Disease Modifying Research Articles

The utility of animal models in understanding osteoarthritis (OA) pathogenesis – an update on the impact of genetically modified mice

ABSTRACT Osteoarthritis (OA) is one of the most common health conditions worldwide leading to immense individual and societal burden. Current treatments for OA are inadequate with no approved structural disease modifying therapies, and existing options for chronic pain only moderately successful long-term. Improving this bleak picture requires a better understanding of OA molecular pathophysiology, how this differs between individuals and over time. Critical in this goal are animal models. There have been four key advancements in this field that have dramatically improved OA pathophysiology discovery research: (1) initial studies showing mouse OA-risk is modified by the same factors as humans—age, sex/sex-hormones, diet and genetics (1952–65); (2) first studies of naturally-occurring OA in mice with spontaneous (1972–81) and induced (1993) genetic mutations (GMs); (3) developing reproducible inducible models with good structural and symptomatic fidelity to human OA (1990–2005); and (4) using inducible and spontaneous OA-models in GM-mice to show disease and symptom modification and define molecular causality (1999-present). These milestones revolutionized OA pathophysiology research, such that there are now >500 unique genes/gene-products identified as having significant effects on OA (beneficial or detrimental). Studies in different mouse OA-models have underpinned the concept of OA-phenotypes, and more particularly endotypes and theratypes, with ~35% of tested molecular targets having different effects on post-traumatic (pt)OA versus spontaneous/age-associated-OA. Deciphering and translating the enormous and growing data from animal-models into effective therapeutics for people remains challenging. This will require better identification and stratification of patients with different OA pheno/endotypes, and improved collaboration between clinical and pre-clinical researchers.

Real-World Comparison of High-Efficacy Versus Non-High-Efficacy Therapies in Multiple Sclerosis.

The choice of the first disease modifying treatment (DMT) in multiple sclerosis (MS) is a topic of great interest, and whether high-efficacy DMTs should be the first choice remains debated. We compared treatment outcomes (no evidence of disease activity [NEDA] and its components) between treatment-naïve relapsing-remitting MS (RRMS) patients commencing high-efficacy therapies (HET) and non-high-efficacy therapies (non-HET), using propensity score matching. This is an observational prospective study of two real-world, single-centre, longitudinal cohorts: (1) Relapsing-remitting MS (RRMS) patients initiated dimethyl fumarate, fingolimod, glatiramer acetate and natalizumab between 2002 and 2020; (2) RRMS patients initiated ocrelizumab between 2019 and 2021. We selected treatment-naïve patients and had at least 2 years of follow-up. We compared the two groups at years 1 and 2 using Cox and Logistic regression models as appropriate. After propensity score matching, we included 448 patients: 110 HET and 338 non-HET. The probability of losing NEDA was 57% and 39% lower in the HET group at year 1 and 2 (HR = 0.43; 95% CI = 0.35, 0.52; p < 0.01 and HR = 0.61; 95% CI = 0.45, 0.84; p < 0.01, respectively). The probability of relapse in the HET group was 94% and 71% lower at year 1 and 2 (OR = 0.06; 95% CI = 0.01, 0.28; p < 0.01 and OR = 0.29; 95% CI = 0.10, 0.84; p < 0.02, respectively). The EDSS in the HET group was 30% and 18% lower at year 1 and 2 (Coeff = -0.30; 95% CI = -0.42, -0.18; p < 0.01 and Coeff = -0.16; 95% CI = -0.34, 0.02; p < 0.09, respectively). The probability of MRI activity in the HET group was 82% lower at year 1 (OR = 0.18; 95% CI = 0.04, 0.86; p < 0.03). This study demonstrated that treatment-naïve RRMS patients should be considered for high-efficacy therapies based on a greater suppression of disease activity at 2 years.

Proposed mechanisms of neuroprotection for nicotine in Parkinson's disease.

Parkinson's disease (PD) is a neurological disorder that is characterized by the death of dopaminergic neurons in the substantia nigra. Despite extensive research, the exact cause of PD is unknown, and current treatment options are centered on symptom management rather than disease modification. Most, though not all, epidemiologic studies have demonstrated reduced risk of development of PD among smokers, generating interest in nicotine, a key component of tobacco. Many preclinical investigations have investigated nicotine's neuroprotective properties, especially through its interaction with nicotinic acetylcholine receptors in the central nervous system. Nicotine has been linked to a variety of cellular activities, including neurotransmitter release, neuronal survival, and anti-inflammatory responses. Animal studies in PD models have indicated that nicotine administration can attenuate the degeneration of dopaminergic neurons and ameliorate behavioral abnormalities. Clinical investigations evaluating nicotine as a treatment for PD have yielded mixed results in terms of efficacy. Thus, central questions remain about the effects of nicotine in patients with established PD, and neither nicotine nor smoking are recommended for treatment or prevention of PD. Further research on the multiple proposed mechanisms of nicotine is required, with particular emphasis on elucidating symptomatic versus neuroprotective effects. The aim of this scoping review is to provide a comprehensive discussion of the proposed mechanisms of neuroprotection for nicotine in Parkinson's disease.

Ion channels as therapeutic targets in osteoarthritis.

Ion channels as therapeutic targets in osteoarthritis.

GLP-1 Receptor Agonists in Orthopaedic Surgery: Implications for Perioperative and Outcomes: An Orthopaedic Surgeon's Perspective.

➢ Glucagon-like peptide-1 (GLP-1) receptor agonists are a promising tool for preoperative weight loss in the patient who is undergoing orthopaedic surgery and has concomitant obesity and type-2 diabetes mellitus.➢ With regard to the perioperative management of GLP-1 receptor agonists for the orthopaedic surgeon, the American Society of Anesthesiologists (ASA) recommends withholding daily-dose GLP-1 therapy on the day of the elective surgical procedure and withholding weekly-dose therapy for the week prior to the procedure.➢ The ASA recommends postponing surgery or proceeding with "full stomach precautions" if the patient undergoing an orthopaedic procedure and taking GLP-1 therapy exhibits gastrointestinal symptoms on the day of the elective procedure.➢ In the trauma setting, patients taking GLP-1 therapy should proceed with the surgical procedure at the discretion of the surgeon with full stomach precautions or a preoperative point-of-care gastric ultrasound.➢ GLP-1 receptor agonists show the potential for disease modification in osteoarthritis and osteoporosis.

Impact of a Nurse Care Coordinator on Time to Treatment in a Pediatric Multiple Sclerosis Clinic, a Retrospective study.

Early treatment improves long-term outcomes for persons living with multiple sclerosis. Patients with pediatric-onset multiple sclerosis (POMS) experience delays in diagnosis and treatment with disease-modifying therapy (DMT). Here we explore how a dedicated nurse care coordinator decreases time to treatment in POMS. We included a retrospective cohort of 60 pediatric-onset multiple sclerosis (POMS) at a single center between 2018-2024. The primary outcome was time to disease modifying therapy (DMT) initiation. Secondary outcomes included relapse rates and Extended Disability Status Scale (EDSS). In 60 participants, 39 were in the pre-coordinator group and 21 were in the post-coordinator. Age, race, ethnicity, insurance, and the area deprivation index did not affect outcomes. However, the post-coordinator group had a shorter time from diagnosis to initiation of DMT (median 49 days, IQR 40-57 days) compared to the pre-coordinator group (median 126 days, IQR 57-254 days, p < 0.001). Here, we found that a care coordinator decreased time to DMT initiation and should be implemented in clinical care. Practical Implications Having a dedicated nurse coordinator to help patients with multiple sclerosis with obtaining their treatments including their disease modifying therapies (DMTs) can result in shorter time to starting a DMT.

From Diagnosis to Health Practice: Polycythemia Vera. A Literature Review

Introduction and purpose: Polycythemia vera (PV) is a chronic myeloproliferative neoplasm, part of the group of Philadelphia-negative neoplasms alongside essential thrombocythemia and myelofibrosis. It is characterized by elevated red blood cell mass, frequently accompanied by leukocytosis and thrombocytosis. A JAK2 mutation is present in about 95% of cases, typically with low erythropoietin levels. This study aims to review the current understanding of PV, including its pathophysiology, diagnostic criteria, treatment options, and emerging therapies. A brief description of the state of knowledge: PV is rare, with an incidence of 0.01–4 cases per 100,000 annually, and is usually diagnosed between the ages of 60 and 65. Symptoms stem from increased blood viscosity and include headaches, aquagenic pruritus, thrombosis, and splenomegaly. Diagnosis relies on elevated hemoglobin/hematocrit, bone marrow findings, and JAK2 mutation. According to ICC and WHO criteria, diagnosis can sometimes be made without bone marrow biopsy. Standard treatment includes low-dose aspirin and phlebotomy, with cytoreductive therapy (hydroxyurea or pegylated interferon) based on thrombotic risk. New drugs such as rusfertide, idasanutlin, and givinostat show promise in symptom control and potential disease modification. Summary: While current therapies effectively manage hematocrit and thrombotic risk, they do not address the root cause of PV. Novel treatments targeting molecular mechanisms may improve quality of life and reduce the risk of progression to myelofibrosis or acute leukemia. Further research is needed to develop curative strategies.

3154 Lumbar puncture to diagnose Alzheimer's disease within a Geriatrician-Led Memory Service is well-tolerated

Abstract Introduction With the emergence of disease modifying treatments for Alzheimer’s disease (AD), there is an increasing emphasis on the earlier detection and diagnosis of AD. Cerebrospinal fluid (CSF) sampled using lumbar puncture (LP) can be used to establish a biological diagnosis of AD. One potential obstacle to the widespread adoption of CSF biomarkers for AD diagnosis has been a perceived association with poor patient tolerability and safety of LP. LPs have been undertaken within our Geriatrician-Led Memory Service since May 2022. Patients are provided with a written information sheet prior to LP. Method A survey was developed in-house by the clinical team. A service evaluation initiative was registered within the local trust. All patients attending for LP since May 2022 were posted a feedback form with an enclosed pen and stamped addressed return envelope on 5th August 2024. Questions included: what the patient’s understanding was of why they were having a LP, whether the written information sheet provided sufficient information, their overall experience of the LP and whether there were any concerns about the procedure. Results Of the 36 feedback forms posted, 17 (47%) were returned. Of the 17 responses received, 12/17 (71%) of patients strongly agreed and 4 (24%) patients agreed that they understood why they were having a LP, what a LP involved before attending and that the leaflet provided sufficient information about a LP procedure. All 17 patients agreed that they were satisfied with their overall experience of the LP procedure. 5/17 (29%) patients stated they had concerns during or after the procedure; these included length of time taken for results to become available. Conclusion This survey of patients attending a Geriatrician-Led Memory Service for LP found obtaining CSF biomarkers for AD to be a well-tolerated procedure with high overall patient satisfaction.

Unraveling the Genetics of Feline Hypertrophic Cardiomyopathy: A Multiomics Study of 138 Cats.

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease in cats, often leading to congestive heart failure, arterial thromboembolism, and sudden cardiac death. The genetics of feline HCM are poorly understood and limited genetic discoveries remain breed or family specific. We aimed to identify novel causative or disease modifying variants in a large cohort of cats reflective of the general cat population. In a second cohort, we sought to characterize transcriptomics differences between HCM-affected cats and healthy controls. DNA was isolated from 138 domestic cats (109 HCM and 29 controls). No single or combination of variants of high, moderate or modifying impact were identified in genome wide analysis to cause or modify disease severity of HCM. Several rare high and moderate impact variants in genes associated with human HCM were detected in diseased cats. In a second cohort, left ventricular (LV), interventricular septal (IVS) and left atrial (LA) tissues of 27 HCM-affected and 15 control cats were submitted for stranded mature RNA-sequencing at 50 million reads/sample. A total of 74, 115, and 45 DEGs were upregulated and 8, 53, and 48 DEGs were downregulated in LVPW, IVS, and LA tissue, respectively, in HCM-affected cats compared to controls. Similar to humans, the genetic etiology of feline HCM remains unknown in a high proportion of cases. Transcriptomics revealed molecular signatures that may help identify novel HCM biomarkers or drug targets in future investigations.

Prognostic Value of Malnutrition, Frailty, and Physical Performance in Transthyretin Cardiac Amyloidosis: Insights From a Prospective Multicenter Cohort Study.

The prevalence of transthyretin cardiac amyloidosis among older adults (often octogenarians) is increasing. We aimed to determine whether age and geriatric syndromes bear any impact on the management and outcomes in transthyretin cardiac amyloidosis and assess the risk of ageism. In a prospective, multicenter cohort study, 256 patients diagnosed with transthyretin cardiac amyloidosis from March 2021 to March 2024 underwent comprehensive geriatric assessment (CGA). The study evaluated the prevalence and clinical associations of CGAs across different disease stages (National Amyloidosis Centre stage). Key CGA domains included disability, malnutrition, depression, frailty, Short Physical Performance Battery, and cumulative deficits (sum of the single CGA items). Associations of these measures with disease-modifying therapy and overall mortality were analyzed. Median age was 82 years (men: n=223 [87%]; variant: n=19 [7.4%]); 129 (50.3%) patients received disease modifiers. Those ≥85 years had significantly lower odds of receiving disease-modifying therapy even after adjusting for disability, frailty, and cumulative deficits. Over 1.9 (interquartile range, 1.0-2.3) years, 45 (17.6%) patients died. After adjustment for National Amyloidosis Centre stage, diuretics and disease modifiers, CGA domains of disability, malnutrition, Short Physical Performance Battery, frailty, and number of deficits, but not age, were significantly associated with mortality. Assessment of CGA domains improved National Amyloidosis Centre prognostic accuracy. In a national prospective cohort of patients with transthyretin cardiac amyloidosis, older age was associated with lower prescription of disease modifiers, even among individuals with a low burden of geriatric syndromes. However, when adjusted for geriatric domains, age was not associated with survival, indicating potential ageism. Because some geriatric syndromes may be modifiable, a CGA could enhance risk stratification, reduce age-related bias, and improve outcomes.

Evidence-based rehabilitation of the competition horse

The rehabilitation of horses requires a multifaceted approach tailored to specific goals at each phase of recovery, considering the horse's overall health, temperament and the owner's capacity for care. Key goals include pain management, resolving inflammation, promoting healing and enhancing strength and range of motion. Rehabilitation may integrate controlled exercise, electrophysical therapies and injectables, all chosen based on evidence and the specific needs of the horse. Controlled exercise is the foundation of rehabilitation, with careful management of limb loading to promote tissue repair without exacerbating injuries. The frequency, type and conditions of exercise can all be adjusted to achieve different goals. Electrophysical therapies, like shockwave and LASER, offer additional benefits in pain management and healing, while injectables such as bisphosphonates and orthobiologics support tissue repair and disease modification. Collaboration with an equine physiotherapist is recommended to ensure a comprehensive and individualised rehabilitation programme.

Targeting HIF-P4H-2 in APP/PS1 Alzheimer's mouse model improves glucose metabolism, reduces dystrophic neurites and maintains exploratory activity.

Targeting HIF-P4H-2 in APP/PS1 Alzheimer's mouse model improves glucose metabolism, reduces dystrophic neurites and maintains exploratory activity.

Difficult-to-treat rheumatoid arthritis among elderly patients from the KOBIO registry.

Difficult-to-treat rheumatoid arthritis among elderly patients from the KOBIO registry.

The journey of the patient living with NMOSD with area postrema syndrome as the inaugural Attack, a single center retrospective study.

The journey of the patient living with NMOSD with area postrema syndrome as the inaugural Attack, a single center retrospective study.

The Discontinuation and Effectiveness of Sequential Advanced Therapy in Rheumatoid Arthritis: Real-World Data

ObjectivesPatients with rheumatoid arthritis (RA) who fail conventional synthetic treatment with disease modifying antirheumatic drugs (csDMARDs) are eligible for biological DMARDs (bDMARDs) or targeted synthetic DMARDs (tsDMARDs). Many patients experience a lack of response or intolerance to their first advanced therapy (AT), requiring a change in medication. Subsequent treatment choice is important for achieving successful long-term disease control. The current study aimed to describe the pattern of sequential AT use in RA patients in a multicentre observational cohort and to evaluate the survival rate and effectiveness of each line of therapy.MethodsAdult RA patients participating in the Ontario Best Practice Research Initiative (OBRI) and initiating their first AT (line 1) between Jun. 1, 2008, and Jan. 1, 2023, were included. Drug retention was defined as the time from initiation to discontinuation of therapy (due to any reason). We evaluated effectiveness using Clinical Disease Activity Index (CDAI) change, the proportion of patients reaching the minimally clinically important difference (MCID), CDAI low disease activity (LDA), and remission at 6 months. Time to event analysis was used for treatment discontinuation and general linear mix model for effectiveness. An exploratory analysis compared outcomes in patients who started their first AT before and after 2010, the year treat to target guidelines were published. We also compared drug survival of the first AT in 3 therapeutic groups (TNFi, non-TNFi, tsDMARDs).ResultsA total of 2449 patients were included (line 1=1117, line 2=679, line 3=339, and lines 4 to 7=314). TNFi was predominantly used as first-line AT, with Etanercept and Adalimumab being the 1st and 2nd most common choices. Subsequent AT lines exhibited lower TNFi usage. Risk of discontinuation increased in later lines (Figure 1). Persisting after adjustments for confounders. Pre-2010 and post-2010 cohorts displayed significant differences in first-line AT retention, suggesting quicker switches post-2010 (Median survival 12.2 vs 7.6 years). Efficacy outcomes favored first-line AT, with lower CDAI change and attainment of clinical targets in subsequent lines.ConclusionWe found that TNFi remains the most common first AT, however, there has been a downward trend in using TNFi. The first AT has longer survival and better efficacy when compared to subsequent lines. Clinicians tend to switch the first-line therapy earlier since 2010, likely due to a shift toward a treat to target approach and more available therapeutic options.

“I see diet almost as another disease modifying therapy. It’s that important.” A qualitative study of dietitian and nursing perspectives on the role of diet and brain health for multiple sclerosis

“I see diet almost as another disease modifying therapy. It’s that important.” A qualitative study of dietitian and nursing perspectives on the role of diet and brain health for multiple sclerosis

The alcohol hangover product market of the United States of America

A 2019 study revealed more than 80 products available online with implied benefits to alcohol hangover. Since then, several developments may have influenced the market. In order to gauge the extent to which this may have changed in the ensuing 5 years, two market evaluations (25 March 2023 and 7 November 2024) were conducted via the online web shop www.amazon.com , using the search term “hangover treatment.” In 2023, there were 38 different hangover products available. The most common dosage forms were capsules (14) and tablets (6), and most frequently reported ingredients were dihydromyricetin (DHM, 52.6% of products), vitamin B1 (42.1%), vitamin B12 (42.1%), sodium (42.1%), and vitamin B6 (39.5%). Only one product contained N-acetyl L-cysteine. Exactly half of the marketed products (19, 50.0%) made illegal disease modification claims. The second market evaluation (7 November 2024) revealed 46 hangover products. The most common dosage forms were capsules (18) and transdermal patches (13), and the most frequently reported ingredients were vitamin B6 (56.5% of products), vitamin C (54.3%), vitamin B1 (50.0%), and vitamin B12 (50.0%). Also, DHM (47.8%) and milk thistle extract (47.8%) were popular. In conclusion, over the 5 years to 2024 the US hangover product market has dramatically changed, including a significant reduction in the number of marketed hangover products. DHM, vitamins, and minerals remained the most popular ingredients of hangover products. Illegal disease claims were made by 41.3% of the marketed products. Of concern, the efficacy to prevent or reduce alcohol hangover has not been demonstrated for any product on the US hangover market.

The suitability of mesenchymal stem cells for treating immune-mediated inflammatory skin diseases: a systematic review.

Mesenchymal stem cell (MSC) therapy holds promise for treating immune-mediated inflammatory skin diseases (IMIDs), particularly when conventional therapies are ineffective. Encouraged by their immunomodulatory capabilities and potential for disease modification, different clinical trials are investigating the efficacy and safety of MSCs in single IMIDs. This review aims to summarize the application of MSCs in IMIDs and explore their future clinical potential. We reviewed published studies from January 2016 to January 2024 on MSC treatment for IMIDs. We retrieved 18 clinical trials and 5 observational studies, encompassing 609 patients with psoriasis, atopic dermatitis (AD), chronic spontaneous urticaria (CSU), alopecia areata (AA), systemic sclerosis (SSc), and systemic lupus erythematosus (SLE). Improvements or complete remission were observed in up to 100% of cases for AA, SSc, and SLE, though complete remission rates were less frequent than improvement rates, ranging from 0% in AD to 50% in CSU. Adverse events (AEs) were generally mild; moderate-to-severe AEs were uncommon (4% in psoriasis, 2.6% in SLE, and 0.7% in SSc), and deaths from all causes were rare (6 patients with SSc and 15 patients with SLE). In conclusion, MSC therapy shows promising results in terms of at least partial clinical improvement for most IMIDs. Its effect is achievable after a single or a few administrations, with no significant toxicity. MSCs may fulfill an unmet need for patients unresponsive to conventional immunomodulating agents. However, most evidence still comes from clinical trials with heterogeneous designs and endpoints. Future larger controlled trials are needed to better elucidate their role in refractory IMIDs.

Omega-3 Polyunsaturated Fatty Acids (PUFAs) and Diabetic Peripheral Neuropathy: A Pre-Clinical Study Examining the Effect of Omega-3 PUFAs from Fish Oil, Krill Oil, Algae or Pharmaceutical-Derived Ethyl Esters Using Type 2 Diabetic Rats

Background and Objectives: We have previously reported that omega-3 polyunsaturated fatty acids (PUFAs) derived from fish oil (FO) is an effective treatment for type 1 and type 2 diabetes neural and vascular complications. As omega-3 PUFAs become more widely used as a nutritional and disease modifying supplement an important question to be addressed is what is the preferred source of omega-3 PUFAs? Methods: Using a type 2 diabetic rat model and early and late intervention protocols we examined the effect of dietary treatment with omega-3 PUFAs derived from menhaden (fish) oil (MO), krill oil (KO), algal oils consisting primarily of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) or combination of EPA + DHA, or pharmaceutical-derived ethyl esters of EPA, DHA or combination of EPA + DHA. Nerve related endpoints included motor and sensory nerve conduction velocity, heat sensitivity of the hind paw, intraepidermal nerve density, cornea nerve fiber length, and cornea sensitivity. Vascular reactivity to acetylcholine and calcitonin gene-related peptide by epineurial arterioles that provide blood to the sciatic nerve was also examined. Results: The dose of each omega-3 PUFA supplement increased the content of EPA, docosapentaenoic acid (DPA), and/or DHA in red blood cell membranes, serum and liver. Diabetes caused a significant decrease of 30–50% of neural function and fiber occupancy of the skin and cornea and vascular reactivity. Treatment with MO, KO or the combination of EPA + DHA provided through algal oil or ethyl esters provided significant improvement of each neural endpoint and vascular function. Algal oil or ethyl ester of EPA alone was the least effective with algal oil or ethyl ester of DHA alone providing benefit that approached combination therapies for some endpoints. Conclusions: We confirm that omega-3 PUFAs are an effective treatment for DPN and sources other than fish oil are similarly effective.

Trajectories of allergic diseases in children: Destination unknown?

The trajectories of allergic diseases represent one of the most currently debated topics both when referred to childhood and likewise adulthood. Data from cohorts show their heterogeneity as well as the key role of genetic and environmental factors. More insight has been recently provided in the pathophysiological mechanisms underlying the development and amplification of T2 (hyper)inflammation. Recent data support the hypothesis of associated allergic diseases (multimorbidity) reflecting, at a given time and in given organ(s)/tissue(s), the expression of the same favorable predisposition. In particular, the impairment of the epithelial barrier, especially in subjects genetically predisposed, and the dysregulation of the host's microbiome promote the onset of allergic diseases and multimorbidity, their persistence and/or severity. These findings challenge the classical theory of the atopic march with a temporal sequence characterized by the transition from one disease (eczema) to another (food allergy, airway allergic diseases). A better understanding of the diversity of disease trajectories and the underpinning mechanisms is crucial for prevention and identification of children at risk of a "unfavorable trajectory" (early intervention, i.e., early primary or secondary prevention), for a personalized therapeutic approach based on identification of specific endotypes, and, therefore, addressing specific pathophysiological pathways (treat to target strategies). In the perspective of the so-called "remission" and "treatment-induced-remission", the whole spectrum of the long-term consequences of the disease(s) including their treatment has to be considered. The concept of disease modifying treatment able to interfere with their trajectories and overall long-term induced morbidity is emerging.