Sclerosis, Volume 2, Issue 4 (December 2024) – 9 articles

Background/Objectives: People with multiple sclerosis (MS) often experience sensory, psychomotor, and cognitive impairment, sphincter disturbances, and fatigue, which can affect their ability to perform work-related tasks, self-care, and daily activities. This study aimed to analyze the lifestyle changes, cognitive function, and disability outcomes over a seven-year follow-up period, exploring potential associations with predictive markers. Methods: At the end of the seven-year follow-up period, 32 participants returned for cognitive and clinical reassessment with the Twenty-Five-Foot Walk Test, Nine-Hole Peg Test, and Brief Repeatable Neuropsychological Battery. Lifestyle data were acquired via interviews regarding sleep quality, reading habits, technology use, physical activity levels, household responsibilities, and participation in leisure and cultural activities. Results: The occupational profile did not demonstrate significant changes, but 11 (34%) participants showed disability accumulation, and the number of relapses increased (p = 0.001). Over time, improvement was observed in verbal episodic memory and worsening in psychomotor speed. Better cognitive performance in mental agility was associated with higher levels of physical activity (p = 0.021) and technology use (p = 0.039). In addition, better cognition (verbal memory p = 0.038 and processing speed 0.015) and psychomotor speed (upper limbs p = 0.017 and lower limbs p = 0.003) and lower functional disability (p = 0.022) were associated with maintenance of household activities. Conclusions: The changes in verbal memory and psychomotor speed were more prominent over time, and verbal memory, psychomotor and processing speed, and mental agility were associated with good lifestyle habits, mainly household activities. The treatment strategies should include lifestyle changes and pharmacological interventions. Full article

Collagen export from the endoplasmic reticulum is required for normal tissue homeostasis, and yet, in fibrotic disorders, this process is significantly upregulated. In this review, we will focus on the signaling cascade from the inflammasome and how that promotes collagen via proinflammatory/profibrotic cytokines. Concordantly, these cytokines also induce the expression of TANGO1 to cope with the increased movement of collagen through the endoplasmic reticulum. In normal and fibrotic cells, this pathway is finely tuned to meet the necessary demand in collagen export. Currently, the role of TANGO1 in fibrotic disorders and how the inflammasome induces its expression is not well understood. In this review, we will assimilate the current information concerning inflammasome activation and how it induces TANGO1 expression, leading to fibrosis. Full article

Background/Objectives. Social cognition (SC), which implies the emotional and intellectual understanding of oneself and others, is an important facet of neuropsychological functioning concurrently to academic cognition (AC), which concerns non-social abilities (memory, language…). In relapsing-remitting multiple sclerosis (RRMS), it is not clear whether a cognitive decline occurs in both SC and AC nor whether a link exists between these two cognitive domains. The objective of the present longitudinal study was to conduct an extensive examination of both AC and SC in RRMS to document a 2-year evolution and to look for potential correlations between AC and SC. Methods. The neuropsychological results (AC and SC) of 48 RRMS patients obtained in clinical practice were retrospectively considered; 38 of the patients (30 females) were assessed again about 2 years later. Non-parametric tests were applied to test the intra-group cognitive evolution (Wilcoxon) and the link between AC and SC evolution (Spearman). Results. Whereas AC showed a stability or an improvement of performances during the retest, SC presented the reverse pattern, with a stability or a significant decline in facial emotion (recognition and discrimination) and humor perception. No significant statistical correlation was found between the significant modification of AC and SC during follow-up. Conclusions. The short-term deleterious evolution observed selectively for SC in the present study suggests that SC should be selected as a cognitive marker for RRMS follow-up, and that extensive examination may be preferred to investigate specific SC changes. Full article

The origins of multiple sclerosis (MS) have been a subject intriguing researchers and scholars for generations. The multifactorial etiological nature of the disease continues to be studied as a complex combination of genetic aspects and environmental or external risk elements contributing to the development of the disease. Descriptions of symptoms or clinical disorders suggestive of MS affecting historical figures or prominent individuals (i.e., Lidwina of Schiedam, Heinrich Heine, Augustus d’Este) did not provide clues on the origin of the disease, except for the observation that all these early possible cases were white European individuals. MS was initially framed as a neurological entity and named in the 19th century by the historical participation of the French masters Cruveilhier, Vulpian, and Charcot, among others, but the question of how the disease originated was not addressed until Charles Poser raised his conjecture on the origins of MS in two historical essays (1994 and 1995), raising the question if the Viking voyages and invasions from the 8th to the 11th century carried the Scandinavian MS genetic risk factor to Europe and the rest of the known world at that time. Poser did not have the benefit of access to ancient molecular DNA data and based his theoretical postulation on interesting historical and archeological observations. A series of studies and opinions published in 2024, utilizing sophisticated genetic analyses and genome identification, archeological DNA analysis, and other advanced techniques and biological computation, distinctly demonstrate the installation of HLA-DRB1*15:01 (class II allele) in Europe (with a higher prevalence in Scandinavia) following the massive Yamnaya pastoralists migration from the Pontic Steppe in Eurasia to western Europe (~5000 to 2500 BCE). The data suggest HLA-DRB1*15:01, the strongest genetic association with MS, underwent an evolutive switch (“thrifty drift”) from immune protector against novel zoonotic diseases appearing among the early pastoralists of the Yamnaya civilization to an autoimmune deleterious reactor to molecular mimicry and self-antigens, enabled by lifestyle changes and reduction of pastoralism once communities settled in Europe after the migration from the Pontic Steppe. This writer offers a new perspective on the origins of MS through a phase 1, the ancient east to west migration in the late Bronze Age, consolidating the HLA-DRB1*15:01 haplotype in Europe, and phase 2, the additional dissemination of the genetic MS risk through the Viking invasions, reinforcing inheritability by enabling a homozygous dominant inheritance. Full article

Introduction: Lifetime stressors (e.g., poverty, violence, discrimination) have been linked to features of multiple sclerosis (MS); yet mechanistic pathways and relationships with cumulative disease severity remain nebulous. Further, protective factors like resilience, that may attenuate the effects of stressors on outcomes, are seldom evaluated. Aim: To deconstruct pathways between lifetime stressors and cumulative severity on MS outcomes, accounting for resilience. Methods: Adults with MS (N = 924) participated in an online survey through the National MS Society listserv. Structural equation modeling was used to examine the direct and indirect effects of lifetime stressors (count/severity) on MS severity (self-reported disability, relapse burden, fatigue, pain intensity, and interference) via resilience, mental health (anxiety and depression), sleep disturbance, and smoking. Results: The final analytic model had an excellent fit (GFI = 0.998). Lifetime stressors had a direct relationship with MS severity (β = 0.27, p < 0.001). Resilience, mental health, sleep disturbance, and smoking significantly mediated the relationship between lifetime stressors and MS severity. The total effect of the mediation was significant (β = 0.45). Conclusions: This work provides foundational evidence to inform the conceptualization of pathways by which stress could influence MS disease burden. Resilience may attenuate the effects of stressors, while poor mental health, smoking, and sleep disturbances may exacerbate their impact. Parallel with usual care, these mediators could be targets for early multimodal therapies to improve the disease course. Full article

Background: Systemic sclerosis (SSc) represents a multidimensional disease affecting various organs and systems, with the common denominator being the vascular pathology encountered in the micro- and macrocirculation of SSc patients. Recently, much progress has been made toward understanding the molecular basis of endothelial injury and subsequent fibroblast activation, thus paving the way for specific therapy that can target and counteract these processes. Aim: In this review, we examined the latest preclinical and clinical data on therapeutic options to address vascular abnormalities in SSc. Results: We discuss the efficacy of current treatments, including pharmacological agents and emerging therapies, in mitigating vascular damage and improving patient outcomes based on preclinical models and clinical trials that offer evidence of their safety and effectiveness. Conclusions: Although promising therapeutic strategies emerge, optimizing the management of vascular abnormalities in SSc requires further research. Full article

Introduction: Although panniculitis-like T cell lymphoma (SPTCL) and hemophagocytic syndrome (HSP) have been described as complications following immunosuppressive treatments, there are no reported cases of concomitant SPTCL/HSP and multiple sclerosis (MS). Materials and Methods: We describe the case of a patient affected by an aggressive phenotype of relapsing remitting MS, characterized by consecutive severe relapses with no complete remission. He developed panniculitis-like T cell lymphoma (SPTCL) and hemophagocytic syndrome (HSP) after receiving multiple immunosuppressive treatments in sequence. Despite the aggressive nature of these complications, the patient responded well to a combination of Gemcitabine and Cisplatin. Discussion and Conclusions: With this case, we suggest that physicians always consider blood diseases as possible MS therapy complications, especially in the sequencing setting, and also consider uncommon treatments in those with autoimmune predispositions. Full article

Introduction: Calcinosis cutis (CC), the pathological deposition of calcium salts in the skin, is a frequent and challenging complication of systemic sclerosis (SSc). Despite its high prevalence, the underlying pathophysiology remains poorly understood, complicating treatment strategies. Material and Methods: This narrative review synthesizes the literature on CC in the context of SSc. The current understanding and treatment of CC in SSc is reviewed, focusing on the role of hypoxia in its pathogenesis and the therapeutic potential of sodium thiosulfate (STS). Results and Discussion: Research indicates a potential link between hypoxia and the development of CC in SSc, shedding light on novel pathogenic mechanisms. Additionally, promising results from treatments such as STS spurs interest in conducting larger, randomized controlled trials to validate these findings. Full article

Background: Interstitial lung disease (ILD) has replaced scleroderma renal crisis as the leading cause of mortality in systemic sclerosis (SSc), with a 10-year mortality of 40%. There have been well-powered randomised control trials (RCTs) demonstrating the effect of cyclophosphamide (CYC), mycophenolic acid (MMF), nintedanib and tocilizumab (TCZ) in SSc-ILD but a paucity of sufficiently powered studies investigating other agents in the disease. Methods: This is a narrative review which examines the existing evidence for immunosuppressive treatments, transplant and adjunctive therapies in SSc-ILD by reviewing the key landmark trials in the last two decades. Results: MMF for 2 years is as effective as oral CYC for 1 year. Rituximab (RTX) is non-inferior to CYC. TCZ appears to have a beneficial effective regardless of the extent of lung involvement. Conclusions: There is now a strong evidence base supporting the use of MMF as the first line option in SSc-ILD. RTX, CYC and TCZ are viable therapeutic options if there is ILD progression on MMF. Anti-fibrotic and pulmonary arterial (PAH) treatments likely add long-term synergistic benefits. There remains a role for lung transplantation in select patients. Full article