapitulates the central hallmarks of the early stages of SLE. We compared 564Igi heterozygous offspring on either H2b/b, H2b/d, or H2d/d background.
RESULTS
This revealed significantly higher germinal center (GC) B cell levels in the spleens of H2b/b and H2b/d as compared to H2d/d (p<0.0001) mice. In agreement with this, anti-dsDNA-antibody levels were higher in H2b/b and H2b/d than in H2d/d (p<0.0001), with H2b/b also being higher compared to H2b/d (p<0.01). Specifically, these differences held true both for autoantibodies derived from the knock-in clone and from wild-type (WT) derived clones. In mixed chimeras where 564Igi H2b/b, H2b/d and H2d/d cells competed head-to-head in the same environment, we observed a significantly higher inclusion of H2b/b cells in GC and PC compartments relative to their representation in the B cell repertoire, compared to H2b/d and H2d/d cells. Furthermore, in mixed chimeras in which WT H2b/b and WT H2d/d cells competed for inclusion in GCs associated with an epitope spreading process, H2b/b cells participated to a greater extent and contributed more robustly to the PC compartment. Finally, immature WT H2b/b cells had a higher baseline of BCRs with an autoreactive idiotype and were subject to more stringent negative selection at the transitional stage.
DISCUSSION
Taken together, our findings demonstrate that B cell intrinsic MHC haplotype governs their capacity for participation in the autoreactive response at multiple levels: follicular inclusion, GC participation, and PC output. These findings pinpoint B cells as central contributors to precipitation of autoimmunity.
Topics: Animals; Mice; Haplotypes; Germinal Center; Lupus Erythematosus, Systemic; Autoimmune Diseases; Cell Differentiation
PubMed: 38090594
DOI: 10.3389/fimmu.2023.1258046 -
Respiratory Research Dec 2023Biomarkers are needed to inform the choice of biologic therapy in patients with asthma given the increasing number of biologics. We aimed to identify proteins associated...
INTRODUCTION
Biomarkers are needed to inform the choice of biologic therapy in patients with asthma given the increasing number of biologics. We aimed to identify proteins associated with response to omalizumab and mepolizumab.
METHODS
Aptamer-based proteomic profiling (SomaScan) was used to assess 1437 proteins from 51 patients with moderate to severe asthma who received omalizumab (n = 29) or mepolizumab (n = 22). Response was defined as the change in asthma-related exacerbations in the 12 months following therapy initiation. All models were adjusted for age, sex, and pre-treatment exacerbation rate. Additionally, body mass index was included in the omalizumab model and eosinophil count in the mepolizumab model. We evaluated the association between molecular signatures and response using negative binomial regression correcting for the false discovery rate (FDR) and gene set enrichment analyses (GSEA) to identify associated pathways.
RESULTS
Over two-thirds of patients were female. The average age for omalizumab patients was 42 years and 57 years for mepolizumab. At baseline, the average exacerbation rate was 1.5/year for omalizumab and 2.4/year for mepolizumab. Lower levels of LOXL2 (unadjusted p: 1.93 × 10E-05, FDR-corrected: 0.028) and myostatin (unadjusted: 3.87 × 10E-05, FDR-corrected: 0.028) were associated with better response to mepolizumab. Higher levels of CD9 antigen (unadjusted: 5.30 × 10E-07, FDR-corrected: 0.0006) and MUC1 (unadjusted: 1.15 × 10E-06, FDR-corrected: 0.0006) were associated with better response to omalizumab, and LTB4R (unadjusted: 1.12 × 10E-06, FDR-corrected: 0.0006) with worse response. Protein-protein interaction network modeling showed an enrichment of the TNF- and NF-kB signaling pathways for patients treated with mepolizumab and multiple pathways involving MAPK, including the FcER1 pathway, for patients treated with omalizumab.
CONCLUSIONS
This study provides novel fundamental data on proteins associated with response to mepolizumab or omalizumab in severe asthma and warrants further validation as potential biomarkers for therapy selection.
Topics: Humans; Female; Adult; Male; Omalizumab; Anti-Asthmatic Agents; Myostatin; Proteomics; Asthma; Biomarkers; Mucin-1
PubMed: 38057814
DOI: 10.1186/s12931-023-02620-1 -
BMC Pulmonary Medicine Dec 2023A significant breakthrough has been made in treating severe asthma, with the recognition of various asthma phenotypes and an updated management guideline. Type 2...
BACKGROUND
A significant breakthrough has been made in treating severe asthma, with the recognition of various asthma phenotypes and an updated management guideline. Type 2 targeted therapies, such as benralizumab and omalizumab; have been identified as an effective treatment for severe asthma, improving patient response, lung function tests and asthma symptom control. This study aimed to evaluate factors contributing to poor response to therapy.
METHODS
A retrospective single-center cohort study of 162 patients with severe asthma who started biologic therapy; their data were retrieved from medical records for further analysis. Poor responders were patients remained clinically and functionally uncontrolled despite even after augmenting all treatment options.
RESULTS
Childhood-onset asthma, bronchiectasis, poor symptom control (ACT below 19), severe airway obstruction (< 60% predicted), and maintenance oral corticosteroid (mOCS) use were significantly associated with poor response to omalizumab and benralizumab; p = 0.0.4 and 0.01; 0.003 and 0.01; 0.01 and 0.001, 0.05 and 0.04; 0.006 and 0.02, respectively. However, chronic rhinosinusitis and IgE < 220kIU/L were associated with higher poor response rates to omalizumab (p = 0.01 and 0.04, respectively). At the same time, female patients and those with blood eosinophils level < 500 cells/mm3 had a higher poor response rate to benralizumab (p = 0.02 and 0.01, respectively). Ischemic heart disease (IHD), bronchiectasis, and continued use of OCS increased the likelihood of poor response to omalizumab by 21, 7, and 24 times (p = 0.004, 0.008, and 0.004, respectively). In contrast, the female gender, childhood-onset asthma and higher BMI increased the likelihood of poor response to benralizumab by 7, 7 and 2 times more, p = 0.03, 0.02 and 0.05, respectively.
CONCLUSION
Poor response to omalizumab treatment was independently associated with ischemic heart disease (IHD), bronchiectasis, and a history of maintenance oral corticosteroid (mOCS) use. Conversely, poor response to benralizumab therapy was independently linked to female gender, childhood-onset asthma and higher body mass index (BMI).
Topics: Humans; Female; Child; Omalizumab; Anti-Asthmatic Agents; Retrospective Studies; Cohort Studies; Immunoglobulin E; Asthma; Adrenal Cortex Hormones; Bronchiectasis; Myocardial Ischemia
PubMed: 38053108
DOI: 10.1186/s12890-023-02786-w -
Journal of Neuroimmunology Dec 2023In this paper the authors provide evidence that hydroxyurea (hydroxycarbamide) interacts with α7 nicotinic acetylcholine receptor, exerts anti-inflammatory and...
In this paper the authors provide evidence that hydroxyurea (hydroxycarbamide) interacts with α7 nicotinic acetylcholine receptor, exerts anti-inflammatory and pro-survival effect, prevents α7 nicotinic receptor interaction with angiotensin-converting enzyme-2 and stimulates IgM to IgG class switch upon immunization with SARS spike protein fragment 674-685. Hydroxyurea shifts immunoglobulin glycosylation profile to anti-inflammatory phenotype and prevents the appearance of anti-idiotypic α7(179-190)-specific antibodies, as well as memory impairment. According to these results, interaction with α7 nicotinic acetylcholine receptor may underlie positive therapeutic effects of hydroxyurea upon SARS-Cov-2 infection by interfering with virus penetration into the cell and providing anti-inflammatory and immunomodulatory effects.
Topics: Humans; alpha7 Nicotinic Acetylcholine Receptor; COVID-19; Hydroxyurea; SARS-CoV-2; Anti-Inflammatory Agents; Receptors, Nicotinic
PubMed: 38016403
DOI: 10.1016/j.jneuroim.2023.578244 -
Pediatric Pulmonology Feb 2024Asthma is one of the most common diseases in children, with a variable range of severity. In recent years, treatment for severe asthma has been largely improved by the...
INTRODUCTION
Asthma is one of the most common diseases in children, with a variable range of severity. In recent years, treatment for severe asthma has been largely improved by the availability of targeted biologic therapies. Nevertheless, studies reporting real-world data and cost-effectiveness analyses are lacking. The aim of this study was to evaluate, on a population-based cohort of children with asthma, the impact of the treatment with biologics on healthcare service utilization and associated costs.
METHODS
Data were retrieved from Healthcare Utilization database of Lombardy region (Italy). A cohort of 46 asthmatic children aged 6-11 in treatment with dupilumab, mepolizumab or omalizumab was identified during 2017-2021. We compared healthcare resources use between the year before ("baseline period") and the year after the treatment initiation ("follow-up period"). Average 1-year healthcare costs were also calculated.
RESULTS
Comparing the baseline with the follow-up period, the number of patients with at least one exacerbation-related hospitalization and ER access decreased by 75.0% and 85.7%, respectively. The use of biologic agents, namely omalizumab, mepolizumab and dupilumab, significantly reduced oral corticosteroids (OCS), short-acting β2-agonists and the association inhaled corticosteroids/long-acting β2-agonists use. ER admissions for non-respiratory causes were also significantly reduced, while discontinuation rate was low (6.5%). The overall costs increased, due to the costs of the biologic agents, but the hospital admission-related costs due to respiratory causes reduced significantly.
CONCLUSIONS
Our real-world investigation suggests that biologic agents reduced hospital admissions for respiratory causes and use of anti-asthmatic drugs, including OCS. However, long-term healthcare sustainability still needs more in-depth assessments.
Topics: Child; Humans; Omalizumab; Cohort Studies; Asthma; Anti-Asthmatic Agents; Health Care Costs; Biological Therapy; Adrenal Cortex Hormones
PubMed: 37991180
DOI: 10.1002/ppul.26764 -
Antibodies (Basel, Switzerland) Nov 2023We have previously produced a toolkit of antibodies, comprising recombinant human antibodies of all but one of the human isotypes, directed against the polcalcin family...
We have previously produced a toolkit of antibodies, comprising recombinant human antibodies of all but one of the human isotypes, directed against the polcalcin family antigen Phl p 7. In this work, we complete the toolkit of human antibody isotypes with the IgD version of the anti-Phl p 7 monoclonal antibody. We also raised a set of nanobodies against the IgD anti-Phl p 7 antibody and identify and characterize one paratope-specific nanobody. This nanobody also binds to the IgE isotype of this antibody, which shares the same idiotype, and orthosterically inhibits the interaction with Phl p 7. The 2.1 Å resolution X-ray crystal structure of the nanobody in complex with the IgD Fab is described.
PubMed: 37987253
DOI: 10.3390/antib12040075 -
Biomedicine & Pharmacotherapy =... Dec 2023Analytical and functional comparison is key for substantiating the level of convergence (essential sameness) or divergence between versions or variants of a given...
Analytical and functional comparison is key for substantiating the level of convergence (essential sameness) or divergence between versions or variants of a given biological medicine. Accordingly, an overlapping biological activity between products meant to be equal probably reflects a highly similar structure and anticipates a comparable pharmacodynamic behavior. We developed an orthogonal approach to compare the human IgE binding features of different lots and versions of Xolair® (omalizumab), an anti-human IgE monoclonal antibody. The IgE binding affinity and kinetics were measured by surface plasmon resonance. Ability to prevent mast cell activity was assessed in vitro and in vivo in mast cell-based models. The variability of monoclonal antibodies with identical amino acid sequences produced either in Chinese hamster ovarian cells or in human HEK293 cells, was compared. Monoclonal antibodies from the two sources exhibited slightly different human IgE binding and neutralizing features. A known variant exhibiting a three amino acid replacement in the Fab region had lower IgE binding affinity than the original omalizumab. The lower binding affinity translated into reduced IgE neutralizing capacity and, in turn, a difference in the ability to prevent mast cell activation in vitro and in vivo. The proposed set of analytical and functional assays was sensitive enough to detect Fab-linked differences between anti-IgE antibody versions exhibiting an identical aminoacid sequence. In addition to add value to the comparative assessment of biosimilar candidates bearing omalizumab, these methods can aid pre-assessments of new anti-IgE agents that aim to improve therapeutic performance.
Topics: Humans; Omalizumab; Biosimilar Pharmaceuticals; Antibodies, Monoclonal, Humanized; HEK293 Cells; Immunoglobulin E; Antibodies, Monoclonal; Immunosuppressive Agents
PubMed: 37976893
DOI: 10.1016/j.biopha.2023.115848 -
Annals of Allergy, Asthma & Immunology... Mar 2024Patients with chronic rhinosinusitis with nasal polyps (CRSwNP) often have atopic comorbidities, including elevated IgE levels and comorbid asthma. Omalizumab, an IgE...
BACKGROUND
Patients with chronic rhinosinusitis with nasal polyps (CRSwNP) often have atopic comorbidities, including elevated IgE levels and comorbid asthma. Omalizumab, an IgE monoclonal antibody, is an effective treatment for CRSwNP, but the impact of allergy or asthma status on response to omalizumab in patients with CRSwNP has not been well studied.
OBJECTIVE
To evaluate the impact of allergy and asthma status on omalizumab treatment in patients with CRSwNP, this posthoc exploratory analysis assessed sinonasal outcomes from subgroups of patients included in POLYP 1 and POLYP 2 and the open-label extension (OLE) trials.
METHODS
Patients (N = 249) were grouped by the presence/absence of comorbid allergy (≥ 1 physician-reported allergic rhinitis, allergic sinusitis, food allergy, or atopic dermatitis), presence/absence of comorbid asthma, baseline serum total IgE (≥ 150 or <150 IU/mL), and baseline blood eosinophil levels (>300 or ≤ 300 cells/µL). Sinonasal outcomes were the nasal polyps score, nasal congestion score, and sino-nasal outcome test-22.
RESULTS
During POLYP 1 and POLYP 2 and the OLE, omalizumab treatment improved the nasal polyps score, nasal congestion score, and sino-nasal outcome test-22 score in patients with/without physician-reported allergic comorbidities, with/without asthma, with higher/lower total IgE levels, and with higher/lower blood eosinophil counts. In the OLE, the pattern of improvement was similar in patients who continued or switched to omalizumab.
CONCLUSION
In patients with CRSwNP, omalizumab improved sinonasal outcomes independent of allergic status, which suggests that a wide range of patients with different endotypes and phenotypes of CRSwNP may benefit from omalizumab treatment.
TRIAL REGISTRATION
Clinicaltrials.gov Identifier: NCT03280550, NCT03280537, NCT03478930.
Topics: Humans; Antibodies, Monoclonal; Asthma; Chronic Disease; Immunoglobulin E; Nasal Polyps; Omalizumab; Rhinitis; Rhinosinusitis; Sinusitis; Clinical Trials as Topic
PubMed: 37951571
DOI: 10.1016/j.anai.2023.11.001 -
Medicine Oct 2023In obese severe asthmatics, the degree of type 2 inflammation may vary according to their atopic status and past smoking history. In this study, we aimed to analyze the...
In obese severe asthmatics, the degree of type 2 inflammation may vary according to their atopic status and past smoking history. In this study, we aimed to analyze the clinical and physiopathological features of obese and nonobese severe asthmatics treated with omalizumab or mepolizumab treatment. In addition we aimed to compare the clinical, spirometric outcomes and total peripheral eosinophilic count (TEC) changes after treatment with these 2 biologic agents in obese and nonobese groups. In this retrospective, cross sectional study, 121 severe asthmatic treated with biologic agents (omalizumab = 88 or mepolizumab = 33) for at least 16 weeks were included. Obese (n: 44) and nonobese severe asthmatics (n: 77) were analyzed according to whether they provided a ≥ 10 pack/years (p/y) or <10 p/y smoking history and were found to be atopic. Obese and nonobese groups were compared in terms of the change in the asthma control test, asthma attacks, TEC, and forced expiratory volume in the first second (FEV1) after treatment. In patients with ≥10 p/y smoking history, nonobese group had a significantly higher TEC compared to obese group [median (min-max) 660 cells/μL (200-1500) vs 300 cells/μL (110-770); p: 0.013]. Within the nonobese group, nonatopic patients had a significantly higher TEC compared to atopic patients [median (min-max) 1200 cells/μL (100-2100) vs 310 cells/μL (0-2730); p: 0.021]. Both biologic agents had similar effects on improving asthma control test and in reducing asthma attacks; however, mepolizumab was more effective in suppressing TEC. The improvement in FEV1 in obese group following biologic 2 agents was very similar but in nonobese group, mepolizumab was found to be superior (510 mL vs. 295 mL; p: 0.034). In our real-life study, nonobese severe asthmatics with ≥10 p/y smoking history and those that were nonatopic had higher TEC. Compared to omalizumab, mepolizumab was superior at reducing TEC in all asthmatics and in improving FEV1 in nonobese group.
Topics: Humans; Omalizumab; Anti-Asthmatic Agents; Retrospective Studies; Cross-Sectional Studies; Treatment Outcome; Asthma; Obesity; Biological Factors
PubMed: 37904405
DOI: 10.1097/MD.0000000000035247