Disease Modifying Research Articles

Nose-to-Brain Targeting of Resveratrol Nanoformulations.

Resveratrol [RES] is a polyphenolic stilbene with therapeutic potential owing to its antioxidant, anti-inflammatory, neuroprotective, and cardioprotective properties. However, the very poor oral bioavailability, fast metabolism, and extremely low stability under physiological conditions pose a severe detriment to the clinical use of RES. This newly developed field of nanotechnology has led to the formulation of RES into nanoformulations with the goal of overcoming metabolicpharmacokinetic limitations and enhancing the targeted transport of RES to the central nervous system [CNS]. Among the various routes of administration, the combination of nose-to-brain [N2B] delivery via the intranasal [IN] route has recently garnered attention as a straightforward, noninvasive route for transport to the blood-brain barrier [BBB] for greater effects and less harmful systemic side effects by transporting nano-encapsulated RES into the neural tissues. This review critically summarizes the mechanisms and benefits of the N2B route for the delivery of RES nanoformulations, collating in vivo data demonstrating increased CNS bioavailability and stability and, consequently, improved therapeutic efficacy in animal models of neurodegenerative diseases. Compared with the more 'traditional' routes of administration, IN administration of RES nanoformulations is less toxic, cost-effective, and efficient in crossing the BBB. Therefore, this route represents a promising approach to the management of CNS disorders. Further optimization of nanoformulation design and clinical protocols is required to translate these promising findings into therapeutic strategies aimed at neuroprotection and disease modification in human CNS pathologies.

A STRONG call for intensive oral heart failure therapy in acute heart failure patients.

Heart failure (HF), a chronic and progressive disease, is increasing in prevalence worldwide and is associated with increased hospitalizations and death. Despite notable improvements in medical therapy for HF, patients are still at risk of future negative outcomes. Current guidelines recommend four classes of medication for treating patients with HF, deemed guideline-directed medical therapy (GDMT). The use and adherence of these GDMTs serve as a major predictor of outcomes in those with chronic HF; however, implementation of therapy remains poor, despite substantial evidence of benefit. The acute hospitalization for HF and the subsequent vulnerable period serve as important milestones for adequate disease modification, and implementing a strategy for aggressive medical therapy can improve HF outcomes. Current guidelines also recommend that follow-up withmultidisciplinary chronic disease management specific to HF be provided to those living with heart failure, which is essential for improving readmissions and mortality. This follow-up, although important by itself, serves as an important avenue for disease modification through medication titration, and implementing such structured follow-up is essential for further population-wide improvements in HF mortality. In this context, the STRONG-HF trial investigators developed an implementation trial providing evidence for the rapid inpatient initiation and subsequent titration of HF GDMT, demonstrating the importance of implementation strategies in the care of HF patients. In this narrative review, we review the evidence base for treating patients with HF, highlight deficits in our current real-world experience, and provide support for trial evidence like STRONG-HF in the global fight to reduce the burden of HF.

Unravelling ATTR Cardiac Amyloidosis in Iceland: A Nationwide Epidemiological Study

Introduction: Cardiac amyloidosis (CA) arises from the deposition of misfolded amyloid proteins in the heart's extracellular matrix, leading to significant cardiac disease. Recent data suggest that CA is under recognised and advances in treatment have increased focus on this condition with the intention of implementing treatment earlier to improve prognosis. There is limited knowledge regarding the prevalence of Transthyretin-CA (ATTR-CA) on a national level, particularly in Iceland. Therefore, this study represents the first nationwide effort to evaluate the baseline characteristics, diagnostics, and treatment of ATTR-CA in Iceland. Methods: A retrospective study of all patients diagnosed with ATTR-CA in Iceland from 6 May 2013 to 11 March 2024 were identified in the Icelandic Cardiac Amyloid Registry (ICE-CAR) created in 2023 by heart failure (HF) specialists at Landspitali University Hospital in Reykjavik, Iceland. Diagnosis was based on different combinations of transthoracic echocardiography (TTE), an elevated Perugini score on bone scintigraphy and heart biopsies, as well measurements of free light chains, M-component measurements in blood and urine. Patients were grouped according to the National Amyloidosis Centre (NAC) prognostic staging system for ATTR-CA. Results: In total, 65 patients with ATTR-CA were identified (males n=60, females n=5, median age 81.4 years [IQR 75.5-85.5 years]), all wild-type and no mutant variant. Diagnosis was made with myocardial biopsy in 7 cases. Upon diagnosis, 83% of the patients had an interventricular septum thickness of ≥15mm and 92% showed a posterior wall thickness of ≥12mm. Approximately 57% of patients belonged to New York Heart Association (NYHA) functional class I-II. The HF phenotypes according to left ventricular ejection fraction (LVEF) were distributed as follows: reduced (HFrEF) n=24 (37%), mildly reduced (HFmrEF) n=9 (14%), preserved (HFpEF) n=29 (44.5%), and unknown LVEF n=3 (4.5%). A total of 54 patients had reported NAC stage: Stage I 23 (35.4%), Stage II 20 (30.8%), Stage III 11 (16.9%). Around 32% received disease modifying treatment. Conclusion Despite the low NYHA class observed in the study population, our findings in Iceland's nationwide assessment of ATTR-CA indicate more advanced age and lower LVEF at diagnosis compared to other studies. This highlights the critical need for early detection and appropriate therapeutic interventions in managing ATTR-CA.

A case report on Pseudo Felty’s syndrome

Pseudo-Felty’s syndrome is a rare disease entity defined by the presence of monoclonal expansion of T lymphocytes with neutropenia in association with rheumatoid arthritis. T-large granular lymphocyte (LGL) leukemia is a lymphoproliferative disease with an indolent behavior. LGL leukemia arises in a setting of sustained immune stimulation, such as autoimmune disorders and chronic viral infections, where there is a clonal expansion of T-LGL (cluster of differentiation [CD]3+/CD8+) cells. In this article, we present the case of a 60-year-old gentleman with Pseudo-Felty’s syndrome who presented with LGL proliferation. He is presently stable on disease modifying anti-rheumatoid drugs including methotrexate.

FABP4 as a therapeutic host target controlling SARS-CoV-2 infection.

Host metabolic fitness is a critical determinant of infectious disease outcomes. Obesity, aging, and other related metabolic disorders are recognized as high-risk disease modifiers for respiratory infections, including coronavirus infections, though the underlying mechanisms remain unknown. Our study highlights fatty acid-binding protein 4 (FABP4), a key regulator of metabolic dysfunction and inflammation, as a modulator of SARS-CoV-2 pathogenesis, correlating strongly with disease severity in COVID-19 patients. We demonstrate that loss of FABP4 function, by genetic or pharmacological means, reduces SARS-CoV-2 replication and disrupts the formation of viral replication organelles in adipocytes and airway epithelial cells. Importantly, FABP4 inhibitor treatment of infected hamsters diminished lung viral titers, alleviated lung damage and reduced collagen deposition. These findings highlight the therapeutic potential of targeting host metabolism in limiting coronavirus replication and mitigating the pathogenesis of infection.

DOP081 The EXTENT Study (Calculating the LEmann indeX using inTEstiNal ulTrasound): Results from an international expert Delphi consensus

Abstract Background A primary objective in the management of Crohn's disease (CD) is the prevention of bowel tissue damage. The Lémann index (LI) characterizes structural bowel damage based on magnetic resonance enterography (MRE) or computed tomography enterography (CTE) and, for colonic CD, colonoscopy. Intestinal ultrasonography (IUS) provides a non-invasive imaging alternative, though its role in the LI assessment remains unexplored. This study aimed to establish a consensus on parameters and standardized acquisition for scoring small bowel and colonic damage using IUS in accordance with the LI. Methods Thirty international experts in IUS and/or MRE participated in a three-round Delphi process. Participants provided feedback and rated agreement with statements outlining IUS parameters and standardized acquisition in two virtual rounds. During the final in-person round, unresolved items were discussed and voted upon. Statements with at least 80% agreement were accepted. Results Twenty-two statements reached a consensus: 10 defined IUS parameters for stricturing and penetrating lesions for scoring LI-IUS, and 12 addressed optimal IUS cineloop acquisition for centralized review (Table 1). No consensus was reached regarding IUS equivalents for grade 1 stricturing lesions in the small bowel and colon. Conclusion Ultrasonographic equivalents for assessing small bowel and colonic damage in CD were derived to align with the validated LI criteria for MRE/CTE and colonoscopy. These statements mark the first phase of the EXTENT project, supporting the potential use of IUS in clinical practice and disease modification trials as an alternative tool for bowel damage assessment. The lack of consensus on grade 1 stricturing lesions suggests further exploration of IUS parameters is required.

A review on disease modifying pharmacologic therapies for sickle cell disease.

Sickle cell disease (SCD) is an inherited hematologic disease caused by sickle hemoglobin as the predominant RBC hemoglobin or by sickle hemoglobin in combination with other abnormal β-hemoglobin variants like HbC, HbD and others. Sickling of erythrocytes under deoxygenated conditions is the basis of inflammatory and thrombotic cascades which result in multiple serious complications, leading to early morbidity and mortality. While HLA-matched allogeneic bone marrow transplantation is potentially curative, it has considerable limitations due to potential severe toxicities. Despite slow progress towards novel therapeutic strategies for SCD and hydroxyurea being the sole medication that is shown to reduce vaso-occlusive events and mortality for almost 20 years, several pharmacological agents targeting different mechanisms have been examined in clinical trials and recently US- US-FDA-approved, including L-glutamine and crizanlizumab. Voxelotor was previously US-FDA-approved but has been voluntarily withdrawn from the market as the overall benefit did not outweigh the risks. Gene therapies based on CRISPR-Cas9 and lentiviral vectors have been very recently approved. However, excessive costs are a barrier to widespread use. Nonetheless, there is still a large area of unmet needs for patients with SCD, and further research towards better care is warranted.

Enhanced Interleukin 6 Trans-Signaling Modulates Disease Process in Amyotrophic Lateral Sclerosis Mouse Models.

Background/Objectives: Charcot first described ALS in 1869, but the specific mechanisms that mediate the disease pathology are still not clear. Intense research efforts have provided insight into unique neuroanatomical regions, specific neuronal populations and genetic associations for ALS and other neurodegenerative diseases; however, the experimental results also suggest a convergence of these events to common toxic pathways. We propose that common toxic pathways can be therapeutically targeted, and this intervention will be effective in slowing progression and improving patient quality of life. Here, we focus on understanding the role of IL6 trans-signaling in ALS disease processes. Methods: We leveraged unique mouse models of IL6 trans-signaling that we developed that recapitulate the production of active sIL6R in a genotypic and quantitative fashion observed in humans. Given that the SOD1 transgenic mouse is one of the most highly studied and characterized models of ALS, we bred SOD1G93A mice with IL6R trans-signaling mice to determine how enhanced trans-signaling influenced symptom onset and pathological processes, including neuromuscular junction (NMJ) denervation, glial activation and motoneuron (MN) survival. Results: The results indicate that in animals with enhanced trans-signaling, symptom onset and pathological processes were accelerated, suggesting a role in disease modification. Administration of an IL6R functional blocking antibody failed to alter accelerated symptom onset and disease progression. Conclusions: Future work to investigate the site-specific influence of enhanced IL6 trans-signaling and the tissue-specific bioavailability of potential therapeutics will be necessary to identify targets for precise therapeutic interventions that may limit disease progression in the 60% of ALS patients who inherit the common Il6R Asp358Ala variant.

Use of disease modifying anti-rheumatic drugs and risk of multiple myeloma in US Veterans with rheumatoid arthritis

BackgroundBiologic (b) and targeted synthetic (ts) disease-modifying anti-rheumatic drugs (DMARDs) used in the management of rheumatoid arthritis (RA) target inflammatory pathways implicated in the pathogenesis of multiple myeloma (MM). It is unknown whether use of b/tsDMARDs affects the incidence of MM.MethodsIn this cohort study using Veterans Health Administration (VHA) data, we identified Veterans newly diagnosed with RA from 1/1/2002 to 12/31/2018 using diagnostic codes and medication fills. DMARD exposure was categorized as follows: conventional synthetic (cs)DMARDs; bDMARDs, which included tumor necrosis factor inhibitors (TNFi), non-TNFi; and a tsDMARD, tofacitinib. A Cox proportional hazards model with time-varying exposure was used to estimate the hazard ratio for developing MM among those who received b/tsDMARD medications relative to b/tsDMARD-naïve persons.Results27,540 veterans with RA met eligibility criteria of whom 8322 (30%) took a b/tsDMARD during follow-up. There were 77 incident cases of MM over 192,000 person-years of follow-up. The age-adjusted incidence rate (IR) of MM among b/tsDMARD-naïve patients was 0.37 (95% CI 0.28–0.49) per 1000 person-years and 0.42 among current or former b/tsDMARD users (95% CI 0.25–0.65). Adjusting for age and other demographic characteristics, the hazard ratio for MM associated with use of b/tsDMARDs was 1.32 (95% CI 0.78, 2.26).ConclusionIn this study of Veterans with RA, the rate of MM did not differ between b/tsDMARD and csDMARD users. The relatively short duration of follow-up and few events limited our power to detect treatment-related differences in MM risk.

Dynamic Expansion and Contraction of Multiple Sclerosis T2-Weighted Hyperintense Lesions Are Present Below the Threshold of Visual Perception.

The study of T2-weighted hyperintense lesions resulting from autoimmune inflammatory injury and associated volumes within the CNS remains fundamental to the diagnosis and disease surveillance of MS. We investigated the dynamic changes of individual T2-weighted hyperintense MS lesions on MRI and hypothesized that variations may be present below the threshold of visual perception when evaluating longitudinal data. A retrospective study was performed of people with MS, incorporating data from 3 consecutive MRI time points acquired within a single academic center. All included MRI studies lacked formal imaging interpretations of newly enlarging or contracting T2-weighted hyperintensities. Well-defined, noncoalescing, individual T2-weighted hyperintense lesions were targeted. A total of 8-12 lesions were randomly selected in a blinded fashion at MRI time point 1 and 3D lesion volumes were followed over MRI time points 2 and 3. The impact of treatment on lesion expansion and relationship to brain MRI advancement, patient-reported progression of disease, and physician-identified progression was also studied. The study cohort comprised 115 people (81 (70.4%) women; mean disease duration of 9.36 years [standard deviation: 7.72 years]) who were primarily White (79.1%). A total of 1426 focal T2-weighted hyperintense MS lesions were identified on MRI time point 1 and longitudinally followed over MRI time points 2 and 3. In the evaluation of raw changes in individual T2-weighted hyperintense lesion volumes from MRI time point 1 to MRI time point 2, a similar number of individuals were observed with predominantly expanding (49/115; 42.6%) or contracting (51/115; 44.3%) lesions. However, most lesions expanded in volume (48/115; 41.7%) versus those that contracted (45/115; 39.1%) when evaluating MRI time point 3 to time point 1. Those individuals not on active treatment had a 67.15% reduction in the odds of more individual lesions predominantly contracting in volume relative to those on low-efficacy disease modifying therapy treatment (95% CI = [-83.89% to -33.01%], P = .0008) and 74.02% reduction relative to high-efficacy treatment individuals (95% CI = [-87.37% to -46.56%], P < .0001). Dynamic changes in T2-weighted hyperintense lesions are abundant, occurring below the threshold of visual perception and are present more frequently in untreated individuals.

New Multiomic Studies Shed Light on Cellular Diversity and Neuronal Susceptibility in Parkinson's Disease.

Parkinson's disease is a complex neurodegenerative disorder characterized by degeneration of dopaminergic neurons, with patients manifesting varying motor and nonmotor symptoms. Previous studies using single-cell RNA sequencing in rodent models and humans have identified distinct heterogeneity of neurons and glial cells with differential vulnerability. Recent studies have increasingly leveraged multiomics approaches, including spatial transcriptomics, epigenomics, and proteomics, in the study of Parkinson's disease, providing new insights into pathogenic mechanisms. Continued advancements in experimental technologies and sophisticated computational tools will be essential in uncovering a network of neuronal vulnerability and prioritizing disease modifiers for novel therapeutics development. © 2025 International Parkinson and Movement Disorder Society.

TRANSIENT ALTERATIONS IN THALAMO-CEREBELLAR FUNCTIONAL CONNECTIVITY IN PREMANIFEST HUNTINGTON'S DISEASE.

There are no disease modifying therapies for Huntington's disease (HD), a rare but fatal genetic neurodegenerative condition. To develop and test new management strategies, a better understanding of the mechanisms underlying HD progression is needed. Aberrant changes in thalamo-cortical and striato-cerebellar circuitry have been observed in asymptomatic HD, along with transient enlargement of the dentate nucleus. To evaluate the relationship between thalamo-cerebellar connectivity and HD progression. Prospective and retrospective. Patients with HD and healthy controls from a single-center dataset (n=34), and patients from the public TRACK-HD dataset (n=91). 3T and 7T. Thalamo-cerebellar connectivity was compared across patients and controls and related to motor scores and predicted years to symptom onset. Cross-sectional findings were validated within-patient by mapping changes in individual connectivity over time. HD effects on cognitive performance were also explored and related to connectivity. Kruskal-Wallis with post hoc Dunn's tests and Pearson correlations (p significant <0.05). In the 7T cohort, significant premanifest and control group differences in thalamo-dentate connectivity were observed (p Dunn <0.05, η 2 =.19-.22), with manifest HD connectivity approaching normative values. Thalamic connectivity with the dentate nucleus and anterior cerebellum also correlated with years to onset (p Den =0.06, r=0.42, p Ant <0.05, r=-0.45), together indicating potential transient functional alterations in premanifest HD. Similar patterns were observed between connectivity (thalamus to dentate nucleus and anterior lobe) and cognitive performance scores across all subjects (p<0.05, r Den =-0.17, r Ant =-0.18). In the premanifest TRACK-HD cohort, connectivity of multiple thalamo-cerebellar connections correlated with years to onset, revealing distinct patterns for patients with low versus high motor scores, again indicative of potential transient alterations. Exploratory non-parametric regression of serial imaging data further supported these findings. Transient changes in thalamo-cerebellar connectivity are seen in premanifest HD with increasing progression. More studies are needed to validate this potentially useful biomarker.

Targeting mitophagy in neurodegenerative diseases.

Mitochondrial dysfunction is a hallmark of idiopathic neurodegenerative diseases, including Parkinson disease, amyotrophic lateral sclerosis, Alzheimer disease and Huntington disease. Familial forms of Parkinson disease and amyotrophic lateral sclerosis are often characterized by mutations in genes associated with mitophagy deficits. Therefore, enhancing the mitophagy pathway may represent a novel therapeutic approach to targeting an underlying pathogenic cause of neurodegenerative diseases, with the potential to deliver neuroprotection and disease modification, which is an important unmet need. Accumulating genetic, molecular and preclinical model-based evidence now supports targeting mitophagy in neurodegenerative diseases. Despite clinical development challenges, small-molecule-based approaches for selective mitophagy enhancement - namely, USP30 inhibitors and PINK1 activators - are entering phase I clinical trials for the first time.

Functional resting state connectivity is differentially associated with IL-6 and TNF-α in depression and in healthy controls

Inflammatory processes have been implicated in the pathophysiology of depression. In human studies, inflammation has been shown to act as a critical disease modifier, promoting susceptibility to depression and modulating specific endophenotypes of depression. However, there is scant documentation of how inflammatory processes are associated with neural activity in patients with depression. We therefore tested the hypothesis that the peripheral inflammation markers IL-6 and TNF-α correlate with neural resting state network functional connectivity in depression using functional magnetic resonance imaging (fMRI) and compared it with healthy controls. We used fMRI to investigate the functional connectivity (FC) of the resting state Default Mode Network (DMN) and Salience/Ventral Attention Network (SAL) and their association with the peripheral inflammation markers IL-6 and TNF-α in 25 patients with depression and compared it to 24 healthy subjects. Results of this imaging study revealed that both DMN and SAL resting state networks are differentially associated with distinct immunological pathways depending on whether a person has a depressive phenotype or is healthy. While the DMN FC correlated with the concentration of the cytokine IL-6 in healthy subjects, SAL FC’s connectivity correlated with the cytokine TNF-α's concentration. This study highlights the importance of peripheral inflammatory processes in depression and suggests a modulatory effect on neural resting state networks depending on the state of depression.

Time Delay: Searching for a Meaningful Outcome of Disease Modification in Alzheimer Disease: A Report of the Educational Symposium Held at ISPOR Europe 2023.

Time Delay: Searching for a Meaningful Outcome of Disease Modification in Alzheimer Disease: A Report of the Educational Symposium Held at ISPOR Europe 2023.

Seizing the opportunity to therapeutically address neuronal hyperexcitability in Alzheimer's disease.

Seizures in people with Alzheimer's disease are increasingly recognized to worsen disease burden and accelerate functional decline. Harnessing established antiseizure medicine discovery strategies in rodents with Alzheimer's disease associated risk genes represents a novel way to uncover disease modifying treatments that may benefit these Alzheimer's disease patients. This commentary discusses the recent evaluation by Dejakaisaya and colleagues to assess the antiseizure and disease-modifying potential of the repurposed cephalosporin antibiotic, ceftriaxone, in the Tg2576 mouse model. The use of established epilepsy models in Alzheimer's disease research carries the potential to advance novel disease-modifying treatments.

Modifiable Health Behaviours in Children with HCM: Lessons from the Heart Health Survey.

Obesity factors into hypertrophic cardiomyopathy (HCM)-related risk as a disease modifying environmental factor. Behaviours such as diet and sleep are seldom reported upon in children with HCM. It was our aim to report on these factors in this population. A multicenter cross-sectional study recruited children and teens with HCM aged 10-19years old from 10 Canadian pediatric care sites. Patient demographics were obtained from review of medical charts. Participants completed the Healthy Hearts Survey, involving 92 questions related to family health history, personal health, smoking, nutrition, and physical or sedentary activity. A cohort of n = 56 patients with median (IQR) age of 15.5 (13.8-16.8) years were enrolled. Over half (53.6%) were classified as overweight or obese based on BMI, with 75% under activity restriction. Consumption of sugar-rich and starchy foods alongside skipping of meals (43.6%) and snacking (87.5%) were reported. A desire to lose weight was prevalent (48.2%) despite general perceptions of good health. Participants slept a median duration of 8 (7.4-9.0) hours on weekdays, however, sleep disturbances were widely reported. A majority (96.4%) reported less than 20min of exercise per day over the course of the week. Unhealthy patterns regarding diet, sleep, and physical or sedentary activities that associate with cardiovascular risk are present within children with HCM. These habits may worsen disease burden in children with HCM. It is unclear how activity restriction factors into such patterns. There are modifiable lifestyle factors in children with HCM which, if addressed, could positively impact cardiovascular risk.

Treatment of idiopathic granulomatous mastitis: a retrospective case series.

Idiopathic granulomatous mastitis (IGM) is a rare inflammatory disease of the breast. Various clinical management approaches have been described, but their efficacy and optimal sequential order remain uncertain. We describe the first Canadian cohort of patients with IGM, discuss treatment outcomes and outline a practical management approach. This retrospective study included patients diagnosed with biopsy-confirmed IGM between 2014 and 2023, aged over 18 years. Based on a scoping review of the literature, a diagnostic and management approach was developed, and we present here the disease course and outcomes using this approach. 22 females were included, with a mean age of 40 (24-65) years, mostly presenting with a breast lump (n =22, 100%) and breast pain (n = 15, 68%). Mean rheumatology follow-up was 28.7 months (range 3-79). Mean time from first symptom to diagnosis was 3.5 months (range 1-13). Corynebacterium kroppenstedtii was found in 8 patients. Treatment including lipophilic antibiotics, corticosteroids and disease modifying anti-rheumatic drugs (DMARDs), led to complete remission in 95% of patients, in a mean time of 11.6 months (range 1-36), and relapse in only 1 patient. 11 patients required DMARDs (50%), most commonly methotrexate (n=9). We highlight the variable severity of IGM and the benefits of a severity-based treatment approach. A diligent evaluation and work-up is essential to manage IGM. The proposed severity-based management approach with medical treatment and less aggressive surgical intervention led to complete remission in 95%.

The effect of HLA genotype on disease onset and severity in CTLA-4 insufficiency.

Human Cytotoxic-T-lymphocyte-antigen-4 (CTLA-4) insufficiency caused by heterozygous germline mutations in CTLA4 is a complex immune dysregulation and immunodeficiency syndrome presenting with reduced penetrance and variable disease expressivity, suggesting the presence of disease modifiers that trigger the disease onset and severity. Various genetic and non-genetic potential triggers have been analyzed in CTLA-4 insufficiency cohorts, however, none of them have revealed a clear association to the disease. Multiple HLA haplotypes have been positively or negatively associated with various autoimmune diseases and inborn errors of immunity (IEI) due to the relevance of MHC in the strength of the T cell responses. In this exploratory study, we investigated the association of disease onset, severity and clinical manifestations of CTLA-4 insufficiency with specific HLA class I (A, B and C) and class II (DRB1 and DQB1) alleles in forty-three individuals harboring heterozygous mutations in CTLA4. Twenty-six out of the 43 recruited individuals presented moderate or severe clinical symptoms whereas 17 were completely healthy. HLA frequency analysis, odds ratio analysis and genetic linkage analysis were used. The principal statistical analyses showed no positive association between the HLA genotypes analyzed with the disease onset or the disease severity. We found potential risk associations of HLA-DQB1*05:01 and HLA-DRB1*01:02 with respiratory tract involvement and HLA-C*05:01 with affection of the neurological system in the CTLA-4-insufficient patients. Additionally, wefound a potential protective association of HLA-DRB1*01:01 with gastrointestinal symptoms. Even though, our findings suggest that HLA-A, -B, -C, DRB1, and DQB1 do not contribute to the onset or severity of disease in CTLA-4 insufficiency, certain HLA-alleles may influence the manifestation of specific symptoms. We advocate for further investigation of specific class I and class II HLA alleles as potential disease modifiers in larger clinical cohorts of CTLA-4 insufficiency.

Redosing with Intralymphatic GAD-Alum in the Treatment of Type 1 Diabetes: The DIAGNODE-B Pilot Trial.

Immunotherapies aimed at preserving residual beta cell function in type 1 diabetes have been successful, although the effect has been limited, or raised safety concerns. Transient effects often observed may necessitate redosing to prolong the effect, although this is not always feasible or safe. Treatment with intralymphatic GAD-alum has been shown to be tolerable and safe in persons with type 1 diabetes and has shown significant efficacy to preserve C-peptide with associated clinical benefit in individuals with the human leukocyte antigen DR3DQ2 haplotype. To further explore the feasibility and advantages of redosing with intralymphatic GAD-alum, six participants who had previously received active treatment with intralymphatic GAD-alum and carried HLA DR3-DQ2 received one additional intralymphatic dose of 4 μg GAD-alum in the pilot trial DIAGNODE-B. The participants also received 2000 U/day vitamin D (Calciferol) supplementation for two months, starting one month prior to the GAD-alum injection. During the 12-month follow-up, residual beta cell function was estimated with Mixed-Meal Tolerance Tests, and clinical and immune responses were observed. C-peptide decreased minimally, and most patients showed stable HbA1c and IDAA1c. The mean % TIR increased while the mean daily insulin dose decreased at month 12 compared to the baseline. Redosing with GAD-alum seems to be safe and tolerable, and may prolong the disease modification elicited by the original GAD-alum treatment.