Real-World Healthcare Cost Savings and Reduced Relapse Rate with Off-Label Rituximab versus Disease-Modifying Treatments Approved for Relapsing-Remitting Multiple Sclerosis: A Nationwide Cost-Effectiveness Study.

OBJECTIVE: Although off-label use of rituximab is a common alternative to disease-modifying therapies (DMTs) approved for multiple sclerosis (MS) in several countries, the impact of this on treatment cost-effectiveness is not well known. METHODS: We evaluated the relative cost-effectiveness of rituximab and MS-approved DMTs in a register-based cohort study of Swedish residents with relapsing-remitting MS, aged 18-65 years, starting treatment with rituximab, natalizumab, fingolimod, or dimethyl fumarate between January 2010 and July 2016, and followed through July 2021 (n = 5,924). By linking the population-based Swedish MS register to several Swedish health care and demographic registers, we estimated health care costs in relation to number of relapses, over 5 years from treatment start. Differences between treatments were estimated in inverse probability of treatment-weighted regression models, adjusting for a broad range of potential confounders covering demographics, medical history, and MS-related clinical characteristics. RESULTS: Off-label rituximab was associated with both lower total health care costs (mean cost savings ranged $35,000-$66,000 vs. each approved DMT), and fewer relapses (mean number of prevented relapses ranged 0.12-0.22), per started therapy over 5 years. Results were robust to variations in discounting and pricing of health care visits, with the main driver of cost-savings being the price of the index drug itself. INTERPRETATION: The cost-effectiveness of rituximab dominated the MS-approved alternatives. Off-label, low-dose rituximab should be considered for persons with MS and could reduce barriers to treatment, especially in resource-limited settings. ANN NEUROL 2024;95:1099-1111.

Burden of treatment and quality of life in relapsing remitting multiple sclerosis patients under early high efficacy therapy in Argentina: Data from the Argentinean registry.

The objective of this study was to describe and compare the burden of treatment (BOT) and the quality of life (QoL) in early high efficacy therapy (HET) vs. escalation therapy in relapsing remitting multiple sclerosis (RRMS) patients included in RelevarEM, the Argentinean registry of MS (RelevarEM, NCT 03,375,177). METHODS: cross sectional study conducted between September and December 2022. Participating patients were adults, RRMS patients who initiated (during the last three years) their treatment with a HET (natalizumab, ocrelizumab, alemtuzumab, cladribine) or with escalation treatment (beta interferon, glatiramer acetate, teriflunomide, dimethyl fumarate or fingolimod). Clinical and demographic aspect were collected. QoL and BOT was measured with the validated to Spanish MusiQol and BOT questionnaire. Propensity score (PS)-based nearest-neighbor matching was applied to homogenize groups. Comparisons were be done using a linear regression analysis model stratified by matched pairs, with BOT and QoL assessments as main outcomes. RESULTS: 269 patients were included in the analysis, mean age 33.7 ± 5.7 years, 193 (71.7 %) were female. A total of 136 patients were on early HET while 133 were on escalation therapy. In the entire group the mean total BOT score (±SD) was 48.5 ± 15.3 while in the group of patients receiving early HET we observed that the mean BOT score (±SD) was 43.5 ± 12.2 vs. 54.3 ± 13.3 in escalation treatment (p < 0.0001). Regarding the score QoL (±SD), in the entire sample we observed a global score of 77.4 ± 11.2. When we stratified groups, in HET (±SD) it was 81.3 ± 14 vs. 74.1 ± 18.3 in escalation therapy (p = 0.0003). CONCLUSION: in this multicenter study that included 269 patients from Argentina we observed in early HET a significantly lower BOT and higher QoL than patients receiving escalation therapy.

Multi-actor system dynamics in access to disease-modifying treatments for multiple sclerosis in Southeast Asia: A regional survey and suggestions for improvement.

BACKGROUND: Despite the global availability of multiple sclerosis (MS) treatments, accessing and financing them in Southeast Asia (SEA) remains a challenge. This descriptive survey-based study aimed to describe the current state of MS treatment access and local access dynamics within this region. METHODS: The survey questionnaire, comprising of 15 closed-ended and five open-ended questions, was developed by three neurologists with expertise in MS and routine MS patient management, or had training in neuroimmunology. Questionnaire development was guided by the recent Atlas of MS and in alignment with the Access to Treatment framework, focusing on MS diagnosis and treatment issues in SEA. Fifteen neurologists experienced in managing MS across the region were identified as key informants for this study. RESULTS: All fifteen neurologists participated in the survey via email and videoconferencing between January 2020 and February 2023, which included the following countries: Brunei, Cambodia, Indonesia, Malaysia, Myanmar, Lao PDR, Philippines, Singapore, Thailand, Timor-Leste, and Vietnam. All had at least five years of experience in managing MS patients and six had previously completed a neuroimmunology fellowship programme. SEA countries showed disparities in healthcare financing, availability of neurologists, MS treatments, and investigative tools. Access to MS disease-modifying treatments (DMTs) is hindered by high cost, lack of MS specialists, and weak advocacy efforts. On-label DMTs are not listed as essential medicines regionally except for interferon beta1a and teriflunomide in Malaysia. On-label monoclonals are available only in Malaysia, Singapore, and Thailand. Generic on-label DMTs are unavailable due to lack of distributorship and expertise in using them. Off-label DMTs (azathioprine, methotrexate, and rituximab) predominate in most SEA countries. Other challenges include limited access to investigations, education, and knowledge about DMTs among general neurologists, and absence of registries and MS societies. Patient champions, communities, and MS organisations have limited influence on local governments and pharmaceutical companies. Despite its increasing prevalence, there is a lack of concerted priority setting due to MS being perceived as a rare, non-communicable disease. CONCLUSION: This study highlights the distinct dynamics, challenges, and research gaps within this region, and provides suggestions to improve MS diagnosis, education, and medicine access.

Benefits of sphingosine-1-phosphate receptor modulators in relapsing MS estimated with a treatment sequence model.

BACKGROUND: Three sphingosine-1-phosphate receptor (S1PR) modulators are currently available as disease-modifying therapies (DMTs) for relapsing MS in the Netherlands (i.e. fingolimod, ozanimod and ponesimod). We aimed to identify which S1PR modulator yields the highest benefit from a health-economic and societal perspective during a patient's lifespan. METHODS: Incorporating Dutch DMT list prices, we used the ErasmusMC/iMTA MS model to compare DMT sequences, including S1PR modulators and eight other DMT classes, for treatment-naïve patients with relapsing MS in terms of health outcomes (number of lifetime relapses, time to Expanded Disability Status Scale (EDSS) 6, lifetime quality-adjusted life years (QALYs)) and cost-effectiveness (net health benefit (NHB)). We estimated the influence of list price and EDSS progression on cost-effectiveness outcomes. RESULTS: In deterministic and probabilistic analysis, DMT sequences with ponesimod have lower lifetime costs and higher QALYs resulting in a higher average NHB compared to sequences with other S1PR modulators. Ponesimod remains the most cost-effective S1PR modulator when EDSS progression is class-averaged. Given the variable effects on disability progression, list price reductions could make fingolimod but not ozanimod more cost-effective than ponesimod. CONCLUSION: Our model favours ponesimod among the S1PR modulators for the treatment of relapsing MS. This implies that prioritizing ponesimod over other S1PR modulators translates into a more efficacious spending of national healthcare budget without reducing benefit for people with MS. Prioritizing cost-effective choices when counselling patients contributes to affordable and accessible MS care.

Cost-effectiveness of tumor necrosis factor-alpha inhibitors: a systematic review and meta-analysis of cost-utility studies.

OBJECTIVE: To systematically review the cost-utility evidence of TNF-a-i treatment for rheumatoid arthritis (RA) and to estimate the pooled incremental net benefit (INBp). METHODS: We selected economic evaluation studies reporting the cost-utility of TNF-a-i compared to other disease-modifying anti-rheumatic drugs (DMARDs) after a systematic search in PubMed, Embase, Scopus, and Tufts Medical Centers' cost-effective analysis registry. The results were reported as pooled INB in purchasing power parity-adjusted US dollars, along with 95% confidence intervals. We used GRADE quality assessment to present summaries of evidence and random-effects meta-analysis to synthesize cost-utility of TNF-a-i. RESULTS: We included 86 studies for systematic review, of which 27 for meta-analysis. TNF-a-i is not cost-effective [$ -4,129(-6,789 to -1,469)] compared to other DMARDs but with high heterogeneity. There was no evidence of publication bias (p = 0.447). On separate analysis, TNF-a-i is not cost-effective [$ -4,805(-7,882 to -1,728)] compared to conventional synthetic DMARDs for RA treatment. GRADE assessment indicated very low confidence in pooled cost-utility results and likely presence of risk of bias on the overall ECOBIAS checklist in studies. CONCLUSION: Based on the available evidence during the study period, TNF-a-i is not a cost-effective option for treating RA compared to other DMARDs. However, high heterogeneity and low confidence in GRADE quality assessment preclude the results from being generalizable.

Assessment of Reported Adverse Events After Interchanging Between TNF-α Inhibitor Biosimilars in the WHO Pharmacovigilance Database.

BACKGROUND AND OBJECTIVE: Observational studies have shown that a significant proportion of patients interchanging between tumor necrosis factor-α inhibitor biosimilars withdraws from the new treatment because of adverse effects. We aim to analyze adverse events related to interchanging from tumor necrosis factor-α (TNF-α) inhibitor reference products to biosimilars and between biosimilars reported in the World Health Organization pharmacovigilance database. METHODS: We extracted all cases reporting the Medical Dictionary for Regulatory Activities term "Product substitution issue (PT)" for TNF-α inhibitors. Then, we analyzed and categorized all adverse events reported in more than 1% of cases. We compared the adverse events reported according to reporter qualification, type of switch, and type of TNF-α inhibitor using Chi2 tests. We conducted a network analysis coupled with a clustering approach to identify syndromes of co-reported adverse events. RESULTS: In the World Health Organization pharmacovigilance database, 2543 cases and 6807 adverse events related to TNF-α inhibitor interchangeability have been reported up to October 2022. Injection-site reactions were the most reported adverse events with 940 cases (37.0%), followed by modifications in drug effect in 607 cases (23.9%). Musculoskeletal, cutaneous, and gastrointestinal disorders linked to the underlying disease were reported in 505 (20.0%), 145 (5.7%), and 207 (8.1%) cases, respectively. Adverse events non-related to the underlying disease were nonspecific (n = 458, 18.0%), neurologic (n = 224, 8.8%), respiratory (n = 132, 5.2%), and psychological disorders (n = 64, 2.5%). Injection-site reactions and infection-related symptoms (e.g., nasopharyngitis, urinary tract infection, lower respiratory tract infection) were more reported by non-healthcare professionals while adverse events related to reduced clinical efficacy (e.g., drug ineffective, arthralgia, psoriasis) were more reported by healthcare professionals. The proportions of injection-site reactions were higher when switching between biosimilars of the same reference product, but the proportions of adverse events related to reduced clinical efficacy (e.g., psoriasis, arthritis, psoriatic arthropathy) were more reported when switching from a reference product. The main differences in the proportions of reported cases between adalimumab, infliximab, and etanercept were driven by symptoms related to the underlying targeted diseases, except for a higher reporting rate of injection-site pain with adalimumab. Adverse events evocative of hypersensitivity reactions were reported in 192 (7.6%) cases. Most of the network clusters concerned non-specific adverse events or were related to reduced clinical efficacy. CONCLUSIONS: This analysis highlights the burden of patient-reported adverse events when interchanging between TNF-α inhibitor biosimilars, notably injection-site reactions, non-specific adverse events, and symptoms related to reduced clinical efficacy. Our study also highlights differences in reporting patterns between patients and healthcare professionals and depending on the type of switch. The results are limited by missing data, the lack of precision of the coded Medical Dictionary for Regulatory Activities terms, and by the variability of reporting rate of adverse events. Thus, incidence rates of adverse events cannot be inferred from these results.

Preclinical risk assessment strategy to mitigate the T-cell dependent immunogenicity of protein biotherapeutics: State of the art, challenges and future perspectives.

Protein therapeutics hold a prominent role and have brought significant diversity in efficacious medicinal products. Not just monoclonal antibodies and different antibody formats (pegylated antigen-binding fragments, bispecifics, antibody-drug conjugates, single chain variable fragments, nanobodies, dia-, tria- and tetrabodies), but also purified blood products, growth factors, recombinant cytokines, enzyme replacement factors, fusion proteins are all good instances of therapeutic proteins that have been developed in the past decades and approved for their value in oncology, immune-oncology, and autoimmune diseases discovery programs. Although there was an ingrained belief that fully humanized proteins were expected to have limited immunogenicity, adverse effects associated with immune responses to biological therapies raised some concern in biotech companies. Consequently, drug developers are designing strategies to assess potential immune responses to protein therapeutics during both the preclinical and clinical phases of development. Despite the many factors that can contribute to protein immunogenicity, T cell- (thymus-) dependent (Td) immunogenicity seems to play a crucial role in the development of anti-drug antibodies (ADAs) to biologics. A broad range of methodologies to predict and rationally assess Td immune responses to protein drugs has been developed. This review aims to briefly summarize the preclinical immunogenicity risk assessment strategy to mitigate the risk of potential immunogenic candidates coming towards clinical phases, discussing the advantages and limitations of these technologies, and suggesting a rational approach for assessing and mitigating Td immunogenicity.

[Therapeutic Strategies and Disease-Modifying Therapies for Multiple Sclerosis].

Multiple sclerosis is an inflammatory demyelinating disease of unknown cause that affects the central nervous system. Although it was once deemed "incurable," many disease-modifying therapies have been introduced since the beginning of the 20th century; eight of these are now available in Japan. Treatment for multiple sclerosis is undergoing a significant shift from the safety-oriented "escalation strategy," in which the patient is initially administered medications with low risks of side effects but moderate efficacy, to a "personalized approach" based on individual prognostic factors followed by an "early top-down strategy" in which higher efficacy treatments are initiated first. Disease-modifying drugs for multiple sclerosis can be high- (fingolimod, ofatumumab, natalizumab) or moderate-efficacy (interferon beta, glatiramer acetate, dimethyl fumarate), and there are also disease-modifying therapies for secondary progressive multiple sclerosis (siponimod and ofatumumab). Approximately 20,000 Japanese patients have multiple sclerosis, and this number continues to increase. Many neurologists are expected to prescribe high-efficacy drugs in the future. The risk management of adverse events, particularly progressive multifocal leukoencephalopathy, is required to ensure that the importance of safety never be underestimated, even though treatment efficacy is the main focus.

Clinical and economic evaluations of natalizumab, rituximab, and ocrelizumab for the management of relapsing-remitting multiple sclerosis in Saudi Arabia.

INTRODUCTION: The advent of new disease-modifying therapies (DMTs), such as monoclonal antibodies (mAbs), resulted in significant changes in the treatment guidelines for Multiple sclerosis (MS) and improvement in the clinical outcomes. However, mAbs, such as rituximab, natalizumab, and ocrelizumab, are expensive with variable effectiveness rates. Thus, the present study aimed to compare the direct medical cost and consequences (e.g., clinical relapse, disability progression, and new MRI lesions) between rituximab and natalizumab in managing relapsing-remitting multiple sclerosis (RRMS) in Saudi Arabia. Also, the study aimed to explore the cost and consequence of ocrelizumab in managing RRMS as a second-choice treatment. METHODS: The electronic medical records (EMRs) of patients with RRMS were retrospectively reviewed to retrieve the patients' baseline characteristics and disease progression from two tertiary care centers in Riyadh, Saudi Arabia. Biologic-naïve patients treated with rituximab or natalizumab or those switched to ocrelizumab and treated for at least six months were included in the study. The effectiveness rate was defined as no evidence of disease activity (NEDA-3) (i.e., absence of new T2 or T1 gadolinium (Gd) lesions as demonstrated by the Magnetic Resonance Imaging (MRI), disability progression, and clinical relapses), while the direct medical costs were estimated based on the utilization of healthcare resources. In addition, bootstrapping with 10,000 replications and inverse probability weighting based on propensity score were conducted. RESULTS: Ninety-three patients met the inclusion criteria and were included in the analysis (natalizumab (n = 50), rituximab (n = 26), ocrelizumab (n = 17)). Most of the patients were otherwise healthy (81.72%), under 35 years of age (76.34%), females (61.29%), and on the same mAb for more than one year (83.87%). The mean effectiveness rates for natalizumab, rituximab, and ocrelizumab were 72.00%, 76.92%, and 58.83%, respectively. Natalizumab mean incremental cost compared to rituximab was $35,383 (95% CI: $25,401.09- $49,717.92), and its mean effectiveness rate was 4.92% lower than rituximab (95% CI: -30-27.5) with 59.41% confidence level that rituximab will be dominant. CONCLUSIONS: Rituximab seems to be more effective and is less costly than natalizumab in the management of RRMS. Ocrelizumab does not seem to slow the rates of disease progression among patients previously treated with natalizumab.

Comparison of three risk assessment models for thromboembolism in multiple myeloma patients receiving immunomodulators: a Brazilian historical cohort.

Venous thromboembolism (VTE) is among the complications of Multiple Myeloma (MM) and may occur in up to 10% of this patient population. However, medications used in MM therapy such as immunomodulators (IMID) may raise these rates. Thus, risk prediction models have been developed to quantify the risk of VTE in MM patients. The aim of this study is to compare the performance of three risk assessment models for VTE in newly diagnosed MM (NDMM) patients using immunomodulatory agents. A historical cohort study during a 10-year period in a Brazilian metropolis with NDMM treated with IMID. Data were collected from patient's medical charts for the period of one year to calculate the scores using IMPEDE VTE, SAVED, and International Myeloma Working Group (IMWG) guidelines. The area under the curve (AUC) of the Receiver Operating Characteristic curve analysis was calculated to assess the discriminative power of three risk assessment models. We included 131 patients (9 in the VTE group versus 122 in the non VTE group). According to IMPEDE, 19.1, 62.6, and 18.3% of patients were considered low, intermediate, and high risk, respectively. SAVED classified 32.1% as high risk and 64.9% had ≥2 risk factors based on IMWG guidelines. The AUC of the IMPEDE VTE score was 0.80 (95% CI 0.66-0.95, p = 0.002), of the SAVED score was 0.69 (95% CI 0.49-0.89, p = 0.057), and of the IMWG risk score was 0.68 (95% CI 0.48-0.88, p = 0.075). IMPEDE VTE was the most accurate in predicting the development of VTE in Brazilian patients on IMID therapy. The SAVED score and the IMWG guidelines did not show discriminative ability in predicting VTE based on the population involved in this study.

Evaluation of risk management in a natalizumab home infusion procedure.

Natalizumab is a well-established disease-modifying therapy used in active multiple sclerosis (MS). The most serious adverse event is progressive multifocal leukoencephalopathy. For safety reasons, hospital implementation is mandatory. The SARS-CoV-2 pandemic has deeply affected hospital practices leading French authorities to temporarily authorize to administer the treatment at home. The safety of natalizumab home administration should be assessed to allow ongoing home infusion. The aim of the study is to describe the procedure and assess the safety in a home infusion natalizumab model. Patients presenting relapsing-remitting MS treated by natalizumab for over two years, non-exposed to John Cunningham Virus (JCV) and living in the Lille area (France) were included from July 2020 to February 2021 to receive natalizumab infusion at home every four weeks for 12 months. Teleconsultation occurrence, infusion occurrence, infusion cancelling, JCV risk management, annual MRI completion were analyzed. The number of teleconsultations allowing infusion was 365 (37 patients included in the analysis), all home infusions were preceded by a teleconsultation. Nine patients did not complete the one-year home infusion follow-up. Two teleconsultations canceled infusions. Two teleconsultations led to a hospital visit to assess a potential relapse. No severe adverse event was reported. All 28 patients who have completed the follow-up benefited from biannual hospital examination and JCV serologies and annual MRI. Our results suggested that the established home natalizumab procedure was safe using the university hospital home-care department. However, the procedure should be evaluated using home-based services outside the university hospital.

Clinical and fringe benefits of rituximab in multiple sclerosis treatment in a poor resource setting: Case series and cost analysis.

BACKGROUND: Multiple sclerosis (MS) is an inflammatory demyelinating condition of the central nervous system that leads to neurological disability and a poor quality of life (QoL). Rituximab has been used off-label in many countries to treat MS because of its high efficacy and affordability. However, there is no evidence of its effectiveness in Thailand. Therefore, the objective of this study was to evaluate the efficacy and additional benefits of rituximab in Thai patients with MS. METHODS: This was a prospective cohort study of patients diagnosed with MS who started treatment with rituximab between November 1, 2020, and October 31, 2022. Patients with MS eligible for the study received intravenous rituximab with a starting dose of 1000 mg at the first visit and another 1000 mg dose 2 weeks later. Thereafter, 1000 mg rituximab was administered every 6 months until the end of the study. The primary outcome was the annualized relapse rate (ARR). In addition, magnetic resonance imaging (MRI) activity of the gadolinium-enhancing lesion, QoL, number of hospital visits, and treatment costs were considered secondary outcomes. RESULTS: Ten patients diagnosed with relapsing-remitting multiple sclerosis were included in the study. The median ARR markedly decreased from 2.14 (0-4) to 0 (0-0.5) (p=0.005). The median Expanded Disability Status Scale score improved from 3.25 (1.5-6.0) to 1 (1-4) (p=0.005). The median number of enhancing lesions decreased from 1 (0-7) to 0 (0-3) (p=0.017). In addition, the median EuroQoL 5 Dimension 5 Level score, indicating QoL, improved from 0.7 (0.41-0.85) to 0.88 (0.68-1.00) (p=0.005). The median number of outpatient department visits significantly decreased from 6 (4-12) to 3 (2-5) (p=0.009). Hospitalization or inpatient department visits diminished from 1 (0-2) to 0 (0-1) (p=0.007). The total direct medical cost of rituximab treatment was not significantly different from that of the pre-treatment condition: 70,891 THB (65,391-116,358) VS 66,961 THB (33,927-109,248) or 1,904 USD (1,756-3,125 USD) VS 1,798 USD (911-2,934) (p=0.173). CONCLUSION: Rituximab was effective in the treatment of MS in Thailand. The use of rituximab reduced the number of relapses, reduced disability, decreased the number of active MRI lesions, and improved QoL. Moreover, the benefit of rituximab in treating MS in Thailand surpasses the current cost of treatment.

Prescription Claims for Immunomodulator and Antiinflammatory Drugs Among Persons With Ehlers-Danlos Syndromes.

OBJECTIVE: Joint hypermobility in Ehlers-Danlos Syndromes (EDS) predisposes persons with EDS to frequent subluxations and dislocations, chronic arthralgia, and soft-tissue rheumatism. Epidemiologic trends of rheumatologic conditions among persons with EDS are lacking. Prescription claims databases can reflect underlying disease burdens by using medication claims as disease proxies. We examined the prevalence of prescription claims for commonly prescribed immunomodulator and antiinflammatory (IMD) drugs among persons with EDS compared with their matched control person, and hypothesized peripubertal increases among female persons with EDS. METHODS: We compared the percentages of IMD drug prescription claims among 3,484 persons with EDS (ages 5-62 years) against their age-, sex-, state of residence-, and earliest claim date-matched control persons using 10 years (2005-2014) of private prescription claims data and a minimum 2-year enrollment inclusion criterion. RESULTS: Our cohort comprised 70% adults and 74% female persons. At least 1 IMD medication was prescribed to 65.4% of persons with EDS compared with 47.4% of control persons. We observed 1.3 to 4.2 times higher odds (P < 0.0001) for 5 out of 6 IMD drug classes among persons with EDS compared with matched control persons, except for biologic agents (conditional odds ratio 1.3, 95% confidence interval 0.8-2.0). Peripubertal increases were observed for nonsteroidal antiinflammatory drugs, oral, and injectable steroids. CONCLUSIONS: To our knowledge, our study is the first to examine the full range of IMD drug prescription claim trends among persons with EDS. We believe our research findings can have notable diagnostic and management implications for EDS patients who present with multiple comorbidities and generally require a more granular assessment of their medical conditions.

A real-world retrospective study of safety, efficacy, compliance and cost of combination treatment with rush immunotherapy plus one dose of pretreatment anti-IgE in Chinese children with respiratory allergies.

Background: The efficacy of allergen immunotherapy (AIT) in treating pediatric allergy has been clearly demonstrated, however, many patients hesitate to initiate AIT due to weekly hospital visits during the 3-4 months up-dosing phase. Meanwhile, rush immunotherapy (RIT) shortens the duration of the up-dosing phase to 7 days. However, considering that patients receiving RIT are exposed to the allergens during a much shorter period of time and thus may be at a greater risk of systemic reactions, RIT is currently underused, especially in children. This study investigated the utility of combination treatment with RIT plus 1 dose of pretreatment anti-IgE in children with respiratory allergies. Methods: In this retrospective study, we reviewed records of children with allergic rhinitis (AR) and/or allergic asthma (AA) sensitized to dust mite allergens receiving RIT+1 dose of pretreatment anti-IgE (the RIT group) or conventional immunotherapy (the CIT group) at our hospital from January 2020 to March 2021. Data such as visual analogue scale (VAS) scores, comprehensive symptom and medication score (CSMS), allergy blood test results, adverse reactions, compliance and cost were collected and analyzed. Results: 40 patients in the RIT group and 81 patients in the CIT group were included in this study. Both treatments were well tolerated and patients in the 2 treatment groups had comparable local and systemic reactions. Compared to CIT, RIT + anti-IgE combination led to significantly faster symptomatic improvement as demonstrated by significantly decreased VAS and CSMS starting as early as 1 month after AIT initiation (P<0.05). Nobody dropped out in the RIT group during the 1 year follow-up, while 11 out of 81 patients in the CIT group dropped out (loss rate 13.5%). Thus, the RIT group had a significantly higher compliance rate than the CIT group (P<0.05). Finally, the 2 treatment regimens had comparable cost per patient per injection (P> 0.05). Conclusions: RIT + 1 dose of pretreatment anti-IgE combination has practical advantages over CIT, including comparable safety, better compliance, and probably a faster onset of clinical efficacy at no additional cost, so it can be an useful regimen for the treatment of Chinese children with respiratory allergies.

Assessment of immunological anti-platelet factor 4 antibodies for vaccine-induced thrombotic thrombocytopenia (VITT) in a large Australian cohort: A multicenter study comprising 1284 patients.

BACKGROUND: Vaccine-induced thrombotic thrombocytopenia (VITT) is a rare complication of adenovirus-based vaccines aimed to prevent and minimize COVID-19 and related pathophysiology. OBJECTIVES: To describe patterns of testing for anti-platelet factor 4 (PF4) antibodies using various ELISA assays in a large Australian cohort and comparative functional platelet activation assays in a subset. PATIENTS/METHODS: Asserachrom HPIA IgG ELISA was performed in 1284 patients over a period of 12 months, supplemented in select cohorts by comparative ELISA using three other methods (n = 78-179), three different functional assays (flow cytometry, serotonin release assay, and/or Multiplate; n = 476), and rapid immunological chemiluminescence anti-PF4 assay (n = 460), in a multicenter study. RESULTS: For first episode presentations, 190/1284 (14.8%) ELISA tests were positive. Conversely, most (445/460; 96.7%) chemiluminescence anti-PF4 test results were negative. All functional assays showed associations of higher median ELISA optical density with functional positivity and with high rates of ELISA positivity (64.0% to 85.2%). Data also identified functional positivity in 14.8%-36.0% of ELISA negative samples, suggesting false negative VITT by HPIA IgG ELISA in upward of one third of assessable cases. CONCLUSION: To our knowledge, this is the largest multicenter evaluation of anti-PF4 testing for investigation of VITT. Discrepancies in test results (ELISA vs. ELISA or ELISA vs. functional assay) in some patients highlighted limitations in relying on single methods (ELISA and functional) for PF4 antibody detection in VITT, and also highlights the variability in phenotypic test presentation and pathomechanism of VITT.

Model-informed approach for risk management of bleeding toxicities for bintrafusp alfa, a bifunctional fusion protein targeting TGF-ß and PD-L1.

PURPOSE: Bintrafusp alfa (BA) is a bifunctional fusion protein composed of the extracellular domain of the transforming growth factor-ß (TGF-ß) receptor II fused to a human immunoglobulin G1 antibody blocking programmed death ligand 1 (PD-L1). The recommended phase 2 dose (RP2D) was selected based on phase 1 efficacy, safety, and pharmacokinetic (PK)-pharmacodynamic data, assuming continuous inhibition of PD-L1 and TGF-ß is required. Here, we describe a model-informed dose modification approach for risk management of BA-associated bleeding adverse events (AEs). METHODS: The PK and AE data from studies NCT02517398, NCT02699515, NCT03840915, and NCT04246489 (n = 936) were used. Logistic regression analyses were conducted to evaluate potential relationships between bleeding AEs and BA time-averaged concentration (Cavg), derived using a population PK model. The percentage of patients with trough concentrations associated with PD-L1 or TGF-ß inhibition across various dosing regimens was derived. RESULTS: The probability of bleeding AEs increased with increasing Cavg; 50% dose reduction was chosen based on the integration of modeling and clinical considerations. The resulting AE management guidance to investigators regarding temporary or permanent treatment discontinuation was further refined with recommendations on restarting at RP2D or at 50% dose, depending on the grade and type of bleeding (tumoral versus nontumoral) and investigator assessment of risk of additional bleeding. CONCLUSION: A pragmatic model-informed approach for management of bleeding AEs was implemented in ongoing clinical trials of BA. This approach is expected to improve benefit-risk profile; however, its effectiveness will need to be evaluated based on safety data generated after implementation.

First-line immunotherapy of neuronal surface antibody-mediated autoimmune encephalitis: Assessment of therapeutic effectiveness and cost-efficiency.

OBJECTIVE: To evaluate the therapeutic effectiveness and cost-efficiency of first-line immunotherapies on neuronal surface antibody-mediated autoimmune encephalitis (AE) based on a real-world observational study in China. METHODS: Our study retrospectively collected the clinical and paraclinical data of patients with definite neuronal surface antibody-mediated AE between July 2014 and July 2020. Regular follow-up was performed after administering standard regimens of first-line immunotherapies, including intravenous methylprednisolone (IVMP) and / or intravenous immunoglobulin (IVIG). Therapeutic effectiveness was reflected by modified Rankin Scale scores. The health resource utilization and direct medical costs were extracted to analyze the cost-efficiency. RESULTS: Among the 78 eligible patients, 48 (61.5%) were males with a median age of 40 years. More than half (56, 71.8%) were treated with combination therapy, with the rest receiving IVMP and IVIG monotherapy (both of 11, 14.1%). Related objective variables, i.e., sex, onset age, disease course, onset symptoms, antibody types, abnormal paraclinical results, disease severity, and the health insurance, showed insignificant differences on the selection of therapy. Each therapy showed similar short-term (4-week) and long-term (1-year) therapeutic effects. Yet the single or combination of IVIG had a slightly better effectiveness but higher cost than the monotherapy of IVMP. CONCLUSION: The combination of IVMP and IVIG was used more frequently than either alone, which may be associated with neurologist's personal experience and patient's wishes. Though with similar therapeutic effectiveness, the use of IVMP alone might be a better choice with a better cost-efficiency.

Assessment of rabies immune globulin dose rounding at a university health system.

PURPOSE: Describe a dose rounding strategy for rabies immune globulin (RIG) administration. METHODS: Multicenter, retrospective, observational review of patients that received RIG following an exposure from an animal with potential to transmit rabies infection in one health-system from March 2011 through December 2021. The primary outcome was to describe the RIG dose rounding strategy and population of patients that received RIG rounded to the nearest vial size compared to those that did not. Secondary outcomes evaluated additional costs and RIG international units (IU) wasted that could have occurred (rounded group) or did occur (not rounded group), re-presentation to the ED or primary care provider (PCP) within 7 days due to RIG related complaint, and occurrence of rabies infection. Data collection included patient demographics, exposure information, and RIG dose administered. Descriptive data and univariate analyses are reported. Cost and RIG IU wasted were calculated for the dosing strategies. RESULTS: 426 patients were included; 373 (88%) had RIG rounded to the nearest vial size and 53 (12%) did not (mean age 36.1 years ±20.5, 51.6% male, most common exposures were bats [50%], type was bite [58%], and category III exposures [92%]). Those that had RIG rounded were younger and had lower total RIG doses, but similar IU/kg doses to those not rounded. A cost savings of $144,815 and prevention of 40,572 RIG IU wasted was calculated from those patients that had RIG rounded. There was no difference in the rate of re-presentation within 7 days and no cases of human rabies infection in the region during the study period. CONCLUSIONS: RIG dose rounding to the nearest vial size is associated with cost savings and prevention of wasting RIG IU. There was no association with re-presentation to the ED or PCP with RIG related issues within 7 days from administration.

Cost-effectiveness analysis of house dust mite allergen immunotherapy in children with allergic asthma.

BACKGROUND: Cost-effectiveness studies evaluating allergen immunotherapy (AIT) in children are limited but needed to drive clinical and policy-making decisions such as reimbursement of new interventions. In this study, we compared the cost effectiveness of subcutaneous (SCIT) and sublingual immunotherapy (SLIT) tablets to the standard of care (SOC) treatment in children with house dust mite-driven (HDM) allergic asthma. METHODS: We developed a hypothetical Markov model based on the Global Initiative for Asthma (GINA) severity steps to compare the three strategies over a 10-year horizon divided by cycles of 6 months. SOC was used as a reference to calculate the incremental cost-effectiveness ratio (ICER). Deterministic and probabilistic sensitivity analyses were used to assess models' uncertainty. Other scenarios were evaluated to strengthen the presentation of results. RESULTS: The ICER for SCIT and SLIT tablets was 1281€ and 7717€, respectively. The cost-effectiveness threshold for Portugal was 18,482.80€; both treatment approaches were below this limit. The major contributors to these results were the AIT effects on reducing moderate and severe exacerbations and asthma controller medication. In the sensitivity analysis, SCIT revealed a higher probability of cost-effectiveness than SLIT. When including allergic rhinitis as comorbidity, ICER values reduced markedly, especially for SCIT intervention. CONCLUSIONS: AIT was cost effective in children with HDM-driven allergic asthma, especially when given by the subcutaneous route. The high probability of cost effectiveness, especially for SCIT, may drive future policy decisions and AIT-prescribing habits. AIT adherence greatly influenced the results highlighting the value of implementing strategies to promote adherence rates.

Immunotherapy-induced Colitis: A Comprehensive Review of Epidemiology, Clinical Presentation, Diagnostic Workup, and Management Plan.

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of a variety of malignancies including advanced melanoma, non-small cell lung cancer, renal cell carcinoma, head and neck cancers among others. Since their introduction, there has been significant improvement in survival and prognosis in patients with advanced malignancies. Unfortunately, improved outcomes have come at a price of significant immune-related adverse events, with those of the gastrointestinal tract being the most common. Gastrointestinal immune-related adverse events frequently present as diarrhea and colitis, the severity of which can range from mild diarrhea to fulminant colitis with intestinal perforation. Currently, management of ICI-induced colitis is primarily guided by retrospective studies and expert opinion. A significant number of ICI-induced colitis responds to high-dose corticosteroids; however, some patients require further therapy with biologics. There is limited information on the factors which may predispose patients to ICI-induced colitis. Future research elucidating these risk factors along with development of a scoring system could allow for risk-stratification of patients before initiation of ICI therapy. Such a system may help clinicians and patients keep a high index of suspicion regarding ICI-induced colitis and could hopefully reduce the incidence of severe cases. Similarly, future studies should investigate protective factors against ICI-induced colitis, which could potentially allow more patients to safely benefit from ICI therapy.