Reduce Relapse Rates Research Articles

A two-years real-word study with fingolimod: early predictors of efficacy and an association between EBNA-1 IgG titers and multiple sclerosis progression.

Although fingolimod, a sphingosine 1-phosphate receptor agonist, has shown to be an effective treatment reducing relapse rate and also slowing down the disability progression in relapsing-remitting multiple sclerosis (RRMS) patients, it is important to quickly identify those suboptimal responders. The main objective was to assess different clinical, radiological, genetic and environmental factors as possible early predictors of response in MS patients treated with fingolimod for 24 months. The secondary objective was to analyze the possible contribution of the environmental factors analyzed to the progression and activity of the disease along the 2-years of follow-up. A retrospective study with 151 patients diagnosed with MS, under fingolimod treatment for 24 months, with serum samples at initiation and six months later, and with clinical and radiological data at initiation and 24 months later, were included in the study. Clinical and radiological variables were collected to establish NEDA-3 (no evidence of disease activity: patients without relapses, disability progression and new T2 lesions or Gd+ lesions) and EDA (evidence of disease activity: patients with relapses and/or progression and/or new T2 lesions or gadolinium-positive [Gd+] lesions) conditions. Human leukocyte antigen II (HLA-II), EBNA-1 IgG and VCA IgG from Epstein-Barr virus (EBV) and antibody titers against Human herpesvirus 6A/B (HHV-6A/B) were also analyzed. A total of 151 MS patients fulfilled the inclusion criteria: 27.8% was NEDA-3 (37.5% among those previously treated with high efficacy therapies >24 months). The following early predictors were statistically significantly associated with NEDA-3 condition: sex (male; p=0.002), age at baseline (older; p=0.009), relapses 2-years before fingolimod initiation ≤1 (p=0.010), and absence of Gd+ lesions at baseline (p=0.006). Regarding the possible contribution of the environmental factors included in the study to the activity or the progression of the disease, we only found that EBNA-1 IgG titers decreased in 20.0% of PIRA (progression independent from relapse activity) patients vs. 73.3% of RAW (relapse-associated worsening) patients (p=0.006; O.R. = 11.0). MS patients that are male, older, and with a low clinical and radiological activity at fingolimod initiation have a greater probability to reach NEDA-3 condition after two years with this therapy. An intriguing association of EBV with the progression of the disease has also been described, but it should be further study in a larger cohort to confirm these results.

Preclinical efficacy of BRG1/BRM ATPase inhibitor in B lymphoblastic leukemia.

10030 Background: Acute lymphoblastic leukemia (ALL) is the most common blood cancer in children and young adults. While ALL has a high cure rate, approximately 20% of patients who initially respond to treatment relapse and prognosis post relapse remains poor. New therapeutic treatments are needed to reduce relapse rates in B-ALL pediatric patients and to minimize the toxic side effects seen with current therapies. We and others have previously shown that BRG1/BRM ATPase inhibitors have efficacy in targeting acute myeloid leukemia (AML) and one, FHD-286, is currently being evaluated for its use in AML in an ongoing clinical trial (NCT04891757). BRG1 and BRM are the ATP-dependent catalytic subunits of the SWI/SNF chromatin remodeling complex which has a critical role in controlling gene expression, cell growth and survival of AML cells. Our prior work revealed that BRG1/BRM ATPase inhibition leads to selective transient reduction of normal B cells. Further, data from Depmap also nominates SMARCA4, the gene encoding BRG1, as a dependency in B-ALL cell lines, leading us to hypothesize that BRG1/BRM inhibition may be an effective therapy for B-ALL. Methods: We treated B-ALL cell lines with varying genetic lesions ( KMT2A-rearranged: RS4;11, KOPN-8, SEM; ETV6::RUNX1 fusion: REH and DUX4-rearranged: Nalm6) with dose titrations of FHD-286 and measured cell growth over the course of six days. In addition, at 48- and 72-hours post-treatment, we assayed cells for viability, cell cycle kinetics, and apoptosis induction via flow cytometry to provide insight into FHD-286’s mechanism of action in B-ALL. Results: We found that FHD-286 treatment resulted in decreased cell growth in a dose-dependent manner across all B-ALL cell lines. While all cell lines were displayed reduced proliferation at nanomolar doses, sensitivity varied. Nalm6, REH and SEM cells were the most sensitive with low nanomolar IC50s (2-7nM). In contrast, two of the KMT2Ar B-ALL lines, RS4;11 and KOPN-8, required higher doses to achieve growth inhibition (40-70nM). To better understand the mechanism by which FHD-286 is affecting cell growth, we evaluate whether FHD-286 is targeting cell growth through the apoptotic pathway or through cell cycle arrest. Our preliminary data indicates cell growth inhibition is only slightly attributable to cell cycle arrest and apoptosis induction, leading us to explore terminal differentiation as a mechanism of slowed proliferation. Conclusions: Our results show FHD-286 can strongly inhibit B-ALL cell growth in vitro, indicating FHD-286 as a potential therapeutic agent to treat B-ALL. In vivo validation is ongoing. Further directions include defining the effect of FHD-286 on chromatin remodeling, gene expression, and exploring efficacy in combination therapy, which has been shown to increase FHD-286 efficacy against AML. Our data may ultimately justify inclusion of B-ALL patients in clinical studies of BRG1/BRM inhibitors.

Non-pharmacological interventions to prevent return of gastric ulcers: A systematic review

Recurrence of gastric ulcers is a significant concern, and non-pharmacological interventions play an important role in their prevention. This systematic review aims to evaluate the effectiveness of nonpharmacological interventions in preventing gastric ulcer recurrence. The aim of this research is Non-Pharmacological Interventions to Prevent Recurrence of Gastric Ulcers: A Systematic Review". The research method in this study was the literature method. The literature method was carried out by means of a comprehensive search carried out in several databases, including PubMed, Medline, Scopus, and the Cochrane Library, using predefined search terms. Studies published from (start date) to (end date) were included. Two independent reviewers screened articles, extracted data, and assessed the quality of included studies using standard tools. The results show that non-pharmacological interventions are quite promising in preventing recurrence of gastric ulcers. Dietary modifications, such as avoiding spicy and acidic foods, and adopting a balanced diet rich in fruits and vegetables, are associated with a reduced risk of relapse. Lifestyle changes, particularly smoking cessation and reducing alcohol consumption, have shown a positive impact on healing ulcers and preventing recurrence. Stress management techniques, such as relaxation exercises and cognitive behavioral therapy, show potential benefits in reducing ulcer recurrence rates. Complementary therapies, such as acupuncture and herbal remedies, have shown mixed results, with some studies showing positive effects in preventing recurrence. Non-pharmacological interventions offer a valuable approach to preventing gastric ulcer recurrence. Dietary modifications, lifestyle changes, stress management techniques, and complementary therapies show promising results in reducing relapse rates. These findings highlight the importance of integrating non-pharmacological interventions into gastric ulcer management and prevention strategies. Further research is needed to validate these findings and explore optimal implementation methods.

#3140 Investigating the impact of Anti-IL5 therapy in eosinophilic granulomatosis with polyangiitis (EGPA): a three year longitudinal perspective

Abstract Background and Aims In the randomized, placebo-controlled MIRRA trial [1] for relapsing and refractory eosinophilic granulomatosis with polyangiitis (EGPA), adjuvant therapy with 300 mg anti-IL5 mAB Mepolizumab [MEPO] for 12 months (M), accrued longer times in remission, reduced steroid exposure and reduced relapse rates [1]. The aim of this study is to analyze the outcome of 100 mg MEPO monthly s/c for a minimum of 36 months. Changes to adjuvant immunosuppression and indications for anti-IL5 class switch from MEPO 100 mg s/c to Benralizumab (BRZ) or Reslizumab (Res) were assessed. Method In this observational study, 20 EGPA patients received anti-IL5 therapy for a minimum of 36M (range 49-68M). All commenced on 100 mg s/c MEPO every four weeks. Anti-IL5 therapy switched to BRZ or Res due to partial response or intolerance. Assessment time points included MEPO commencement, 6, 12, 18, 24 and 36 months. Results Overall, there was a 50% reduction in steroid dose by 12 months. This continued to reduce to 24M, by which time 2 were off steroids and a further 10/20 (50%) on weaning dose ≤ prednisolone 5 mg/day. Mean steroid dose continued to decrease to 36 months. The number on adjuvant conventional immunosuppressants (ACIS), reduced over time from 10/20 (50%) at M0 to 4/20 (20%) by M24. Clinical benefits included ANCA serology normalized in all four positive patients by 12 months. Mean eosinophil count reduced from 0.42 mg ± 0.33 × 109/L at M0 to 0.04 ± 0.03 × 109/L at 12 and 24M. BVAS reduced from median 5 [3-7], to 0 [0-1] by 24M. The change in mean FEV1 over 12 months was from (M0) 2.11 ± 0.66 to (M12) 2.39 ± 0.62 and FVC (M0) 3.42 ± 0.87 to (M12) 3.67 ± 0.93/105.60 ± 20.47 respectively. All 20 EGPA patients receiving anti -IL5 therapy, ranging from 49-68M remain on therapy. At 36M, 9 have remained on 100 mg s/c MEPO. 10 (50%) have switched to an alternative anti-IL5 agent—10 switched to benralizumab, 1 initially on benralizumab to reslizumab. 9/10 had achieved partial response prior to switch (reduction in steroids / relapse rate), 1/10 had no response.. During the duration of the study, 3 patients had a break of therapy, but all resumed anti-IL5 treatment with good response. Hence, all 20 remain on anti-IL5 beyond 24M. After 36M, one patient required cyclophosphamide along with anti-IL5 therapy for myocarditis. A further patient had Rituximab for EGPA/ Rheumatoid arthritis overlap between anti-IL5 agents. Conclusion In this study, there was a 50% reduction in steroid dosage by 12 months and steroid requirements continue to decrease to 36M. By 24 months 2 are steroid free and a further 10 on weaning dose ≤5 mg. Furthermore, the number on adjuvant conventional immunosuppression reduced over the 24M (n = 4 at 24M). This study demonstrates that anti-IL5 therapy serves as a favorable model for steroid and conventional immunosuppressant minimization in EGPA. Clinical benefits of reduction in BVAS, improved pulmonary function tests and reduced serum eosinophilia were recorded. The relapsing nature of EGPA places a dependency of therapy on steroids and this study demonstrated sustained and ongoing improvement annually with continued anti-IL5 therapy. Some participants required a switch in anti-IL5 agent.

#2101 Beyond corticosteroids: rituximab in managing minimal change disease and glucocorticoid-related toxicity

Abstract Background and Aims Minimal Change Disease (MCD) is the primary cause of Nephrotic Syndrome in children, accounting for 10 to 20% of cases in adults. Glucocorticoids (GC) remain the cornerstone of treatment. Despite a positive response in the majority of patients, up to 25% experience frequent relapses, and up to 30% are GC-dependent, exposing them to significant GC-related toxicity. Rituximab has been increasingly used in these patients, although 2021 KDIGO guidelines still points to cyclophosphamide as the preferred second-line therapy. This study aims to describe a single-centre experience with RTX, examining its effectiveness and assessing its potential to reduce GC exposure. Method A retrospective cohort study was conducted on 19 patients with MCD who were considered for RTX at adult age at a tertiary hospital centre between 2015 and 2023. Patients who refused treatment, those with MCD associated with other glomerular diseases, and those with less than 6 months of follow-up post-RTX were excluded from the study. Results Twelve patients met the inclusion criteria, including 5 diagnosed before the age of 18. The mean age at RTX initiation was 38.8 ± 14.8 years, with 75% being male. The median MCD duration pre-RTX was 140.5 [18.8–353.5] months, and the median follow-up post-RTX was 18.0 [12.5–41] months. All patients had preserved renal function and exhibited GC-dependency and/or frequent relapses, with 8 patients having received prior cyclophosphamide and/or cyclosporine A (CsA) treatment. At RTX initiation, all patients were on GC therapy (median 11.1 [10–50] mg/day), with 4 also on CsA. 10 patients were in complete remission, while 2 were in a relapse phase, subsequently achieving complete remission. Various induction regimens were employed: 6 patients received 1000 mg of RTX twice within 2 weeks, 1 received a single dose of 1000 mg, and 5 received a single dose of 500 mg. Out of the 12 patients, 5 did not receive RTX maintenance administrations, while 6 received 500 mg of RTX every 6 to 9 months and 1 patient received 1000 mg every 6 months. Only one adverse event was reported, one uncomplicated upper respiratory tract infection. Regardless of the induction regimen, all patients maintained a sustained response with complete remission for the following 6 months. All the 7 patients who underwent RTX maintenance did not experience disease relapse, although 2 continued GC therapy (one due to an associated autoimmune disease). Among the 5 patients who did not undergo RTX maintenance, 3 maintained complete remission throughout the follow-up, with a mean time free from any immunosuppression of 14.8 ± 10.6 months. The other 2 patients relapsed at a mean time of 27.5 ± 0.7 months. After relapse, 1 patient resumed GC therapy, and both started RTX maintenance with 500 mg every 6 to 9 months, subsequently achieving and maintaining complete remission. Among the 12 patients, 9 discontinued GC (1 continued CsA) after an average of 5.9 ± 4.2 months post-RTX, with a mean GC-free period of 16.6 ± 13.2 months during the follow-up period. Conclusion RTX proved to be safe and effective for steroid-dependent and/or frequently relapsing MCD, even with a low induction single dose of 500 mg. This low induction regimen may be an effective and potentially preferable option to minimize toxicity. RTX can significantly reduce relapse rate and steroid dose, avoiding complications associated with extended and high-dose GC administration. Notably, this outcome was not achieved previously with cyclophosphamide or CsA. RTX maintenance therapy may not be universally required for all patients with MCD, since a long period without relapse can be observed after induction therapy. Considering the current absence of a marker for disease activity, it should be taken into account individual patient characteristics and disease severity, particularly previous relapses after RTX induction. Considering the RTX effectiveness, ability to extend remission, safety, and GC sparing ability, it should be seriously considered as the preferred second-line treatment.

Effectiveness of bladder retraining programme on bedwetting frequency and relapse rate of children with nocturnal enuresis

Nocturnal enuresis, or bedwetting, is a prevalent and emotionally challenging condition that has a significant impact on the behavior, psychological well-being, and social lives of school-aged children. This study aimed to assess the effectiveness of bladder retraining programme on bedwetting frequency and relapse rate among children with nocturnal enuresis. The study was conducted in two phases. The Phase I included a survey questionnaire to identify the prevalence of nocturnal enuresis among school children studying in Grade I to Grade X of 3 selected schools in Nashik, India. Out of 2150 prevalence questionnaires, 1900 filled in questionnaires were received back. 226 children were found to be positive for monosymptomatic nocturnal enuresis. A total of 160 children were selected from which 80 samples were included in experimental group and 80 were in control group. A three-step bladder retraining program was provided for parents and children in the experimental group. The parents and children from experimental group were called on the 15th day to reinforce the interventions. Posttests were conducted at 1st month (Posttest I), 3rd month (Posttest II), and 6th month (Posttest III/Relapse) for both experimental and control group. The total prevalence of nocturnal enuresis among 1900 school age children aged 6 years-15 years is found to be 11.89%. Out of the 226 enuretic children, majority 101 (44.69%) wet their beds 1-3 times per week while 48 (21.23%) children wet their beds Every night. Comparison of bedwetting frequency in both groups during Pretest, Posttest I, Posttest II and Posttest III using chi-square test showed that: In pretest there was no significant difference between children in experimental and control group as indicated by the non-significant P value 0.43. Whereas in posttest I, II & III, P value 0.001 indicates highly significant difference in bedwetting frequency of children in both the groups. Children in experimental group had a relapse rate of 3.75% and 100% relapse was observed in control group during posttest III (at 6th month). The study findings revealed a statistically significant reduction in bedwetting frequency within the experimental group (p=0.001), contrasting with the control group's non-significant change (p=0.17). Additionally, the relapse rate was markedly lower in the experimental group (3.75%) compared to the control group (100%). This aligns with Garcia-Fernandez and Petros' (2020) findings, where a squatting-based pelvic floor rehabilitation method demonstrated a significant reduction in bedwetting frequency, curing 86% of children. Van Kampen etal.'s (2009) study also supported the efficacy of pelvic floor muscle training in reducing relapse rates, providing further validation for the current study's findings. The 3 step bladder retraining programme was found to be very effective in reducing the bedwetting frequency and relapse rate among children. This study provides evidence supporting effectiveness of such tailored bladder retraining interventions in managing monosymptomatic nocturnal enuresis in school-aged children.

Effect of family intervention on relapse rate of Chinese patients with alcohol-dependent.

This study explored the impact of a family intervention on the relapse rate of Chinese patients with alcohol dependence. A total of 151 male patients with alcohol dependence who were discharged from the Substance Dependence Department of the Wenzhou Seventh People's Hospital from January to December 2020 were selected. They were divided into the control (n = 73) and experimental (n = 78) groups. Patients in both groups received routine alcohol cessation treatment. Moreover, patients in the experimental group were followed up by a professional psychiatrist to carry out individual family intervention. The Family Function Rating Scale (FAD), a Self-made general information questionnaire, and the Chinese version of the Family Intimacy and Adaptability Scale (FACESI-CV) were performed. Re-drinking rate and readmission rate were assessed. Family intervention could reduce relapse rate (31, 39.74%) and rehospitalization (27, 34.62%) compared with the control group. After family training, FAD factor scores were improved in the experiment group in comparison with the control group. Family training improved communication (18.2 ± 3.7), role (20.8 ± 2.5), emotional response (10.8 ± 1.8), emotional involvement (13.7 ± 1.2), behavioral control (19.8 ± 1.2), and overall functionality (23.5 ± 2.1) in the experiment group in comparison with the control group. After family training, intimacy (70.5 ± 8.7) and adaptability (64.1 ± 6.9) in the experiment group was higher than in the control group. After family intervention, Michigan Alcohol Dependence Scale (MAST) (9.21 ± 0.68) and Short-Form 36 (SF-36) (80.32 ± 4.47) in the experiment group were higher than the control group. Family intervention for families of patients with alcohol dependence can improve their family function, increase their family intimacy and adaptability, and reduce the rate of relapse.

Immunosuppressive therapy in elderly patients with neuromyelitis optica spectrum disorder: a retrospective multicentre study

BackgroundThe risk–benefit relationship of immunosuppressive therapies (ISTs) for elderly patients with neuromyelitis optica spectrum disorder (NMOSD) is not well established. This study aimed to investigate the safety and efficacy of...

Protocol for a randomised controlled trial of ketamine versus ketamine and behavioural activation therapy for adults with treatment-resistant depression in the community

IntroductionAlthough short-term benefits follow parenteral ketamine for treatment-resistant major depressive disorder (TR-MDD), there are challenges that prevent routine use of ketamine by clinicians. These include acute dissociative effects of parenteral...

Iraqi experts consensus on the management of relapsing remitting multiple sclerosis in adults

Objective In Iraq, a lack of evidence-based management protocols for diagnosing, treating, and managing multiple sclerosis (MS) poses risks of suboptimal outcomes and clinical practice variability and potential harm to the patients. This study aimed to develop consensus recommendations regarding the diagnosis and management of MS in Iraq, specifically focusing on treatment-naïve patients, suboptimal responders, and women of childbearing age during preconception, pregnancy planning, and lactation. Methods A survey was conducted to collect feedback from a panel of ten key opinion leaders (KOLs), who evaluated and discussed the statements to determine agreement levels. The mini-Delphi method was employed to establish a consensus on the management recommendations, and a meeting was held to analyze the responses and ensure that the recommendations were based on current evidence and followed a consensus-driven approach. Results The Revised McDonald Criteria is recommended for MS diagnosis, which includes evidence of dissemination of disease characteristics in space and time. Disease activity and progression can be monitored using relapses, MRI activity, and short-term disability progression. Experts suggest initiating treatment at diagnosis using higher efficacy medications, such as cladribine, ocrelizumab, natalizumab, or rituximab, for patients with high disease activity after careful risk stratification. Injectable interferon preparations have a tolerable risk profile but have drawbacks, such as the route and frequency of administration. Overall, disease-modifying therapies (DMTs) have shown efficacy in reducing relapse rates and short-term disability. Conclusion This article presents expert panel recommendations for managing MS in Iraq, taking into account international guidelines, medication updates, and local resources. However, practical questions remain regarding the real-world use of disease-modifying therapies (DMTs). Personalizing treatment based on disease severity, prognosis, and individual risk factors while adhering to guidelines is crucial. A collaborative approach between healthcare providers and patients, considering individual preferences, is vital for achieving treatment goals.

Long-Term Survival in an Adolescent and Young Adult with Metastatic Relapse of an Undifferentiated Embryonal Sarcoma of the Liver.

Undifferentiated embryonal sarcoma of the liver (UESL) is an extremely rare and aggressive malignancy in adults.1 Adults with UESL have a worse prognosis compared to pediatric population.2 Due to the rarity of this disease in adults, there has been a lack of information that assists in treatment decisions within this group. Improved understanding of UESL in adults might assist in understanding biological differences compared to pediatric cohorts as well as tailor treatments to improve their overall outcome. We described the management and outcome of a young adult managed at our center with metastatic relapsed UESL. For comparison, a PubMed search for adolescent and young adult (AYA) and adults with UESL was performed with the aim to review and address any distinct clinical features, different aspects of management and survival outcomes within this population. A 21-year-old male underwent right hepatectomy for a large 16 cm localized UESL with clear surgical margin and did not receive adjuvant chemotherapy. Seven months postsurgery, he relapsed with both local and metastatic disease and underwent chemotherapy with vincristine, doxorubicin, cyclophosphamide alternating with ifosfamide and etoposide achieving a complete metabolic response. This was followed by Stereotactic Ablative Radiation Therapy and surgical resection of residual disease. He remains free of disease 3 years since his diagnosis. We subsequently reviewed 42 AYA and adults (aged >15) with UESL (median age, 33 years) between 1991 and 2022. Most patients presented with localized UESL and for those treated with surgery alone, 67% developed recurrences. Those receiving multimodality treatment, better outcomes, and reduced relapse rate was achieved. Twenty-seven patients developed recurrences, 13 with local recurrences and 14 with metastatic relapse. The median time to relapse was 12 months. We reported a successful outcome in multimodality treatment which resulted in long remission in a young adult with relapsed UESL. Combination of perioperative chemotherapy with locoregional treatment is important to improve long-term survival in adults with metastatic UESL.

Examining the effect of family-based intervention programs used in psychosis on the disease: a systematic review

IntroductionPsychosis is a complex mental health condition that can have a significant impact on individuals and their families. Family-based intervention programs have been developed to provide support and education to both individuals with psychosis and their families. These programs aim to improve clinical and family outcomes, reduce relapse rates, and enhance the overall well-being of individuals and their families . This study examined the effect of family-based intervention programs used in psychosis on the disease by synthesizing evidence from a systematic review of relevant studies.Family interventions have shown promising results in improving clinical and family outcomes in long-standing psychosis (Sadath et al., 2015). These interventions focus on improving relationships through problem-solving and enhancing the understanding of the illness and its treatment (Kuipers et al., 2010).ObjectivesThe aim of this study was to evaluate the effect of intervention programs implemented for the families of individuals diagnosed with psychosis on the course of the disease.MethodsThe study was conducted between August and September 2023 in 3 databases (PubMed, Cochrane Library, Science Direct) using the keywords “psychosis”, “family interventions”, “family in psychosis”. These databases were preferred because they contain a significant amount of evidence-based literature in the field of biomedical sciences and psychology. Studies conducted between 2013 and 2023, whose full texts were accessed and written in Turkish and English were included in the study.ResultsAs of September 2023, 16 national and international research articles on the subject have been reached and the literature review continues. When the literature review is finalized, all study results will be presented together.ConclusionsThis review provides an overview of the effects of intervention programs implemented for the families of individuals diagnosed with psychosis on the course of the disease and solution suggestions. Family-based intervention programs have shown promise in improving clinical and family outcomes in psychosis. These programs focus on enhancing relationships, providing education, and reducing relapse rates. However, the implementation of family interventions in routine clinical services can be challenging due to various barriers. Peer support programs have emerged as a valuable addition to family interventions, providing a supportive environment for families to share their experiences and support one another. Future research should focus on addressing barriers to implementation and further exploring the benefits of peer-driven family support services in early intervention programs for psychosis.Disclosure of InterestNone Declared

Current and Emerging Treatment Options in Pediatric Onset Multiple Sclerosis

Pediatric onset multiple sclerosis (POMS), characterized by the onset of multiple sclerosis before the age of 18, is gaining increased recognition. Approximately 5 percent of MS cases manifest before the age of 18, with less than 1 percent occurring before the age of 10. Despite its rarity, pediatric MS exhibits distinct characteristics, with an association between younger age at onset and a comparatively slower disease progression. Despite this slower progression, individuals with POMS historically reach disability milestones at earlier ages than those with adult-onset multiple sclerosis. While various immunomodulatory agents demonstrate significant benefits in MS treatment, such as reduced relapse rates and slower accumulation of brain lesions on magnetic resonance imaging (MRI), the majority of disease-modifying therapies (DMTs) commonly used in adult MS lack evaluation through pediatric clinical trials. Current evidence is predominantly derived from observational studies. This comprehensive review aims to consolidate existing knowledge on the mechanisms of action, efficacy, safety profiles, and recommended dosages of available DMTs specifically in the context of pediatric MS. Furthermore, this review outlines recent advancements and explores potential medications still in developmental stages, providing a thorough overview of the current landscape and future prospects for treating POMS.

Therapeutic choices and disease activity after 2 years of treatment with cladribine: An Italian multicenter study (CladStop).

Cladribine tablets, a purine analogue antimetabolite, offer a unique treatment regimen, involving short courses at the start of the first and second year, with no further treatment needed in years 3 and 4. However, comprehensive evidence regarding patient outcomes beyond the initial 24 months of cladribine treatment is limited. This retrospective, multicenter study enrolled 204 patients with multiple sclerosis who had completed the 2-year course of cladribine treatment. The primary outcomes were therapeutic choices and clinical disease activity assessed by annualized relapse rate after the 2-year treatment course. A total of 204 patients were enrolled; most patients (75.4%) did not initiate new treatments in the 12 months postcladribine. The study found a significant reduction in annualized relapse rate at the 12-month follow-up after cladribine completion compared to the year prior to starting therapy (0.07 ± 0.25 vs. 0.82 ± 0.80, p < 0.001). Furthermore, patients with relapses during cladribine treatment were more likely to start new therapies, whereas older patients were less likely. The safety profile of cladribine was favorable, with lymphopenia being the primary registered adverse event. This study provides insights into therapeutic choices and disease activity following cladribine treatment. It highlights cladribine's effectiveness in reducing relapse rates and disability progression, reaffirming its favorable safety profile. Real-world data, aligned with previous reports, draw attention to ocrelizumab and natalizumab as common choices after cladribine. However, larger, prospective studies for validation and a more comprehensive understanding of cladribine's long-term impact are necessary.

Bruton tyrosine kinase inhibitors in multiple sclerosis: evidence and expectations.

Despite availability of high-efficacy therapies for multiple sclerosis (MS), many patients experience significant disability worsening due to limited effects of currently available drugs on central nervous system (CNS)-compartmentalized inflammation. Bruton tyrosine kinase (BTK) is an intracellular signaling molecule involved in regulation of maturation, survival, migration, and activation of B cells and microglia, which are central players in the immunopathogenesis of progressive MS. Therefore, CNS-penetrant BTK inhibitors may better prevent disease progression by targeting immune cells on both sides of the blood-brain barrier. This review gives an overview on the preliminary results of clinical trials. Currently, the efficacy and safety of six BTK inhibitors are being evaluated in clinical trials in patients with relapsing and progressive MS. Evobrutinib, tolebrutinib and fenebrutinib have shown efficacy and safety in relapsing MS in phase 2 studies, and evobrutinib and tolebrutinib in their extension studies up to 3-5 years. However, evobrutinib failed to distinguish itself from the comparator drug teriflunomide in reduction of relapse rate (primary end point) in two phase 3 studies in relapsing MS. Inhibition of BTK has emerged as a promising therapeutic approach to target the CNS-compartmentalized inflammation. Results from phase 3 clinical trials will shed light on differences in efficacy and safety of BTK inhibitors and its potential role in the future MS landscape.

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.

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. 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. 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. 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.

Substantial and comparable suppression of disease activity following early initiation of cladribine tablets, ocrelizumab or alemtuzumab as first pharmacologic treatment for relapsing multiple sclerosis: A real world study

BackgroundWe describe the efficacy and safety of recent high efficacy disease DMTs in DMT-naive patients with highly active RMS. MethodsThis was a retrospective, cross sectional study from the Kuwait national MS registry. Patients with RMS who received alemtuzumab, cladribine tablets or ocrelizumab as their first DMT for RMS, with ≥2 year of follow up were included. The primary endpoint was the change in relapse rate from treatment initiation to 1 year; changes in disability (Expanded Disability Status Scale [EDSS]), radiologic activity, the proportion with no evidence of disease activity-3 (NEDA-3), and the frequency of adverse events were secondary endpoints. ResultsAmong 123 RRMS patients, 59 received ocrelizumab, 32 received cladribine tablets and 32 received alemtuzumab. About two-thirds (65%) were women. Substantial and similar (p>0.05) reductions occurred at the end of follow-up in annual relapse rate (by 93.2% for ocrelizumab, 87.5% for cladribine tablets, and 90.6% for alemtuzumab). The proportion with new T2 of gadolinium-enhancing MRI lesions across the three groups was reduced from 85–100% to 7–13%. Rates of confirmed disability progression were low (ocrelizumab 6.9%, cladribine tablets 3.1%, alemtuzumab 0%; p=0.280); disability was reduced in 15%, 22% and 38%, respectively. NEDA-3 was observed in 89.8%, 87.5%, and 84.4, respectively (p=0.784). No new or unexpected safety issues occurred. ConclusionOcrelizumab, cladribine tablets and alemtuzumab reduced relapse rates and MRI activity, and prevented disease progression, when are initiated early in DMT-naive RMS patients. These data support the early use of high-efficacy DMTs for people with highly active RMS.

The impact of fluphenazine withdrawal: a mirror-image study.

Fluphenazine decanoate licenced as a long-acting injectable (LAI) first-generation antipsychotic (FGA) was withdrawn from sale in 2018. This study evaluates if its withdrawal resulted in increased relapse rates of psychosis in an Irish patient cohort and examines which prescribed alternative antipsychotic medications were associated with more optimal outcomes. Fifteen participants diagnosed with a psychotic disorder were included. A mirror-image study over 24-months' pre-and post-withdrawal of fluphenazine was conducted. Kaplan-Meier survival and proportional hazards analyses were conducted. The impact of alternate antipsychotic agents (LAI flupenthixol compared to other antipsychotic medications) was evaluated. Semi-structured interviews with participants examined subjective opinions regarding the change in their treatment. Seven participants (46.7%) relapsed in the 24-month period subsequent to fluphenazine discontinuation compared to one individual (6.7%) in the previous identical time-period (p = 0.035). Flupenthixol treatment was associated with reduced relapse rates compared to other antipsychotics (χ2 = 5.402, p = 0.02). Thematic analysis revealed that participants believed that the discontinuation of fluphenazine deleteriously impacted the stability of their mental disorder. The withdrawal of fluphenazine was associated with increased relapse rate in individuals previously demonstrating stability of their psychotic disorder. While acknowledging the limitation of small sample size, preliminary evidence from this study suggests that treatment with the first-generation antipsychotic (FGA) flupenthixol was associated with a lower risk of relapse compared to SGAs. Reasons for this lower risk of relapse are not fully clear but could be related to dopamine hypersensitivity with this treatment change.

Association of oral disease-modifying agents and their adherence trajectories with annual relapses in multiple sclerosis

BackgroundReal-world effectiveness can vary across oral disease-modifying agents (DMAs) and their adherence trajectories in patients with multiple sclerosis (MS). However, previous studies have not considered longitudinal adherence patterns while evaluating oral DMAs. ObjectivesThis study aimed to evaluate the association of oral DMAs and their adherence trajectories with annualized relapse rate (ARR) in patients with MS. MethodsThis retrospective observational cohort study based on the 2015–2019 MarketScan Commercial Claims and Encounters Database involved continuous enrolled adults (18–64 years) with ≥1 MS diagnosis (ICD-9/10-CM:340/G35) and ≥ 1 oral DMA prescription. Patients were grouped into incident fingolimod (FIN), teriflunomide (TER), and dimethyl fumarate (DMF) users based on the index DMA with a one-year washout period. Annual DMA adherence trajectories based on the monthly Proportion of Days Covered (PDC) one year after treatment initiation were identified using Group-Based Trajectory Modeling (GBTM). The validated claims-based ARR was evaluated during the one-year follow-up period using generalized boosted model-based inverse probability treatment weights with negative binomial regression model. ResultsThe study cohort consisted of 994 MS patients who initiated with FIN (23.0%), TER (22.3%), and DMF (54.7%) during the study period. GBTM grouped eligible patients into three adherence trajectories: complete adherers (59.2%), slow decliners (23.8%), and rapid decliners (17.0%). The proportion of complete adherers varied across the oral DMAs (FIN: 67.1%, TER: 55.4%, and DMF: 57.4%). The negative binomial regression modeling revealed that, while there was no difference in ARR across the three DMAs, rapid decliners (adjusted incidence rate ratio[aIRR]: 1.6, 95% CI: 1.1–2.4) had a higher rate of relapses compared to completely adherent patients. The type of oral DMAs did not moderate the relationship between ARR and the adherence trajectory groups. ConclusionsAdherence trajectories classified as rapid decliners were associated with a higher ARR than complete adherers after adjusting for their type of oral DMAs. Longitudinal medication adherence patterns are critical in reducing relapse rates in MS.

The first study of real-world efficacy and safety of Natalizumab (Tysabri®) in Iran

Objectives: Natalizumab is an injectable DMT (disease-modifying therapy) which used for RRMS (relapsing-remitting multiple sclerosis) since 2006. The drug has been available in Iran since 2014. Introduction: This study was aimed to evaluate the real-world effectiveness of Natalizumab in a referral center in Tehran, Iran. This study is the first real world analysis of efficacy and safety of Natalizumab in our country. Methods: In this retrospective study, patients with RRMS were investigated in a high-volume center in Tehran from 2019 to 2021. MS (Multiple Sclerosis) patients under treatment with Natalizumab who have received at least 3 infusions of the drug and had completed follow-up data, have been evaluated for safety and efficacy of Natalizumab. Results: 100 patients were included in the final analysis. The mean follow-up time was 20 months (6–33 months). The median EDSS (Expanded Disability Status Scale) score of patients reached to 2 from 2.5 after the treatment course (P &lt; 0.0001). The annualized relapse rate (ARR) decreased from 0.81 (95% CI: 0.73–0.87) to 0.023 (95% CI 0.009–0.061). The median JCV (John Cunningham virus) index remained unchanged before treatment 0.85 (IQR: 0.21–2.41) compare to after the treatment 0.85 (IQR: 0.21–2.31). The number of patients with active brain and cervical MRI (Magnetic Resonance Imaging) lesions decreased significantly (P = 0.001). NEDA-3 (No evidence of disease activity) was improved from 9% to 87% after the treatment with Natalizumab. No serious adverse events except than one progressive multifocal encephalopathy (PML) case have been found. The main reasons of switching from Natalizumab to the other DMDs (Disease Modifying Drugs) were positive JC index, starting phase, noncompliance, pregnancy, MRI activity and seroconversion after starting the drug. Conclusion: Natalizumab is a safe and effective choice in RRMS patients for reducing relapse rate, disability score, active MRI lesion, and improving the NEDA (No evidence of disease activity).