Sclerosis, Volume 3, Issue 3 (September 2025) – 12 articles

Background: Multiple sclerosis is a multifactorial neurodegenerative disease characterized by autoimmune and inflammatory processes. Despite advancements in disease-modifying therapies, multiple sclerosis remains challenging due to its complex pathophysiology and variable clinical presentation. Current therapies focus on managing inflammation and promoting immunosuppression but do not achieve complete symptom regression or enhance remyelination. Emerging therapies, such as Peroxisome Proliferator-Activated Receptor gamma (PPARγ) agonists and Bruton tyrosine kinase (BTK) inhibitors, show promise in modulating inflammation and targeting immune cells. Innovative approaches like human fetal neural precursor cells (hfPNCs) and mesenchymal stem cell transplantation are being explored to reduce neural inflammation and improve neuroprotection. Early diagnosis and intervention are crucial for managing multiple sclerosis effectively and preventing progression to severe forms and permanent disability. Therapeutic education for individuals with multiple sclerosis and their caregivers is essential, emphasizing the need for clear, reliable information to support disease management and improve quality of life. Objectives: This review provides an up-to-date overview of multiple sclerosis pathophysiology, current treatments, and emerging therapies, aiming to enhance the knowledge base of healthcare professionals and researchers, facilitating informed decision-making and contributing to ongoing research efforts. Full article

Objectives: Cardiac involvement in scleroderma due to myocardial inflammation and fibrosis is associated with poor outcomes, but there is lack of consensus on its investigation and treatment. In this prospective pilot study, we aimed to assess the cardiac uptake of 18F-FDG-PET/CT in suspected scleroderma cardiomyopathy. Methods: The Scleroderma Heart study involved 16 patients with cardiac scleroderma but no coronary artery disease. 18F-FDG-PET/CTs were performed, and the patients with a positive scan were offered a second 18F-FDG-PET/CT scan after 6–9 months. The clinical characteristics and clinical outcomes (all-cause mortality) were compared between the patients with positive and negative 18F-FDG-PET/CT scans. Results: Of the 16 included patients, 8 (50%) had positive myocardial uptake on the 18F-FDG-PET/CT, 2 of whom showed a pattern consistent with cardiac involvement in scleroderma, while 6 patients more likely had physiological uptake. Over a mean follow-up of 603.3 days, all-cause mortality occurred in six patients (37.5%), and the mortality was similar between the two groups. Five patients with repeat 18F-FDG-PET/CTs showed stable or increased FDG uptake despite immunosuppression. Conclusions: To the best of our knowledge, this is the first study to investigate 18F-FDG-PET/CT in scleroderma patients with suspected cardiac involvement. The cardiac PET showed limited clinical utility due to frequent physiological uptake and lack of correlation with the treatment response. Further studies with larger cohorts and standardised interpretation criteria are needed before cardiac PET can be recommended for routine clinical use in scleroderma cardiomyopathy. Full article

Amyotrophic Lateral Sclerosis (ALS) and Multiple Sclerosis (MS) are multifactorial and progressive neurodegenerative diseases (ND), which cause a functional capacity decline. Both diseases etiology remains unclear. They may have a hereditary genetic architecture, but they can also be due to a combination of genetic and environmental factors. Heat shock proteins (HSPs) play a crucial role in protein quality control, avoiding protein dysfunction and, consequently, cell apoptosis, which are well-known pathogenic mechanisms of ND. There are studies about chaperones physiology. However, research on their pathophysiology is scarce. Especially when it comes to their associated dysfunctions with Single nucleotide variants (SNV) on HSPs in ND. Thus, this review aimed to examine the role of genetic variants in genes encoding HSPs and their contribution to the pathophysiology of these sclerosis. We performed a qualitative and descriptive literature review, searching by the indexed terms “amyotrophic lateral sclerosis,” “genetic variants,” “heat shock proteins,” “Hsp40”, “Hsp70”, Hsp90”, “DNAJC7”, “multiple sclerosis,” “neurodegenerative diseases,” “protein quality control”, and “SNV” in the PubMed/NCBI, EMBASE and SciELo databases. Results described by a qualitative synthesis of the most significant studies. Despite the existence of studies with genetic variants in HSPs in patients with ND, we realize in this review the need for more specific research on this topic to demonstrate a significance as to the responsibility for deleterious effects in the modification in genes HSPs linked to sclerosis. Full article

Paediatric Focal Segmental Glomerulosclerosis (FSGS) is a leading cause of steroid-resistant nephrotic syndrome and progressive kidney failure in children. Early subclassification into primary, secondary, genetic, or undetermined forms is crucial for guiding appropriate management. Primary FSGS typically necessitates immunosuppressive therapy, whereas secondary FSGS benefits from supportive measures and treatment of the underlying cause. Emerging treatments—including SGLT2 inhibitors, endothelin receptor antagonists, and APOL1-targeted agents—show promise in reducing proteinuria and preserving kidney function. Insights into podocyte biology, including TRPC channel dysregulation and fibrotic signalling pathways, are opening new therapeutic avenues. As research continues to evolve, the future of paediatric FSGS management lies in individualised, pathophysiology-driven therapies that may significantly improve clinical outcomes. Full article

Multiple sclerosis (MS) is a chronic, immune-mediated disorder of the central nervous system (CNS) characterized by inflammation, demyelination, axonal degeneration, and gliosis. Its pathophysiology involves a complex interplay of genetic susceptibility, environmental triggers, and immune dysregulation, ultimately leading to progressive neurodegeneration and functional decline. Although significant advances have been made in disease-modifying therapies (DMTs), many patients continue to experience disease progression and unmet therapeutic needs. Drug repurposing—the identification of new indications for existing drugs—has emerged as a promising strategy in MS research, offering a cost-effective and time-efficient alternative to traditional drug development. Several compounds originally developed for other diseases, including immunomodulatory, anti-inflammatory, and neuroprotective agents, are currently under investigation for their efficacy in MS. Repurposed agents, such as selective sphingosine-1-phosphate (S1P) receptor modulators, kinase inhibitors, and metabolic regulators, have demonstrated potential in promoting neuroprotection, modulating immune responses, and supporting remyelination in both preclinical and clinical settings. Simultaneously, artificial intelligence (AI) is transforming drug discovery and precision medicine in MS. Machine learning and deep learning models are being employed to analyze high-dimensional biomedical data, predict drug–target interactions, streamline drug repurposing workflows, and enhance therapeutic candidate selection. By integrating multiomics and neuroimaging data, AI tools facilitate the identification of novel targets and support patient stratification for individualized treatment. This review highlights recent advances in drug repurposing and discovery for MS, with a particular emphasis on the emerging role of AI in accelerating therapeutic innovation and optimizing treatment strategies. Full article

Background: Amyotrophic lateral sclerosis is a systemic, complex, multifactorial, and fatal neurodegenerative disease with various factors involved in its etiology. This study aimed to understand the effects of SNPs in the MTHFR, MTR, SLC19A1, and VAPB genes on protein functionality and structure and their influence on ALS susceptibility. Methods: The dbSNP and ClinVar databases were used for SNP data annotation, while UniProt and PDB provided protein sequences. We performed functional and structural predictions of SNPs using PolyPhen-2 and SNAP2. We modeled mutant proteins using AlphaFold 2 and visualized them in PyMOL to compare native and mutant forms. Results: Our results identified SNP rs74315431 as pathogenic, inducing structural and functional changes and exhibiting visible alterations in the three-dimensional structure. Although predicted as non-pathogenic, SNPs rs1801131, rs1805087, and rs1051266 caused protein structural alterations, a finding confirmed by three-dimensional visualization. SNP rs1801133 diverged from the others, being predicted as pathogenic but without causing changes in protein structure or function. Conclusions: Our study found a strong correlation between SNAP2-predicted alterations and those predicted by AlphaFold 2, whereas PolyPhen-2 results did not directly correlate with three-dimensional structure changes. Full article

Background: Systemic sclerosis is a systemic autoimmune disease that also impacts women’s health in very different ways. Methods: This review summarises the most important data on sexuality, fertility, pregnancy, and menopause from the last 10 years. Findings: We identified nine articles with data on sexuality and a prevalence of sexual dysfunction varying between 46 and 90%. Fertility was examined in six studies, with evidence for a negative influence at least on ovarian reserve. With regard to menopause, only three studies are mentioned that show an increased risk for premature menopause in SSc women. Although pregnancies are rare in SSc women after disease onset, there is growing evidence that pregnancies are feasible but go along with a higher maternal and foetal risk compared to healthy controls. Interpretation: SSc is dominated by female gender, but aspects of women’s health influenced by the disease are still often ignored. The treating physician should be aware of the mostly negative impact on sexuality, fertility, and pregnancy and address these topics with the patients to adapt treatment and follow-up examinations to the patients’ complaints and life situation. Full article

Objectives: Systemic sclerosis-related interstitial lung disease (SSc-ILD) has high associated morbidity and mortality. With early diagnosis and treatment, we can improve clinical outcomes with immunosuppression. Some patients develop progressive pulmonary fibrosis (PPF) and are eligible for anti-fibrotic therapy. There are limited data on the incidence and prevalence of PPF in the SSc ILD cohort to guide case finding. We investigated this using data from UK tertiary Rheumatology and ILD centres. Methods: Patients with systemic sclerosis across two UK rheumatology units were identified using electronic records searched from 2021 to 2023 and were compared against established PPF diagnostic criteria. Results: 255 patients were identified. Prevalence of PPF was 5.49% and in those with established SSc-ILD, 23%. Median time to development of PPF was 5 years. In 64% of patients with PPF diagnosis, they had had systemic sclerosis for over 10 years. Incidence of PPF in patients with SSc was 3.9% and in those with known SSc-ILD 16.%. Only 50% of patients who met criteria for PPF had been referred to respiratory for consideration of antifibrotic initiation. Patients with a predominantly fibrotic baseline radiological pattern (UIP) had a trend towards development of PPF (p = 0.07). No patient with a predominantly inflammatory baseline pattern developed PPF (p = 0.021). Conclusions: Real world data have shown a prevalence of PPF in the SSc-ILD cohort of 23% with a median time of 5 years to development from diagnosis of SSc. Our data show active case finding may be incomplete and rheumatologists must be cognisant of PPF when evaluating patients with SSc. Full article

Focal and segmental glomerulosclerosis (FSGS) describes a histological pattern of injury seen by light microscopy in kidney biopsy specimens and is the end result of various injuries to the podocyte. Our understanding of this disease entity has evolved greatly since it was first described, with particular focus on changes in the classification of FSGS as a disease entity and expansion in our understanding of the underlying pathophysiology. The incidence and prevalence of FSGS and FSGS-associated end-stage kidney disease (ESKD) have increased globally, particularly in the United States; it is now the most common primary glomerular disorder in those with ESKD. APOL-1 is likely responsible for this epidemiological trend in kidney disease in the US and is an important focus of clinical trials and potential targeted therapies. Currently, the goal of treatment in FSGS is to achieve remission of proteinuria and to prevent progression to ESKD. Remission is achieved by using immunosuppressive therapies in primary FSGS, but treatment in secondary and genetic FSGS is largely supportive. Recurrent FSGS (rFSGS) post-transplantation remains a significant clinical challenge to nephrologists; current monitoring and treatment strategies are based on retrospective meta-analysis and observational studies with no clear consensus as to the optimum approach. Emerging therapies are focused on developing more targeted interventions in genetic and secondary FSGS. This review article aims to comprehensively explore this multifaceted disease entity. Full article

Introduction: Timed Twenty-Five Foot Walk (T25FW) and Patient-Determined Disease Steps (PDDSs) are measures commonly used for people with MS (PwMS). However, there is limited knowledge about the utility of using the measures to customize interventions. Aim: This exploratory study aimed to assess the correlation between T25FW and PDDS among PwMS enrolled in the Tele-Exercise and Multiple Sclerosis (TEAMS) study. Methods: The correlation was examined through a Spearman’s rho statistic for T25FW time and PDDS scores. Associations between TEAMS Intervention levels (T25FW baseline benchmarks: <6 s, 6–7.99 s, >8 s, unable to complete) and the PDDS-modified ranges (0–2, 3–4, 5–6, 7) were examined utilizing a chi-square test with Monte Carlo simulations. Results: The results showed a strong statistically significant positive correlation between the T25FW time and the PDDS scores (r_s = 0.72, p < 0.001). An additional Spearman’s correlation showed strong significant positive correlation between T25FW baseline benchmarks and PDDS-modified ranges used for intervention assignment (r_s = 0.73, p < 0.001). A chi-square with Monte Carlo simulations showed a significant association between the TEAMS Intervention Level and PDDS-modified ranges (p = 0.005). Conclusion: In conclusions, the findings suggest that T25FW, when considered with PDDSs, might offer some utility in supporting clinicians as they develop intervention strategies that consider both subjective and objective aspects. These findings also highlight the potential for integrated use of both tools in clinical decision-making, program design, and tailoring interventions to meet individual functional capabilities and self-reported disability in PwMS. Full article

Background: Falls are common among individuals with multiple sclerosis (MS), yet standard clinical mobility assessments—such as the Timed Up and Go (TUG)—may not fully capture the complexities of real-world ambulation, leading to suboptimal fall identification. There is a critical need to evaluate the ecological validity of these assessments and identify alternative tests that better reflect real-world mobility and more accurately detect falls. This study examined the ecological validity of the TUG and novel dual-task clinical assessments by comparing laboratory-based gait metrics to community ambulation in individuals with MS and evaluated their ability to identify fallers. Methods: Twenty-seven individuals with MS (age 59.11 ± 10.57) completed the TUG test and three novel dual-task mobility assessments (TUG-extended, 25-foot walk and turn, and Figure 8 walk), each performed concurrently with a phonemic verbal fluency task. After lab assessments, the participants wore accelerometers for three consecutive days. Gait speed and stride regularity data was collected during both the in-lab clinical assessments and identified walking bouts in the community. The participants were stratified as fallers or non-fallers based on self-reported fall history over the previous six months. Findings: Significant differences were observed between the TUG and real-world ambulation for both gait speed (p < 0.01) and stride regularity (p = 0.04). No significant differences were found in gait metrics between real-world ambulation and both the 25-foot walk and turn and TUG-extended. Intraclass correlation coefficient analysis demonstrated good agreement between the 25-foot walk and turn and real-world ambulation for both gait speed (ICC = 0.75) and stride regularity (ICC = 0.81). When comparing the TUG to real-world ambulation, moderate agreement was observed for gait speed (ICC = 0.56) and poor agreement for stride regularity (ICC = 0.41). The 25-foot walk and turn exhibited superior predictive ability of fall status (AUC = 0.76) compared to the TUG (AUC = 0.67). Conclusions: The 25-foot walk and turn demonstrated strong ecological validity. It also exhibited superior predictive ability of fall status compared to the TUG. These findings support the 25-foot walk and turn as a promising tool for assessing mobility and fall risk in MS, warranting further study. Full article

Introduction: Walking is perceived as the most important bodily function for persons with multiple sclerosis (pwMS) and is impaired in more than 70% of pwMS. In addition, the effect of multiple sclerosis (MS) on gait pattern increases in fast walking and during fatiguing exercises, altering the spatiotemporal gait parameters and walking reserve. Objectives: The objective of this study is to investigate the impact of a 12 min intermittent-walking protocol on spatiotemporal gait parameters and on the fatigability of pwMS, as well as the association with perceived exertion and reported symptoms of fatigue. Methods: Twenty-six persons with relapse-remitting MS and twenty-eight healthy controls (HCs) were included in this cross-sectional study. The Modified Fatigue Impact Scale and the Symbol Digit Modality Test were used to evaluate fatigue symptoms and cognitive function, respectively. Participants walked six times during an uninterrupted 2-min period. Before, during the rest periods and after the last 2 min walk, the rate of perceived exertion (RPE) was measured using the Borg Scale, and the spatiotemporal gait parameters were assessed with GaitRite. The cut-off value of 10% deceleration of the distance walked index classified pwMS into two groups: MS Fatigable (MS-F) and MS Non-Fatigable (MS-NF). One-way and two-way Analyses of variance (ANOVAs) were used to verify the effect of time and groups, respectively. Results: PwMS walked slower, travelled shorter distances, and presented shorter step lengths compared to HCs. No effects of the intermittent-walking protocol were found for all pwMS, but the MS-F group had deteriorated walking speed, step length, and cadence. Walking dysfunction was associated with perceived fatigability, reported symptoms of fatigue, cognitive function, and disability. Reported symptoms of fatigue was associated with perceived exertion but not with performance fatigability. Conclusions: Changes in gait parameters were weak to moderately associated with performance fatigability and the perception of effort and disability but not with reported fatigue symptoms, highlighting distinct constructs. The walking speed reserve and step length reserve also emerged as potential early markers of performance decline. Full article