Disease Modifying Research Articles

25 Years of Biologics For The Treatment of Pediatric Rheumatic Diseases - Advances in Prognosis and Ongoing Challenges.

There are over 100 rheumatic diseases and approximately 300,000 children with a pediatric rheumatic disease (PRD) in the United States (U.S.). The most common PRDs are juvenile idiopathic arthritis (JIA), childhood-onset systemic lupus erythematosus (cSLE), and juvenile dermatomyositis (JDM). Effective and safe medications are essential because there are generally no cures for these conditions. Etanercept was the first biologic therapy for the treatment of JIA, approved in 1999. Since then, other biologic disease modifying antirheumatic drugs (bDMARDs) and targeted synthetic DMARD (tsDMARDs) blocking relevant immunological pathways have been approved for the treatment of JIA, resulting in a marked improvement of disease prognosis. Conversely, there is only one bDMARD that has been approved for cSLE, but none are approved for the treatment of JDM. Lack of approved therapeutic options, with established dosing regimens and known efficacy and safety, remains a central challenge in the treatment of all PRDs, including autoinflammatory diseases, and for complications of PRDs. This review provides an overview of bDMARD and tsDMARD treatments studied for the treatment of various subtypes of JIA, summarizes information from bDMARD studies in other pediatric rheumatic diseases, with a focus on pivotal trials that led to regulatory approvals and highlights improved outcomes in JIA with the use of these newer medications. Further, we outline barriers and challenges in the treatment of other PRDs. Lastly, we summarize the current regulatory landscape for bDMARD studies and medication approvals in PRDs.

Therapeutic Efficacy of the Inositol D-Pinitol as a Multi-Faceted Disease Modifier in the 5×FAD Humanized Mouse Model of Alzheimer’s Amyloidosis

Background/Objectives: Alzheimer’s disease (AD), a leading cause of dementia, lacks effective long-term treatments. Current therapies offer temporary relief or fail to halt its progression and are often inaccessible due to cost. AD involves multiple pathological processes, including amyloid beta (Aβ) deposition, insulin resistance, tau protein hyperphosphorylation, and systemic inflammation accelerated by gut microbiota dysbiosis originating from a leaky gut. Given this context, exploring alternative therapeutic interventions capable of addressing the multifaceted components of AD etiology is essential. Methods: This study suggests D-Pinitol (DPIN) as a potential treatment modifier for AD. DPIN, derived from carob pods, demonstrates insulin-sensitizing, tau hyperphosphorylation inhibition, and antioxidant properties. To test this hypothesis, we studied whether chronic oral administration of DPIN (200 mg/kg/day) could reverse the AD-like disease progression in the 5×FAD mice. Results: Results showed that treatment of 5×FAD mice with DPIN improved cognition, reduced hippocampal Aβ and hyperphosphorylated tau levels, increased insulin-degrading enzyme (IDE) expression, enhanced pro-cognitive hormone circulation (such as ghrelin and leptin), and normalized the PI3K/Akt insulin pathway. This enhancement may be mediated through the modulation of cyclin-dependent kinase 5 (CDK5). DPIN also protected the gut barrier and microbiota, reducing the pro-inflammatory impact of the leaky gut observed in 5×FAD mice. DPIN reduced bacterial lipopolysaccharide (LPS) and LPS-associated inflammation, as well as restored intestinal proteins such as Claudin-3. This effect was associated with a modulation of gut microbiota towards a more balanced bacterial composition. Conclusions: These findings underscore DPIN’s promise in mitigating cognitive decline in the early AD stages, positioning it as a potential disease modifier.

Risk Factors for Gastrointestinal and Hepatic Adverse Reactions in Rheumatoid Arthritis Patients on Biologic and Conventional DMARDs

Background: Rheumatoid arthritis (RA) is a chronic autoimmune disease treated with disease modifying antirheumatic drugs (DMARDs), which includes conventional synthetic (csDMARDs) and biologic (bDMARDs) agents, and are associated with adverse drug reactions (ADRs) in the gastrointestinal (GI) and hepatobiliary systems. Objectives: In RA patients on combination of biologic and conventional DMARD therapies to identify risk factors associated with GI and hepatic ADRs. Methods: We conducted a multi-centre, observational, retrospective study of 500 RA patients treated with csDMARDs, bDMARDs, or in combination of both. Demographics, biomarkers and clinical profiles were collected. Patient characteristics, treatment types and ADR occurrence were monitored over 24 weeks and statistical analysis was performed to find a correlation between patient characteristics, treatment types, and the occurrence of ADRs. Significant associations were identified with logistic regression and chi-square tests. Results: 24.2% of patients had an ADR, with GI ADRs accounting for 16.6% and hepatic ADRs for 9.1%. Compared to csDMARDs, users (4.2%), bDMARDs users (13.8%) had hepatic ADRs more frequently (p < 0.01). High CRP levels decreased the risk of GI ADRs, but elevated IgG levels raised the risk of hepatic ADRs. Both ADR kinds were predicted by systemic symptoms. Conclusion: Biologic DMARDs present a higher risk of hepatic ADRs in RA patients compared to conventional DMARDs. Key predictors of ADRs include elevated IgG levels and systemic symptoms, underscoring the need for close monitoring of biomarkers and patient-reported symptoms to mitigate adverse events during DMARD therapy.

Unbiased Analysis of Knee Cartilage Thickness Change Over Three Years Post-Treatment with Sprifermin vs. Placebo – A Post-Hoc Analysis from the Phase II FORWARD Study

ObjectivePost-treatment cartilage morphometry in the FORWARD study was performed without blinding to MRI acquisition order, involving potential reader bias. Here we obtained unbiased estimates of cartilage change post-treatment, reading year (Y)2 and Y5 MRIs with blinding to time point. We studied whether post-treatment cartilage thickness change differed between sprifermin- and placebo-treated knees. MethodsFORWARD was a 5-year randomized control trial in 549 knee osteoarthritis patients. Here, Y2/Y5 images were analyzed with blinding to relative temporal order and treatment group. Cartilage change during Y2→Y5 was obtained in 337 participants: n=57 treated with placebo intra-articular injections every 6 months (q6M); n=69 with 30μg sprifermin every 12 months (q12M), n=67 with 30μg q6M, n=73 with 100μg q12M, and n=71 with 100μg q6M between baseline (BL) and 18M. Total femorotibial joint (TFTJ) cartilage thickness was the primary analytic focus. ResultsTFTJ cartilage thickness change during Y2→Y5 was -26μm (SD64; 95%CI -32,-19) across the cohort; no statistically significant difference (p=0.80) was observed between treatment or placebo arms (one-way ANOVA). All groups lost cartilage, but the treatment-related difference in cartilage thickness in Sprifermin arms relative to placebo at Y2 was maintained until Y5. Annualized cartilage change in placebo participants was -8.2μm (SD21; 95%CI -14,-2.5) during Y2→Y5 vs. -5.4μm (SD27; 95%CI -13,1.8) during BL→Y2; no significant difference was identified (t-test). ConclusionFORWARD is the first study evaluating post-treatment benefits of a potential disease modifying osteoarthritis drug. Cartilage thickness gained with 100μg sprifermin at Y2 is maintained to Y5 and thus appears viable and sustainable.This is a post-hoc analysis of the FORWARD trial: ClinicalTrials.gov Identifier: NCT01919164

Rheumatoid arthritis: a review of the key clinical features and ongoing challenges of the disease.

Rheumatoid arthritis (RA) is an autoimmune inflammatory condition that primarily affects the joints and periarticular soft tissue. The development of joint swelling is traditionally regarded as the starting point of the disease. Emerging evidence indicates that RA patients often experience a preclinical stage characterized by immunological and inflammatory changes before developing the disease. The review discusses ongoing efforts to predict the transition from this preclinical phase to clinical RA and describes studies aimed at preventing the onset of RA in individuals at risk. Over the past two decades, there have been significant advancements in RA management and outcomes. An increasing number of patients can now achieve disease remission, and in some cases, this remission persists without ongoing treatment, which is effectively a cure. As new therapies and evolving scientific evidence emerge, recommendations for RA management are continuously evolving. Despite these improvements in the management of RA, many patients still do not respond to multiple conventional or more advanced therapies, including biologic and targeted synthetic disease modifying anti-rheumatic drugs, or experience disease flares when treatments are tapered or discontinued. This situation underscores the need for reliable biomarkers to guide therapy more effectively, improve personalized treatment approaches and monitoring strategies (i.e. precision medicine). In conclusion, this review provides a comprehensive overview of RA, covering new research on the 'pre-clinical' phase of the disease, as well as its epidemiology, pathogenesis, clinical manifestations, diagnosis, imaging, and management strategies. It highlights key clinical aspects of RA and addresses ongoing challenges in disease management, particularly in the areas of prevention and treatment.

GLP‐1 receptor agonists for Parkinson's disease: An updated meta-analysis

IntroductionTreatments for Parkinson's disease (PD) focus on symptom reduction through dopaminergic therapies, without clear evidence of disease-modifying effects. Glucagon-like peptide-1 (GLP-1) receptor agonists may reduce neuroinflammation by decreasing microglia activation in PD. Clinical trials suggest these agents have disease-modifying potential in PD. ObjectiveEvaluate the efficacy of GLP-1 receptor agonists in PD. MethodsPubMed, Embase and Cochrane Library were searched to identify randomized controlled trials (RCTs) of GLP-1 agonists for PD, up to July 2024. The risk of bias was assessed using the RoB-2 tool, and statistical analysis was performed with RevMan 5.4.1 software. ResultsGLP-1 receptor agonists showed a beneficial effect on MDS-UPDRS part III motor scores compared to placebo. Off-medication state, there was a −1.22 point improvement (95%CI -2.46, 0.22; P = 0.05). On-medication state, scores improved by −2.52 points (95%CI -4.02, −1.01; P = 0.001). The global MDS-UPDRS score showed a −3.43-point difference (95%CI -6.48, −0.48; P = 0.02). Cognitive performance, assessed via the Mattis DRS-2, improved by 1.32 points (95%CI 0.16, 2.52; P = 0.03). There were no significant differences in the NMSS (−0,19; 95%IC -3,44, 3,05; P = 0.91), in MADRS (−1,04; 95%IC -2,57, 0,48; P = 0.18), or PDQ-39 (−0,91; 95%IC -2,22, 0,39; P = 0.17). ConclusionGLP-1 receptor agonists improved motor and cognitive performance in PD, suggesting potential symptomatic benefits. However, further studies are needed to evaluate their long-term effects and their role in disease modification, especially considering ethnic and disease severity variations.

Strategies in Parkinson's Disease Therapeutics - A Need for Synergy of Ayurveda, Small Molecules and Nanoparticles aided Approaches.

Despite extensive research, there is an unmet need for developing disease-modifying therapies for Parkinson's disease (PD). Failure of certain landmark clinical trials has highlighted the need for a better understanding of the disease pathogenesis as well as identifying the hurdles in developing drug candidates and designing clinical trials. While adhering to these needs, several promising trials are currently underway with the hope of developing reliable targets. There is also a need to conduct research on plant-based natural products and use them as therapeutic candidates for PD. In this context, many studies have demonstrated the efficacy of medicinal plants and their principal phytochemicals. This review provides an update on the presently underway clinical trials with a small emphasis on the disease modifying therapies that target small molecules, mitochondria, and oligodendrocytes. The role of ethnopharmacology-based approaches for treatment of PD has also been discussed. The third aspect of the article considers the importance of nanomedicine in this area, including the use of liposomes and nanoparticles to provide a novel approach for the treatment of PD.

Divergent and Convergent TMEM106B Pathology in Murine Models of Neurodegeneration and Human Disease.

TMEM106B is a lysosomal/late endosome protein that is a potent genetic modifier of multiple neurodegenerative diseases as well as general aging. Recently, TMEM106B was shown to form insoluble aggregates in postmortem human brain tissue, drawing attention to TMEM106B pathology and the potential role of TMEM106B aggregation in disease. In the context of neurodegenerative diseases, TMEM106B has been studied in vivo using animal models of neurodegeneration, but these studies rely on overexpression or knockdown approaches. To date, endogenous TMEM106B pathology and its relationship to known canonical pathology in animal models has not been reported. Here, we analyze histological patterns of TMEM106B in murine models of C9ORF72 -related amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD), SOD1-related ALS, and tauopathy and compare these to postmortem human tissue from patients with C9-ALS/FTD, Alzheimer's disease (AD), and AD with limbic-predominant age-related TDP-43 encephalopathy (AD/LATE). We show that there are significant differences between TMEM106B pathology in mouse models and human patient tissue. Importantly, we also identified convergent evidence from both murine models and human patients that links TMEM106B pathology to TDP-43 nuclear clearance specifically in C9-ALS. Similarly, we find a relationship at the cellular level between TMEM106B pathology and phosphorylated Tau burden in Alzheimer's disease. By characterizing endogenous TMEM106B pathology in both mice and human postmortem tissue, our work reveals considerations that must be taken into account when analyzing data from in vivo mouse studies and elucidates new insights supporting the involvement of TMEM106B in the pathogenesis and progression of multiple neurodegenerative diseases.

Time between the first symptom, diagnosis and treatment of multiple sclerosis in a Brazilian cohort. The impact of early diagnosis

IntroductionMultiple Sclerosis (MS) diagnosis can be challenging, especially in populations where the disease is rare. In Brazil, the average prevalence is 14/100,000 inhabitants, lower than the worldwide. Early treatment initiation can markedly reduce disease activity and accumulation of disability. Therefore, delayed diagnosis and access to disease modifying therapy (DMT) can have a negative impact on the course of MS. ObjectivesThe aim of this study was to estimate the mean time between the first relapse, the diagnosis of MS and initiation of treatment in a cohort of Brazilian MS patients. Material and methodWe retrospectively analyzed the medical records of MS patients who met the 2017 McDonald diagnostic criteria followed in a MS reference center in Belo Horizonte, Minas Gerais. We assessed demographic and clinical data with focus on time to first symptom, time to diagnosis and treatment begging. The last Expanded Disability Status Scale (EDSS) was collected to access disability.The program GraphPad Prism 8.4.3. was used for the statistical analysis. ResultsData of 66 patients were analyzed, 77 % (51) were women. The mean age of the first symptom, diagnosis and DMT initiation was, respectively, 30,06 (± 12,43), 35,2 (± 13,59) and 36,10 (± 13,89) years. In 32 (46,38 %) patients the diagnosis was early (<1 year of disease), in 18 (26,09 %) between 1 and 5 years and in 19 (27,54 %) after to five years. Once the diagnosis was established, 65,5 % had access to DMT within 6 months and 79,71 % in the first year.Patients with diagnosis in the two first years had their first symptom at a younger age (p < 0.05). Comparing these two groups, patients with an earlier diagnosis presented less disability (EDSS: 3,5 vs 1,5; p < 0.05). ConclusionMS diagnosis can be challenging especially in low prevalence population of diseased and developing countries. Our study demonstrated the importance of early recognition of MS and its precocious intervention, impacting in reducing of disability a long term

Long-Term Efficacy and Safety of Risankizumab for csDMARD-IR Patients With Active Psoriatic Arthritis: 196-Week Results From the KEEPsAKE 1 Trial

Introduction &amp; Objectives: Here, we report the long-term efficacy and safety of risankizumab (RZB) in patients with active psoriatic arthritis (PsA) through week 196 from the KEEPsAKE 1 trial. Materials &amp; Methods: The ongoing KEEPsAKE 1 clinical trial is a global, phase 3, multicenter study to evaluate the efficacy and safety of RZB versus placebo (PBO) in patients with active PsA. Patients are at least 18 years old and demonstrated an inadequate response, intolerance or contraindication to ≥1 conventional synthetic disease modifying antirheumatic drug (csDMARD-IR). Following a 24-week double-blind, PBO-controlled, parallel-group treatment period (period 1), all patients received open-label RZB every 12 weeks thereafter (period 2). Safety assessments were based on monitoring of treatment-emergent adverse events (TEAEs) reported as events per 100 patient-years (PY). Efficacy and safety analyses were conducted in all randomized patients who received ≥1 dose of the study drug. Results: Overall efficacy results were maintained at week 196 of the KEEPsAKE 1 trial, as compared to previously reported timepoints. At week 196, 39.4% of patients receiving continuous RZB and 38.1% of PBO/RZB patients achieved ACR50; 39.6% of RZB and 35.2% of PBO/RZB patients achieved MDA. In patients with psoriasis severity of ≥ 3% of body surface area (BSA) at baseline, 65.2% on RZB and 62.9% on PBO/RZB achieved PASI90 at week 196. mNAPSI and PGA-F scores improved from baseline by 14.99 and 1.5 points, respectively, for RZB, and by 14.73 and 1.5 points for PBO/RZB patients. In patients with enthesitis at baseline, 60.1% on RZB and 63.4% on PBO/RZB achieved resolution. For patients with dactylitis at baseline, 72.3% on RZB and 77.6% on PBO/RZB achieved resolution. HAQ-DI (RZB -0.40, PBO/RZB -0.33), SF-36 PCS (RZB 8.98, PBO/RZB 7.21) and FACIT-Fatigue (RZB 7.7, PBO/RZB 5.6) scores maintained improvement from baseline to week 196. The overall rates of TEAEs (121.4 E/100PY), serious TEAEs (7.7 E/100PY) and AEs leading to discontinuation of study drug (1.8 E/100PY) have remained stable and comparable to those reported in period 1. Conclusion: The 196-week results of the ongoing KEEPsAKE 1 trial demonstrate the durable efficacy of RZB 150 mg in treating the different clinical manifestations and improving health-related quality of life in csDMARD-IR patients with PsA. RZB continued to be well-tolerated, with no new safety signals.

Maintenance of Response to Risankizumab in Patients With Psoriatic Arthritis: A 4-Year Analysis of the KEEPsAKE 1 and 2 Trials

Introduction: Risankizumab, a humanized immunoglobulin G1 monoclonal antibody, specifically inhibits the p19 subunit of human interleukin 23 and is approved for treatment of active psoriatic arthritis (PsA) in adults. This post hoc analysis evaluated the long-term maintenance of clinical response through ~4 years of risankizumab treatment using data from 2 ongoing phase 3 trials, KEEPsAKE 1 and KEEPsAKE 2. Methods: Eligible patients had active PsA with inadequate response or intolerance to ≥1 conventional synthetic disease modifying antirheumatic drugs (KEEPsAKE 1 [NCT03675308]; KEEPsAKE 2 [NCT03671148]) and/or inadequate response or intolerance to 1–2 biologic therapies (KEEPsAKE 2 only). Patients received double-blinded risankizumab 150 mg or placebo for 24 weeks and open-label risankizumab 150 mg thereafter. This analysis includes patients who received continuous risankizumab through both treatment periods. Assessments included improvement of ≥20%/50%/70% in PsA symptoms using American College of Rheumatology criteria (ACR20/50/70), achievement of minimal disease activity (MDA), reduction of ≥90% in Psoriasis Area and Severity Index (PASI 90; in patients with ≥3% body surface area affected by psoriasis at baseline), and clinically meaningful reduction in pain (≥10 mm on a visual analog scale [VAS]). All data were reported as observed. Results: Among patients who achieved ACR20 at week 24 in KEEPsAKE 1 or KEEPsAKE 2, 70.7% and 86.4% maintained ACR20 responses at week 196. Similarly, ACR20 response was maintained to week 196 by 85.7% and 83.3% of week 52 responders in KEEPsAKE 1 and 2, respectively. Similar patterns of maintenance of response were observed for ACR50 and ACR70. Most patients also maintained MDA at week 196 from weeks 24 and 52 (Week 24: KEEPsAKE 1, 86.0%; KEEPsAKE 2, 81.3%; Week 52: KEEPsAKE 1, 81.2%; KEEPsAKE 2, 85.5%). The PASI 90 response was maintained at week 196 from weeks 24 and 52 (Week 24: KEEPsAKE 1, 88.2%; KEEPsAKE 2, 94.9%; Week 52: KEEPsAKE 1, 92.6%; KEEPsAKE 2, 97.1%). Weeks 24 and 52 responders maintained clinically meaningful reductions in pain VAS at week 196 (Week 24: KEEPsAKE 1, 90.2%; KEEPsAKE 2, 88.9%; Week 52: KEEPsAKE 1, 88.3%; KEEPsAKE 2, 90.1%), respectively. Conclusion: Risankizumab demonstrated durable long-term efficacy in patients with active PsA. A high proportion of patients receiving continuous risankizumab treatment in KEEPsAKE 1 and KEEPsAKE 2 maintained ACR20/50/70, MDA, or PASI90 responses and meaningful pain reduction through week 196.

Neutrophil activation markers can predict rheumatoid arthritis treatment response to the Janus Kinase 1/2 inhibitor baricitinib.

Neutrophils play an important role in regulating immune and inflammatory responses in rheumatoid arthritis (RA). We assessed whether baricitinib, a JAK1/JAK2 inhibitor, could reduce neutrophil activation, and whether a neutrophil activation score could predict treatment response. Markers of neutrophil activation, calprotectin, and neutrophil extracellular traps (NETs) were analyzed using ELISA in RA plasma (n=271) and healthy controls (n=39). For RA patients, neutrophil activation markers were measured at baseline, 12 weeks, and 24 weeks after treatment with placebo, 2 mg, and 4 mg baricitinib. Whole blood RNA analyses from multiple randomized baricitinib RA trials were performed to study neutrophil-related transcripts (n=1651). Baseline levels of plasma neutrophil markers were elevated in RA patients compared to healthy controls (p<0.001). Baricitinib reduced levels of soluble calprotectin at 12 and 24 weeks, especially in RA patients responding to treatment, as determined by ACR20. Whole blood RNA analysis revealed similar changes in the predominant neutrophil markers calprotectin and FcαRI upon treatment with baricitinib in three randomized clinical trials involving RA patients at various stages of disease modifying therapy. Clustering analysis of plasma activation markers showed elevated levels of calprotectin and NETs, e.g., a neutrophil activation score, at baseline, could predict treatment response to baricitinib. In contrast, CRP levels could not distinguish between responders and non-responders. Neutrophil activation markers may add clinical value in predicting treatment response to baricitinib and other drugs targeting RA. This study supports personalized medicine, in treating RA patients, not only based on symptoms, but also based on immunophenotyping.

Current insights on m6A RNA modification in acute leukemia: therapeutic targets and future prospects.

RNA modification is the critical mechanism for regulating post-transcriptional processes. There are more than 150 RNA modifications reported so far, among which N6-Methyladenosine is the most prevalent one. M6A RNA modification complex consists of 'writers', 'readers' and 'erasers' which together in a group catalyze, recognize and regulate the methylation process of RNA and thereby regulate the stability and translation of mRNA. The discovery of erasers also known as demethylases, revolutionized the research on RNA modifications as it revealed that this modification is reversible. Since then, various studies have focused on discovering the role of m6A modification in various diseases especially cancers. Aberrant expression of these 'readers', 'writers', and 'erasers' is found to be altered in various cancers resulting in disturbance of cellular homeostasis. Acute leukemias are the most common cancer found in pediatric patients and account for 20% of adult cases. Dysregulation of the RNA modifying complex have been reported in development and progression of hematopoietic malignancies. Further, targeting m6A modification is the new approach for cancer immunotherapy and is being explored extensively. This review provides detailed information about current information on the role of m6A RNA modification in acute leukemia and their therapeutic potential.

Novel Approaches to Allergen Immunotherapy for Respiratory Allergies.

Allergen immunotherapy (AIT) remains the cornerstone for managing respiratory allergies, offering long-term symptom relief, disease modification, and prevention of disease progression. While novel approaches like intralymphatic and epicutaneous immunotherapy and the combination of allergens with adjuvants show promise, traditional methods remain effective and safe. Hypoallergenic T-cell peptide vaccines and recombinant allergens require further research to confirm their clinical benefits. Passive immunotherapy, while demonstrating effectiveness in specific cases, needs exploration of its long-term efficacy and broader applicability. Combining AIT with biologics may enhance safety and treatment outcomes. Despite emerging innovations, allergen-specific immunotherapy with natural allergen extracts remains the primary disease-modifying treatment, offering long-term symptom relief and prevention of disease progression. Continued research is essential to refine and optimize allergen immunotherapy strategies, providing patients with more effective and personalized treatment options.

Timely escalation to second-line therapies after failure of methotrexate in patients with early rheumatoid arthritis does not reduce the risk of becoming difficult-to-treat

BackgroundTo investigate the frequency of difficult-to-treat (D2T) rheumatoid arthritis (RA) in patients early escalated to biologic/targeted synthetic disease modifying anti-rheumatic drugs (b/tsDMARDs) after failure of treat-to-target with methotrexate (MTX).MethodsFrom a prospective cohort of early RA, all patients with their first access in the years 2005–2018, and eventually starting a b/tsDMARD before the end of 2022, were included and followed-up until April 2024. Study outcomes included drug survival on each consecutive b/tsDMARDs, development of D2T (according to the EULAR definition and subsequent modifications), and its predictors.ResultsOf a total cohort of 722 early RA patients treated with initial MTX and followed-up for at least 3 years from diagnosis, 155 (21.5%) had started a b/tsDMARD after a median of 19 months. In more than 70% of the cases, RA was uncontrolled despite optimal doses of MTX of ≥ 15 mg/day. The retention rates of the first and the second b/tsDMARD were approximatively 70% after 1 year but dropped to 40% after 5 years. After a median (IQR) follow up of 72.6 (34.5-134.2) months, 45 patients (29%) fulfilled the EULAR D2T criteria. At multivariable analysis, higher number of swollen joints and worse pain scores were confirmed as predictors of D2T. Furthermore, in this early RA cohort, shorter disease duration at the start of treatment with b/tsDMARDs, together with negativity for autoantibodies, were also independent predictors of D2T.ConclusionsEarly implementation of treatment after failure of treat-to-target with MTX may not prevent the development of D2T in RA. Patients showing early refractoriness to conventional drugs and those lacking autoantibodies are at higher risk of multiple treatment failures.

A 40-week phase 2B randomized, multicenter, double-blind, placebo-controlled study evaluating the safety and efficacy of memantine in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease with no known cure, limited treatment options with minimal benefits, and significant unmet need for disease modifying therapies. This study investigated memantine's impact on ALS progression, with an additional focus on the effects of memantine on cognitive and behavioral changes associated with the disease. A randomized, double-blind, placebo-controlled clinical trial was conducted from December 2018 to September 2020. ALS patients were enrolled in-person and remotely across 13 sites in the United States. Participants were randomized to memantine (20 mg twice daily) or placebo in a 2:1 ratio and completed 36 weeks of treatment. The primary outcome of disease progression was assessed by the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R), and blood was collected for biomarker analysis. Of the 99 participants enrolled in the study, 89 were randomized to memantine or placebo (ages 24-83 years, male-to-female ratio ~3:2). Fifty-two participants completed the study treatment with no significant differences in disease progression, biomarker changes (including neurofilament light chain [NfL]), or neuropsychiatric testing noted between the groups. Initial NfL values correlated with the rate of ALSFRS-R decline. In this study, memantine did not impact ALS disease progression or neuropsychiatric symptoms. Trials with remote enrollment may help trial participation and success.

Employment status of multiple sclerosis patients in Japan

Aims We conducted a questionnaire survey on Japanese MS patients to determine the relationship of fatigue, depression, and physical activity limitations with employment status. Materials and methods The study was conducted to assess the Patient Reported Outcome of MS patients treated with disease-modifying drug ≥6 months by recruiting MS patients from a web-based patient panel. Multiple regression analysis was performed by using items described in the Work Productivity and Activity Impairment Questionnaire-General Health Version 2.0 (WPAI-GH) and Fatigue Severity Scale (FSS), Quick Inventory of Depressive Symptomatology (Self-Report) (QIDS-SR), and Patient Determined Disease Step (PDDS). Results Employment rates decreased after MS development and were more pronounced in the group with advanced physical disability with PDDS score ≥ 3. Health-related activity limitations were higher with advanced disability. In the analysis of the five subdomains of WPAI-GH by FSS score, the domains “due to health reasons,” “disability rates during work,” “overall work disability among the employed,” and “health-related limitations’ all increased with higher FSS scores.” In WPAI-GH by QIDS-SR, the work disability rate was higher in the depressed group than in the normal group, and health-related activity limitations increased with greater depression. Limitations This is a cross-sectional survey and data are based on PRO, hence are subjective and are collected based on patients’ overall responses. Some bias could be attributed to memory and literacy rates as this is an online survey. Conclusions The results suggested that the onset of MS prevented patients from working and forced them to resign from their jobs or give up full-time work. The rate of employment tended to be lower in the group with advanced limitations; suggesting that controlling the progression of limitations may lead to lower turnover, and the rate of health-related activity limitations was correlated with the degree of physical activity limitations, depression, and fatigue, respectively.

Novel antiseizure medications in the development pipeline: promising candidates and recent failures

AbstractIn the past decade, we have observed a paradigm shift in the discovery of novel antiseizure medications (ASMs), which is a consequence of significant progress in epilepsy genetics, the availability of novel disease models, drug-screening technologies, the discovery of new mechanisms of action, expanding existing drugs into new populations, or new routes of delivery. This resulted in a very rich pipeline of potential future treatments for epilepsy, including gene-modifying treatments for rare genetic epilepsies and mechanistically guided precision treatments. Hopes are high that this pipeline may bring therapeutic breakthroughs similar to those recently achieved with cenobamate for the common drug-resistant focal epilepsy and fenfluramine for seizures in Dravet syndrome. Furthermore, we stand at the beginning of a new era of epilepsy treatment expansion, from traditional seizure suppression to disease prevention and modification. This review discusses the most advanced and promising candidates in the clinical development pipeline but also describes recent failures in the development of novel ASMs.

Shifting the paradigm of type 1 diabetes: a narrative review of disease modifying therapies.

A new diagnosis of type 1 diabetes (T1D) may be accompanied by numerous lifelong financial, emotional, and physical challenges, thus advancements in therapies that can delay the onset of clinical disease are crucial. T1D is an autoimmune condition involving destruction of pancreatic beta cells leading to insulin deficiency, hyperglycemia, and long-term insulin dependence. The pathogenesis of T1D is classified into stages, with the first signal being the detection of autoantibodies without any glycemic changes. In the second stage, dysglycemia develops without symptoms, and in stage 3, symptoms of hyperglycemia become apparent, and at this time a clinical diagnosis of T1D is made. As a greater understanding of these stages of T1D have evolved, research efforts have been devoted to delaying the onset of clinical disease. To date, only one medication, teplizumab, has been approved by the Food and Drug Administration (FDA) for the treatment of stage 2 T1D. This narrative review present published trials and ongoing research on disease modifying therapies (DMT) in T1D, the mechanisms of action for each therapy, and the stages of T1D that these interventions are being studied.

Impact of symptomatic multiple sclerosis therapy on pregnancy outcome

Background: Information on symptomatic therapy (ST) use in women of childbearing age with multiple sclerosis is sparse, and data on the impact of ST pregnancy exposure on pregnancy outcome are lacking. Objective: To investigate (1) ST use patterns pre-conception, during pregnancy and postpartum and (2) pregnancy outcomes. Methods: Pregnancy data from the German Multiple Sclerosis and Pregnancy Registry were analyzed for the ST use from pre-conception to postpartum. Pregnancy outcomes were compared between ST-exposed (n = 282) and matched (disease modifying therapy and age) ST-naive (n = 536) pregnancies. Results: Of 2,449 pregnancies, 1,053 (43.0%) received ST anytime between pre-conception and postpartum, 282 (11.5%) at pre-conception and during pregnancy. The most commonly used drug classes were antidepressants (24.8%), analgetics (31.0%), and anticonvulsives (8.7%). Exposure to ST during pregnancy did not result in an increased incidence of adverse pregnancy outcomes, major congenital abnormalities, or pregnancy complications. Conclusion: Nearly 50% of women used ST between pre-conception and postpartum, but only 12% pre-conception and during pregnancy. ST use during pregnancy did not adversely affect pregnancy outcomes in our cohort. More data are needed to analyze the effect of ST on pregnancy and fetal outcomes stratified by drug to improve recommendations for ST use in family planning.