Relapsing Forms Research Articles

Meaningful Change Thresholds and Fatigue Severity Points on Patient-Reported Outcomes by the Fatigue Symptoms and Impacts Questionnaire in Patients With Relapsing Multiple Sclerosis

ObjectivesThe Fatigue Symptoms and Impacts Questionnaire-Relapsing Multiple Sclerosis (FSIQ-RMS) is a new content-valid, concise, and reliable 20-item patient-reported outcome measure to evaluate the symptoms and impacts of fatigue in patients with relapsing forms of multiple sclerosis. Analyses were performed to derive meaningful change thresholds (MCTs) on patient-reported outcomes as measured by FSIQ-RMS and generate receiver operating characteristic (ROC) curves to determine fatigue severity cut points at baseline and change in severity at post-baseline and supplement the anchor-based MCT results. MethodsAnalyses were based on data from the OPTIMUM trial (NCT02425644). An anchor-based approach using uncollapsed changes on the Patient Global Impression of Severity at week 108 were used to determine the MCT for only the FSIQ-RMS Symptoms domain; distribution-based MCT estimations were conducted using baseline FSIQ-RMS Impacts scores. ROC curves with calculation of area under the curve were used to identify the best cut point. ResultsBased on the evidence provided by the anchor-based analyses using the Patient Global Impression of Severity as an anchor for the FSIQ-RMS Symptoms domain, meaningful score changes for improvement and deterioration were −6.3 and 6.3, respectively. Meaningful score changes for the FSIQ-RMS Physical, Cognitive/Emotional, and Coping Impacts domains using distribution-based methods were 10.8, 8.4, and 9.8, respectively. These results are supported by the ROC analyses. ConclusionsThresholds to support interpretation of the FSIQ-RMS, such as MCTs, can be used to determine and categorize patients who have experienced a meaningful change in their MS-related fatigue (eg, responder analyses) in future clinical research studies.

Personalized treatment options of refractory and relapsed medulloblastoma in children: literature review

Medulloblastoma (MB) is the most common malignant tumor of the central nervous system in pediatric patients. Despite the complex anticancer therapy approach, refractory and relapsing forms of the disease remain fatal in most cases and account for approximately 30%. To date, repeated surgery, radiation, and chemotherapy can be used as life-prolonging treatment options; nevertheless, it should be emphasized that there are no standardized approaches based on existing data of molecular variants of MB. It is obvious that only a deep understanding of the biological mechanisms in association with clinical aspects in refractory and relapsing forms of MB would make it possible to personalize second- and subsequent-line therapy in order to achieve maximum efficiency and minimize early and long-term toxicity. The article presents the current understanding of prognostic factors in relapsed/refractory forms of MB, methods of modern diagnostics, as well as existing and perspective treatment options based on the biological and clinical aspects of the disease.

Successful treatment of multiple sclerosis with refractory rheumatoid arthritis using ofatumumab: A case report

AbstractBackgroundOfatumumab is an anti‐CD20 human monoclonal antibody that is approved in several countries worldwide for the treatment of relapsing forms of multiple sclerosis (MS). Recent studies have shown promising results of ofatumumab therapy for rheumatoid arthritis (RA). We report a case with both MS and refractory RA that was successfully treated with ofatumumab.Case PresentationA 44‐year‐old woman with a history of RA since the age of 40, and prior treatment with methotrexate, prednisolone, and several disease‐modifying antirheumatic drugs (DMARDs), including salazosulfapyridine, iguratimod, tacrolimus, presented with a recent onset of visual acuity loss in the left eye. Ophthalmic examination revealed a decreased central flicker frequency (CFF) and central scotoma. Brain magnetic resonance imaging (MRI) revealed periventricular multiple lesions and contrast enhancement of the left optic nerve. Cerebrospinal fluid analysis revealed mild lymphocytic pleocytosis, elevation of protein, and oligoclonal bands. Serum anti‐aquaporin‐4 (AQP4) antibodies, anti‐myelin oligodendrocyte glycoprotein (MOG) antibodies, and other serological tests for optic neuritis were unremarkable. She was diagnosed with relapsing and remitting MS at 10 months after development of optic neuritis when she experienced a relapse, accompanied by new asymptomatic lesions detected on brain MRI. After ofatumumab administration, we discontinued all DMARDs and maintained remission over a 12‐month period.ConclusionThere is growing evidence of significant involvement of B‐cells in the pathogenesis of RA and the effectiveness of B‐cell depletion therapy in managing RA. Ofatumumab is an effective treatment for patients with MS and refractory RA.

P687 Ozanimod as a once-daily oral therapy for Japanese patients with ulcerative colitis: results from the induction period of a Phase 2/3 study (J-True North)

Abstract Background Ozanimod is an oral, small molecule sphingosine 1-phosphate (S1P) receptor modulator that selectively targets the S1P1 and S1P5 receptor subtypes. Ozanimod is approved in multiple countries outside Japan for the treatment of moderately to severely active ulcerative colitis (UC) and/or relapsing forms of multiple sclerosis. We herein report the efficacy and safety results during the induction period of J-True North, a multi-centre, randomised, double-blind, placebo-controlled clinical Phase 2/3 study consisting of a 12-week induction period, followed by a 40-week maintenance period and an open-label extension period in Japanese patients with moderately to severely active UC. Methods Japanese male and female UC patients aged 18 to 75 years with moderately to severely active UC (defined as Mayo score of 6 to 12, with endoscopic subscore ≥2, rectal bleeding score (RBS) ≥1, and stool frequency score ≥1) were randomised in a 1:1:1 ratio to receive either 0.46 mg or 0.92 mg ozanimod, or placebo capsules orally once daily. All patients had received prior treatment with aminosalicylates or corticosteroids. The primary endpoint was clinical response at Week 12 (defined as a reduction from baseline in the complete Mayo score of ≥ 3 points and ≥ 30%, and a reduction from baseline in the RBS of ≥ 1 point or an absolute RBS of ≤ 1 point), and key secondary endpoints were clinical remission, clinical response, endoscopic improvement, mucosal healing and safety at Week 12 and 52. Results Patients were randomised to the ozanimod 0.46 mg group (n=68), 0.92 mg group (n=65), and the placebo group (n=65). At baseline, 36.4% of patients were female, mean age was 42.6 y and mean complete Mayo score was 8.4. The clinical response rate at Week 12 was 52.9%, 61.5%, and 32.3% in the ozanimod 0.46 mg, 0.92 mg, and placebo groups, respectively, demonstrating a statistically significant improvement of ozanimod vs placebo (Figure 1). Similarly, higher improvement rates were observed in all key secondary clinical and endoscopic endpoints in the ozanimod groups compared with the placebo group at Week 12. Frequent adverse events (AEs) observed in the induction period were nasopharyngitis, headache, et.al. (Table 1). AEs observed in the study were similar to those in the global phase 3 True North study with 0.92 mg ozanimod, and there were no new safety signals with ozanimod in the J-True North study. Conclusion Ozanimod as a once-daily oral therapy was effective as induction therapy for Japanese patients with moderately to severely active UC, and the safety profile was consistent with the results of previous studies. Figure 1 Table 1

Comparison of injective related reactions following ofatumumab and ocrelizumab in patients with multiple sclerosis: data from the European spontaneous reporting system.

In 2021 ofatumumab, a recombinant human anti-CD20 monoclonal antibody (mAb) already authorized for the treatment of chronic lymphocytic leukemia, received the marketing approval for the treatment of relapsing forms of multiple sclerosis (MS). Differently from ocrelizumab, that is administered intravenously, ofatumumab if the first anti-CD20 mAb to be administered subcutaneously without a premedication. In this study we aimed to describe and compare the main characteristics of Individual Case Safety Reports (ICSRs) describing the occurrence of Injective Related Reactions (IRRs) following the treatment with ocrelizumab and ofatumumab reported in the Eudravigilance (EV) database during years 2021-2023. A total of 860 ICSRs with either ofatumumab and ocrelizumab as suspected drug were retrieved from Eudravigilance, of which 51% associated with ofatumumab and 49% with ocrelizumab. The majority of patients who experienced IRRs following ocrelizumab belonged to the age group of 18-64 years (73%), while the age-group was mostly not specified (55%) in ICSRs reporting ofatumumab as suspected. The distribution of gender was almost similar in the two groups, with the majority of ICSRs related to female patients. "Pyrexia" was the Preferred Term (PT) most reported for ofatumumab, while "Infusion related reaction" were more frequently reported with ocrelizumab. Premedication drugs were reported in 148 ICSRs. Out of 89 ICSRs for which the Time to Event (TTE) was calculated, 74 reported IRRs that occurred the same day of the drug administration. Based on the results of this study, although a risk of ofatumumab-induced IRRs cannot be excluded, it should be considered as manageable considering that the drug seems to be mostly associated with the occurrence of fever. Thus, it is important to continue to closely monitor the use of these in clinical practice to improve the knowledge on their long-term safety.

Cladribine tablets after treatment with natalizumab (CLADRINA) - rationale and design.

Individual disease modifying therapies approved for multiple sclerosis (MS) have limited effectiveness and potentially serious side effects, especially when administered over long periods. Sequential combination therapy is a plausible alternative approach. Natalizumab is a monoclonal therapeutic antibody that reduces leukocyte access to the central nervous system that is associated with an increased risk of progressive multifocal leukoencephalopathy and disease reactivation after its discontinuation. Cladribine tablets act as a synthetic adenosine analog, disrupting DNA synthesis and repair, thereby reducing the number of lymphocytes. The generation of prospective, rigorous safety, and efficacy data in transitioning from natalizumab to cladribine is an unmet clinical need. To test the feasibility of transitioning patients with relapsing forms of MS natalizumab to cladribine tablets. Cladribine tablets after treatment with natalizumab (CLADRINA) is an open-label, single-arm, multicenter, collaborative phase IV, research study that will generate hypothesis regarding the safety, efficacy, and immunological impact of transition from natalizumab to cladribine tablets in patients with relapsing forms of MS. Participants will be recruited from three different sites. The primary endpoint is the absolute and percent change from baseline of lymphocytes and myeloid cell subsets, as well as blood neurofilament light levels. The secondary endpoint is the annualized relapse rate over the 12- and 24-month trial periods. Exploratory endpoints include the expanded disability status scale, and magnetic resonance imaging outcomes. The CLADRINA trial will generate data regarding the safety, efficacy, and immunological impact of the transition from natalizumab to cladribine. As the pace of immunological knowledge of MS continues, insight into disease modifying therapy transition strategies is needed.

The role of ocrelizumab in recommendations and in the Polish therapeutic programme

Multiple sclerosis is a heterogeneous and chronic disease, and the primary goal of treatment is to prevent relapses and slow the progression of disability. Ocrelizumab is a generally well-tolerated disease-modifying therapy for multiple sclerosis, with high efficacy in the treatment of active relapsing forms, and a valuable treatment method for delaying the progression of the disease in patients with the primary progressive form. The activity of relapsing multiple sclerosis is defined on the basis of the clinical course of the disease or radiological findings assessed over a year. The occurrence of clinical relapses and/or activity on magnetic resonance imaging is taken into account. In line with the recommendations of the European Committee for Treatment and Research in Multiple Sclerosis and the European Academy of Neurology, as well as in accordance with the guidelines of the American Academy of Neurology, updated in 2021, depending on the disease activity in the early stage of multiple sclerosis, the choice of a disease-modifying drug should be motivated by higher efficacy. Recommendations for the treatment of multiple sclerosis in most countries in Europe and around the world are based on the above-mentioned guidelines. In Poland, recommendations for treatment modifying the course of multiple sclerosis were developed in 2023 by experts from the Multiple Sclerosis and Neuroimmunology Section of the Polish Neurological Society. Treatment based on the B.29 drug programme of the National Health Fund in Poland allows, from 1 July 2023, in addition to escalation, using the induction model based on highly effective therapies as first-line treatment.

Prevalence of G6PD deficiency and submicroscopic malaria parasites carriage in malaria hotspot area in Northwest, Tanzania

BackgroundThe use of primaquine for mass drug administration (MDA) is being considered as a key strategy for malaria elimination. In addition to being the only drug active against the dormant and relapsing forms of Plasmodium vivax, primaquine is the sole potent drug against mature/infectious Plasmodium falciparum gametocytes. It may prevent onward transmission and help contain the spread of artemisinin resistance. However, higher dose of primaquine is associated with the risk of acute haemolytic anaemia in individuals with a deficiency in glucose-6-phosphate dehydrogenase. In many P. falciparum endemic areas there is paucity of information about the distribution of individuals at risk of primaquine-induced haemolysis at higher dose 45 mg of primaquine.MethodsA retrospective cross-sectional study was carried out using archived samples to establish the prevalence of G6PD deficiency in a malaria hotspot area in Misungwi district, located in Mwanza region, Tanzania. Blood samples collected from individuals recruited between August and November 2010 were genotyped for G6PD deficiency and submicroscopic parasites carriage using polymerase chain reaction.ResultsA total of 263 individuals aged between 0 and 87 were recruited. The overall prevalence of the X-linked G6PD A− mutation was 83.7% (220/263) wild type, 8% (21/263) heterozygous and 8.4% (22/263) homozygous or hemizygous. Although, assessment of the enzymatic activity to assign the phenotypes according to severity and clinical manifestation as per WHO was not carried out, the overall genotype and allele frequency for the G6PD deficiency was 16.4% and 13. 2%, respectively. There was no statistically significant difference in among the different G6PD genotypes (p > 0.05). Out of 248 samples analysed for submicroscopic parasites carriage, 58.1% (144/248) were P. falciparum positive by PCR. G6PD heterozygous deficiency were associated with carriage of submicroscopic P. falciparum (p = 0.029).ConclusionsThis study showed that 16.4% of the population in this part of North-western Tanzania carry the G6PD A− mutation, within the range of 15–32% seen in other parts of Africa. G6PD gene mutation is widespread and heterogeneous across the study area where primaquine would be valuable for malaria control and elimination. The maps and population estimates presented here reflect potential risk of higher dose of primaquine being associated with the risk of acute haemolytic anaemia (AHA) in individuals with a deficiency in glucose-6-phosphate dehydrogenase and call further research on mapping of G6PD deficiency in Tanzania. Therefore, screening and education programmes for G6PD deficiency is warranted in a programme of malaria elimination using a higher primaquine dose.

Engineering the best transplant outcome for high-risk acute myeloid leukemia: the donor, the graft and beyond

Allogeneic hemopoietic cell transplantation remains the goal of therapy for high-risk acute myeloid leukemia (AML). However, treatment failure in the form of leukemia relapse or severe graft-versus-host disease remains a critical area of unmet need. Recently, significant progress has been made in the cell therapy-based interventions both before and after transplant. In this review, the Stem Cell Engineering Committee of the International Society for Cell and Gene Therapy summarizes the literature regarding the identification of high risk in AML, treatment approaches before transplant, optimal transplant platforms and measures that may be taken after transplant to ideally prevent, or, if need be, treat AML relapse. Although some strategies remain in the early phases of clinical investigation, they are built on progress in pre-clinical research and cellular engineering techniques that are already improving outcomes for children and adults with high-risk malignancies.

The Efficacy of Fingolimod and Interferons in Controlling Disability and Relapse Rate in Patients with Multiple Sclerosis: A Systematic Review and Meta-Analysis.

Fingolimod and interferons are used in the relapse form of multiple sclerosis (MS). The goal of this systematic review and meta-analysis was to evaluate the efficacy of fingolimod versus interferon in patients with MS. The systematic search was done in PubMed, Scopus, Embase, Web of Science, and Google Scholar. The references of included studies as well as conference abstracts were searched up to July 2021. The literature search revealed 8211 articles, and after deleting duplicates 5594 remained. For the meta-analysis, four studies were included. The standardized mean difference (SMD) of the Expanded Disability Status Scale (EDSS) after treatment (interferon vs fingolimod) was -0.06 (95% CI: -0.28, 0.17) (I2 = 80.2%, P = 0.002). The SMD of the annual relapse rate (ARR) after treatment (interferon - fingolimod) was -0.08 (95% CI: -0.53, 0.36) (I2 = 95.5%, P < 0.001). The SMD of the ARR after treatment and before treatment in the interferon group was - 1.45, (95% CI: -1.55, -1.36) (I2 = 0, P = 0.3). The SMD of ARR after treatment and before treatment in the fingolimod group was - 1.3, (95% CI: -1.94, -0.65) (I2 = 97.4%, P < 0.001). Conclusions: The results of this systematic review show that efficacy of interferon and fingolimod in controlling relapse rate and disability is similar.

Practical Clinical Guidelines for Natalizumab Treatment in Patients With Relapsing Multiple Sclerosis.

Natalizumab (TYSABRI®) was the first high-efficacy monoclonal antibody disease-modifying therapy (DMT) approved as a monotherapy for the treatment of adults with relapsing forms of multiple sclerosis (MS), including clinically isolated syndrome, relapsing-remitting MS, and active secondary progressive MS. Because natalizumab is administered by intravenous infusion, infusion nurses play a key role in the care of natalizumab-treated patients. In the 16 years since approval, substantial data have been gathered on the long-term, real-world effectiveness and safety of natalizumab. This article provides a synopsis of this data, as well as practical information for optimizing patient care. This includes information on strategies to mitigate the risk of progressive multifocal leukoencephalopathy in natalizumab-treated patients, natalizumab use during pregnancy, and use with vaccines. It also includes guidance on the preparation and administration of natalizumab and monitoring of natalizumab-treated patients.

Effectiveness and Safety of Teriflunomide in Relapsing-Remitting Multiple Sclerosis and Improvements in Quality of Life: Results from the Real-World TERICARE Study.

Teriflunomide is a once-daily oral immunomodulator approved for relapsing forms of multiple sclerosis (MS) or relapsing-remitting multiple sclerosis (RRMS; depending on the local label), based on extensive evidence from clinical trials and a real-world setting on efficacy, tolerability and patient-reported benefits. The TERICARE study assessed the impact of teriflunomide treatment over 2years on health-related quality of life (HRQoL) and some of the most common and disabling symptoms of MS, such as fatigue and depression. This prospective observational study in Spain included RRMS patients treated with teriflunomide for ≤ 4weeks. The following patient-reported outcomes (PROs) were collected at baseline and every 6months for 2years: the 29-item Multiple Sclerosis Impact Scale version 2 (MSIS-29), the 21-item Modified Fatigue Impact Scale (MFIS-21), the Beck Depression Inventory (BDI-II), the Short Form (SF)-Qualiveen and theTreatment Satisfaction Questionnaire for Medication v1.4 (TSQM). Annualised relapse rate (ARR), disability progression according to the Expanded Disability Status Scale (EDSS), and no evidence of disease activity (NEDA-3) were also assessed. A total of 325 patients were analysed. Patients had a mean (SD) age of 43.2years (10.4), a mean baseline EDSS score of 1.75 (1.5), a mean number of relapses in the past 2years of 1.5 (0.7), and 64% had received prior disease-modifying therapy (DMT). Patients showed significant improvements in the psychological domain of MSIS-29 from 35.9 (26.6) at baseline to 29.4 (25.5) at 18months (p = 0.004) and 29.0 (24.6) at 24months (p = 0.002). Levels of fatigue and depression were also reduced. After 2years of treatment with teriflunomide, ARR was reduced to 0.17 (95% CI 0.14-0.21) from the baseline of 0.42 (95% CI 0.38-0.48), representing a 60.1% reduction. Mean EDSS scores remained stable during the study, and 79.9% of patients showed no disability progression. 54.7% of patients achieved NEDA-3 in the first 12months, which increased to 61.4% during months 12-24. Patients reported increased satisfaction with treatment over the course of the study, regardless of whether they were DMT naive or not. Teriflunomide improves psychological aspects of HRQoL and maintains low levels of fatigue and depression. Treatment with teriflunomide over 2years is effective in reducing ARR and disability progression.

Relapse recovery in relapsing-remitting multiple sclerosis: An analysis of the CombiRx dataset.

Clinical relapses are the defining feature of relapsing forms of multiple sclerosis (MS), but relatively little is known about the time course of relapse recovery. The aim of this study was to investigate the time course of and patient factors associated with the speed and success of relapse recovery in people with relapsing-remitting MS (RRMS). Using data from CombiRx, a large RRMS trial (clinicaltrials.gov identifier NCT00211887), we measured the time to recovery from the first on-trial relapse. We used Kaplan-Meier survival analyses and Cox regression models to investigate the association of patient factors with the time to unconfirmed and confirmed relapse recovery. CombiRx included 1008 participants. We investigated 240 relapses. Median time to relapse recovery was 111 days. Most recovery events took place within 1 year of relapse onset: 202 of 240 (84%) individuals recovered during follow-up, 161 of 202 (80%) by 180 days, and 189 of 202 (94%) by 365 days. Relapse severity was the only factor associated with relapse recovery. Recovery from relapses takes place up to approximately 1 year after the event. Relapse severity, but no other patient factors, was associated with the speed of relapse recovery. Our findings inform clinical practice and trial design in RRMS.

Real-world treatment patterns and effectiveness of cladribine tablets in patients with relapsing forms of multiple sclerosis in the United States

BackgroundReal-world evidence on the use of cladribine tablets (CladT) for relapsing forms of multiple sclerosis (RMS) in the United States is emerging. The objective of this study was to assess the real-world treatment patterns and effectiveness of CladT in RMS. MethodsAdults with RMS initiating CladT were selected from the Symphony Integrated Dataverse. Baseline and follow-up periods were the 12 months before and 24 months after CladT initiation (index date). Switching to another disease-modifying therapy (DMT) and number of CladT courses were described during follow-up. Annualized relapse rate (ARR), MS disease severity, Expanded Disability Status Scale-Derived Disability Indicators (EDSS-DDI), corticosteroid use, and healthcare resource utilization (HRU) were described during Years 1 and 2 of follow-up and compared with baseline. ResultsA total of 539 CladT-treated patients were included (mean age: 49.9 years; 77.6 % female). Over the 2-year follow-up, 91 % and 59 % of patients had one and two CladT courses, respectively, and 7 % of patients had evidence of switching to another DMT. ARR, MS disease severity score, and corticosteroid use decreased significantly during follow-up compared with baseline, while EDSS-DDI remained stable. All-cause and MS-related HRU decreased during follow-up. ConclusionCladT-treated patients with RMS had low switch rates, reduced ARR, disease severity, corticosteroid use, and HRU.

Real-world use of ofatumumab to treat multiple sclerosis 9 months post-FDA approval during COVID-19 pandemic.

Relapsing multiple sclerosis (MS) is an inflammatory, demyelinating, neurodegenerative disease of the central nervous system that causes episodes of neurological dysfunction (relapse) alternating with variable intervals of stability. Disease-modifying therapies (DMTs) aim to reduce the rate of relapse and slow disease progression in people with MS, particularly in those with relapsing MS. Ofatumumab is a fully human anti-CD20 monoclonal antibody approved to treat patients with relapsing forms of MS. This study describes the demographics, clinical characteristics, and prior DMT use of patients with at least one ofatumumab prescription claim following approval by the United States (US) Food and Drug Administration (FDA). Understanding ofatumumab utilization patterns and patient characteristics can help define the journey of patients with MS and aid future clinical decision-making. This retrospective study is based on data from IQVIA's Longitudinal Prescription Data (LRx) and Medical Claims (Dx) databases in the US, collected between August 01, 2019 and May 31, 2021. The index date was defined as the date of the first ofatumumab prescription. The pre-index period was defined as the 12 months prior to the index date. Adult patients (aged ≥18 years) with a diagnosis of MS and at least one prescription for ofatumumab between August 2020 and May 2021 in the LRx database were included. Only patients with at least one medical claim in the Dx database and a diagnosis of MS 24 months prior to the index date were included. Descriptive analyses were conducted 3, 6, and 9 months after FDA approval. Overall, 3,600 patients with a prescription for ofatumumab were identified in the LRx claims database, and 2,101 patients remained in the study after inclusion and exclusion criteria had been applied. At the 9-month post-approval time point, patients with ofatumumab claims were characterized as primarily female (74%) and middle-aged (median age: 48 years); two-thirds (64.7%) had a mild MS disability level. Patients were otherwise generally healthy with limited comorbid conditions. Most patients (81.7%) in the study did not experience relapse during the pre-index period. DMT-naïve patients who were prescribed ofatumumab at 3, 6, and 9 months post-approval accounted for 46.9%, 54.8%, and 58.4% of the study population, respectively. Over time, this increase in DMT-naïve ofatumumab initiators was statistically significant (p=0.0003). Among patients who had been treated with DMTs during the previous year, most had taken them orally (50.6%), some had received them via intravenous infusion (32.2%), and some via subcutaneous/intramuscular injection (21.1%). Intravenous ocrelizumab was the most common DMT switch observed (n=205, 23.4%) among these patients. This real-world study is the first to describe patients treated with ofatumumab since FDA approval during the COVID-19 pandemic. The majority of patients in this study were middle-aged women with mild MS symptoms. Ofatumumab was increasingly used as a first-line DMT. Additionally, a number of patients aged ≥55 years (beyond the trial population) used ofatumumab, which may suggest expanding clinician confidence in the safety and clinical utility of ofatumumab therapy. However, future long-term observational studies are needed to confirm these results.

Teriflunomide and Epstein-Barr virus in a Spanish multiple sclerosis cohort: in vivo antiviral activity and clinical response.

Epstein-Barr virus (EBV) and human herpesvirus 6 (HHV-6) have been associated with multiple sclerosis (MS). Teriflunomide is an oral disease-modifying therapy approved for treatment of relapsing forms of MS. In the preclinical Theiler's murine encephalitis virus model of MS, the drug demonstrated an increased rate of viral clearance versus the vehicle placebo. Furthermore, teriflunomide inhibits lytic EBV infection in vitro. 1. To evaluate the humoral response against EBV and HHV-6 prior to teriflunomide treatment and 6 months later. 2. To correlate the variation in the humoral response against EBV and HHV-6 with the clinical and radiological response after 24 months of treatment with teriflunomide. 3. To analyze the utility of different demographic, clinical, radiological, and environmental data to identify early biomarkers of response to teriflunomide. A total of 101 MS patients (62 women; mean age: 43.4 years) with one serum prior to teriflunomide onset and another serum sample 6 months later were recruited. A total of 80 had been treated for at least 24 months, 13 had stopped teriflunomide before 24 months, and 8 were currently under teriflunomide therapy but with less than 24 months of follow-up. We analyzed the levels of the viral antibodies titers abovementioned in serum samples with ELISA commercial kits, and the levels of serum neurofilament light chain (Nf-L). Antiviral antibody titers decreased for EBNA-1 IgG (74.3%), VCA IgG (69%), HHV-6 IgG (60.4%), and HHV-6 IgM (73.3%) after 6 months of teriflunomide. VCA IgG titers at baseline correlated with Nf-L levels measured at the same time (r = 0.221; p = 0.028) and 6 months later (r = 0.240; p = 0.017). We found that higher EBNA-1 titers (p = 0.001) and a higher age (p = 0.04) at baseline were associated with NEDA-3 conditions. Thus, 77.8% of patients with EBNA-1 >23.0 AU and >42.8 years (P50 values) were NEDA-3. Treatment with teriflunomide was associated with a reduction of the levels of IgG antibody titers against EBV and HHV-6. Furthermore, higher EBNA-1 IgG titers prior to teriflunomide initiation were associated with a better clinical response.

Resurgence of goal-directed actions and habits.

This study investigated how goal-directed and habitual behaviors recover after extinction within the context of the resurgence effect, a form of relapse induced by the removal or worsening of alternative reinforcement. Rats were trained to press a target lever with one reinforcer (O1) for either minimal (4) or extended (16) sessions. An extinction test after the completion of O1 devaluation confirmed that minimal and extended training formed goal-directed and habitual behaviors, respectively. Then, pressing an alternative lever was reinforced with a second reinforcer (O2) while the target response was placed on extinction. When O2 was discontinued, the minimally trained target response resurged with goal-directed status as in the extinction test. However, the extinguished habitual behavior in the extensively trained rats did not recover as a habit but instead with goal-directed status, possibly due to the context specificity of habits or the introduction of a new response-reinforcer contingency. The critical finding that reinforcer devaluation consistently led to less resurgence regardless of the amount of acquisition training provides a clinical implication that coupling differential-reinforcement-of-alternative-behavior (DRA) treatments with the devaluation of the associated reinforcer of problematic behavior could effectively diminish its recurrence.

Meta‐analysis of the use of Ofatumumab in the treatment of relapsing‐remitting multiple sclerosis

AbstractBackgroundOfatumumab is the first monoclonal antibody developed specifically for treating relapsed multiple sclerosis (RMS). This disease (Multiple Sclerosis) includes relapsing–remitting multiple sclerosis (RRMS), a chronic autoimmune illness that affects the central nervous system (CNS), including the brain and spinal cord. The purpose of this study is to determine whether Ofatumumab is efficacious and safe in the treatment of relapsing–remitting multiple sclerosis.MethodsAn analysis of studies comparing Ofatumumab with placebo in people with relapsing‐remitting multiple sclerosis was done in accordance with PRISMA guidelines. We looked up information in MEDLINE, SciSearch, BIOSIS Previews, Derwent Drug File, Embase, and International Pharmaceutical Abstracts. In patients with relapsing–remitting multiple sclerosis, randomized double‐blind and non‐randomized trials contrasting Ofatumumab with placebo were found by two independent investigators. Utilizing Review Manager 5.4.1, data were examined. The main results were total gadolinium‐enhancing (Gd+) T1 lesions, annualized relapse rate, and new or expanding total T2 lesions. Secondary outcomes concentrated on general adverse events and adverse events related to infections.ResultsThree studies were included involving 334 patients, and the meta‐analysis indicated that Ofatumumab showed good efficacy and safety in patients with relapsing forms of multiple sclerosis. The annual rate of relapse was significantly reduced by Ofatumumab (OR 0.51; 95% CI 0.27, 0.98; P = 0.04). Ofatumumab reduced the number of gadolinium‐enhancing (Gd+) T1 lesions per scan (Mean difference −0.59; 95% CI −0.63, −0.55; P &lt; 0.05). Ofatumumab treatment decreased new or enlarging total T2 lesions significantly (Mean difference −1.03; 95% CI −1.29, −0.76; P &lt; 0.05). Infection‐related adverse effects were seen more frequently with Ofatumumab shown by the odd ratio 0.48; 95% CI 0.22, 1.04; P = 0.06. Infection is, thus, a major limitation to its use.ConclusionThe meta‐analysis indicated that Ofatumumab is efficacious and safe for patients with relapsing forms of multiple sclerosis.

Avacopan (Tavneos)

&#x0D; CADTH recommends that Tavneos not be reimbursed by public drug plans as adjunctive treatment for adults with severe active antineutrophil cytoplasmic autoantibody-associated vasculitis (ANCA-AV) (granulomatosis with polyangiitis [GPA] and microscopic polyangiitis [MPA]).&#x0D; One clinical trial demonstrated that Tavneos in combination with ANCA-AV background therapy (including glucocorticoids and drugs that reduce immune system function) was as good as oral prednisone (60 mg dose reduced over 20 weeks) in combination with ANCA-AV background therapy for showing a reduction in disease symptoms at week 26 and was better than oral prednisone for maintaining symptom improvement at week 52. However, it was unclear if Tavneos offered a meaningful clinical benefit over other treatments used for ANCA-AV mainly because rituximab was not used as maintenance therapy in the trial, as is currently recommended by Canadian guidelines, and there is uncertainty around the clinical meaningfulness of the differences between the treatment groups for outcomes that assessed renal function, relapse, and Short Form [36] Health Survey version 2 (SF-36v2).&#x0D; There was not enough evidence to conclude that Tavneos met patients’ needs for a treatment that reduces or eliminates the use of glucocorticoids and their side effects as well as improves their health-related quality of life (HRQoL).&#x0D;

Real world study of ocrelizumab in multiple sclerosis: Kuwait experience

BackgroundOcrelizumab is a humanized anti-CD20 antibody that has been approved for the treatment of patients with multiple sclerosis (MS). Real-world data in the Middle East is very limited. ObjectivesTo describe the effectiveness and safety of ocrelizumab treatment in MS patients in a real clinical setting. MethodsThis is an observational, registry-based study. MS patients who were treated with ocrelizumab and completed at least one-year follow-up post-treatment were included. Baseline clinical and radiological characteristics were collected before ocrelizumab initiation. The relapse rate, disability measures, magnetic resonance image (MRI) activity (new T2 lesions and/or GD+ enhancing T1 lesions), and adverse events (AE) at the last follow-up visits were assessed. ResultsData from 447 patients were analyzed, of which 260 (58.2%) were females. The mean age and mean disease duration were 37.39 ± 11.61 and 9.38 ± 7.57 years respectively. Most of the cohort was of a relapsing form (74.3%; n = 332), whereas active secondary and primary progressive forms represented 15.4% (n = 69) and 10.3% (n = 46) respectively. In the relapsing cohort, Ocrelizumab was prescribed in 162 (48.8%) patients due to highly active disease, and in 99 (29.8%) patients due to disease breakthrough while on prior therapies. In the last follow-up visits, most of the relapsing cohort was relapse-free (95.8% vs. 27.4%; p <0.001), had no evidence of MRI activity (3.6% vs. 67.5%; p <0.001) while EDSS score was stable (1.80+1.22 vs. 1.87+1.16; p < 0.104) when compared to baseline. NEDA-3 was achieved in 302 (91%) of RRMS patients. Confirmed disability progression was 27.5% and 23.9% in SPMS and PPMS respectively. Adverse events were observed in 139 (31.1%); infusion reactions and infections represented the most. ConclusionThis study showed that ocrelizumab is an effective and safe treatment for MS patients in a real clinical setting similar to what was observed in clinical trials.