Tag: ms

• Association between conventional MRI activity and disability in MS

  57) “A Longitudinal Study of Abnormalities on MRI and Disability From Multiple Sclerosis” by Peter A Brex, MD et al

  -”Clinically definite multiple sclerosis developed in 48 of 71 patients (68 percent) and probably multiple sclerosis in a further 5 (7 percent)”

  -”Clinically definite multiple sclerosis developed in…9 of the 14 patients with brain stem syndromes (64%)…”

  -”Clinically definite multiple sclerosis developed in 44 of 50 patients with abnormal MRI scans at base line (88 percent)”

  -”Overall, 49 of 50 patients (98 percent) had clinical or radiological evidence of multiphasic disease consistent with multiple sclerosis”

  -”The change in lesion volume on MRI correlated moderately with the change in the EDSS score over the first 5 years (r=0.58) and was weaker though still significant over the 5-to-10-year and 10-to-14-year periods (Table 5)”

  -”…after 15 years, 50 percent will require aid to walk (equivalent to an EDSS score of 6)

  -”…suggesting that the development of lesions in the early years has an important influence on long-term disability”

  -”The present MRI study and previous clinical studies suggest that both MRI and clinical measures of disease activity in the first two to five years after the development of an isolated syndrome are important in the long-term prognosis for disability in patients with multiple sclerosis”

  -”The extent of inflammation and demyelination early in the disease course may influence the extent of later axonal loss in several ways.  First, acute inflammation is associated with axonal damage, including transection, widespread axonal loss will diminish the amount of axonal reserved, and a threshold may be reached at an early point when continuing axonal loss-by whatever mechanism-begins to manifest as disability.  Second, widespread inflammation could expose a range of potential autoantigens to immune surveillance, resulting in complex immunopathogenic events due to epitope spreading; such a process may be less regulated and may be likely to cause axonal damage.  Third, widespread early demyelination itself may create an environment that is not conducive to long-term axonal survival”

  112)  “Correlation Analysis of MRI Lesion Load and Clinical Measures in Multiple Sclerosis Cohort Using Structured Clinical Documentation Support Toolkit (1880)”: Afif Hentati, Tiffani Stroup Franada, John Pula, Darryck Maurer, Bryce Hadsell, Alexander Epshteyn, Samuel Tideman, Anna Pham, Roberta Frigerio, Demetrius Maraganore, and Susan Rubin

  -”A weak or absent correlation between MRI lesion load and clinical disability including physical, cognitive and psychological in MS has been the prevailing view. “

  113)  “The Relevance of Neuroimaging Findings to Physical Disability in Multiple Sclerosis”: Rahşan Göçmen

  -”Although T2 hyperintense lesions accrual is the radiological hallmarks of disease activity in MS, a weak correlation was found between T2 lesions disability (32, 33). This weak correlation suggests that silent T2 lesions occur commonly in MS and this describes the clinico-radiological paradox (34). The possible explanations for this may be as follows: Firstly, the MRI lesions in MS occurs commonly “non-eloquent” areas of the brain. Secondly, histopathological correlates of the lesions are not so severe as to cause symptoms, for instance, mild inflammation. Thirdly, histopathologic changes in the normal-appearing white matter (NAWM) on conventional MRI contribute to clinical symptoms. And finally, all compartments of CNS such as spinal cord are not imaged. Many studies have shown that locations of T2 lesions have a more decisive influence on disability than overall lesion load in relapsing-remitting MS (RRMS) (18, 35). Although the correlation between T2 lesion load and disability is weak in the more advanced stage of the disease, T2 lesion load has a prognostic value in the onset of MS (Figure 1). Higher T2 lesion load has been associated with an increased risk of subsequent conversion to definite MS and long-term disability in patients with CIS (18, 35). However, this paradox relatively disappears regarding the topographic distribution of T2 lesions. For instance, infratentorial spinal cord lesions have more determinative value predicting the disability.”

  114) “‘Usual Suspect’ lesions appear not to cause most severe disability in MS patients” by Buffalo Neuroimaging Analysis Center: Friday, February 24th, 2023

  -“The absence of material differences in white matter brain lesion burden means this is not a significant driver of severe disability progression, despite the fact that many MS disease-modifying treatments are focused on slowing accumulation of white matter lesions,” said Robert Zivadinov, MD, PhD, principal investigator and director of UB’s Buffalo Neuroimaging Analysis Center and the Center for Imaging in UB’s Clinical and Translational Science Institute.

  -It is widely accepted that MS is characterized by the formation of brain white matter lesions. Yet in this study participants with severe MS disability showed significantly more gray matter loss in the cortex and thalamus compared to their less-disabled “twin.” Surprisingly, the loss of whole brain volume was comparable among both groups.

  -Severely affected people exhibited lower efficiency in thalamic structural connectivity, meaning they demonstrated lower structural connectivity of the associated brain networks than their less disabled counterparts.

  -Called Comprehensive Assessment of Severely Affected – Multiple Sclerosis, or CASA-MS, the investigator-initiated, privately funded UB study is focused on identifying biomarkers and cognitive differences among people whose MS disability has become severe compared to others whose disease progresses slowly

  119)  “Relapse-Associated and Relapse-Independent Contribution to Overall Expanded Disability Status Scale Progression in Multiple Sclerosis Patients Diagnosed in Different Eras” by Noemi Montobbio, PhdD et al

  -”The average contribution of PIRA to overall EDSS progression, already predominant in patients diagnosed in 1980-1996 (78%)…and in 1997-2008 (76%)…was significantly increased….in patients diagnosed in later years (87%…)”

  -”However, although clinical relapses are almost completely eliminated by modern high-efficacy DMTs, the underlying disability progression independent of relapse activity is far from being halted or reversed.  Our results showed a progressive shift toward a mostly relapse-independent progression”

  120)  “MRI measures and their relations with clinical disability in relapsing-remitting and secondary progressive multiple sclerosis” by E Giugni et al

  -”A weak relationship between disability and total lesion volume on both T1 and T2 weighted images was found in relapsing-remitting Multiple Sclerosis.”

  -”In secondary progressive Multiple Sclerosis, infratentorial lesion volume on T2 weighted images represents the only marker of disability”

  January 21, 2025

  health, mental-health, mri, ms, multiple-sclerosis

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• RAW vs PIRA in MS: RAW is not significant

  1.   “Disease Progression in Multiple Sclerosis”: Genentech (2024)

  -relapses were not associated with long-term disability worsening or confirmed disability worsening

  -data were consistent with 2 simultaneous processes: focal demyelinating lesions and a more diffuse process that contributes to brain and spinal cord atrophy: this is largely independent of relapses or focal lesion formation and may be the most important contributor to long-term MS disability 

  -PIRA was seen early in the MS disease course in a cohort study; 66% had at least 1 PIRA event; 31% developed PIRA within the first 5 years of the disease; 34% had all of their CDA episodes qualify for RAW; 26x greater risk of developing severe disability 

  2. “Contribution of relapse-associated worsening in overall disability accrual in patients with relapsing-onset multiple sclerosis: A mediation analysis” by Bo Chen et al

  -”In relapsing-onset MS, PIRA is the major contributor to the irreversible disability accrual throughout the whole disease course…”

  3. “Real-world evidence of ocrelizumab-treated relapsing multiple sclerosis cohort shows changes in progression independent of relapse activity mirroring phase 3 trials” by J Ingwersen et al

  -”Using data from the pivotal phase 3 randomized controlled trials (RCTs) OPERA I and OPERA II, Kappos et al. investigated RAW and PIRA contributions to the disability accumulation of ocrelizumab-treated vs. interferon-treated patients.  They found that (A) PIRA was responsible for most of the disability accumulation rather than RAW irrespective of the treatment arm (later confirmed by the findings of Lublin et al.) and (B) ocrelizumab was superior in preventing PIRA compared to interferon. However, it was less effective in preventing PIRA than RAW.”

  -”In both, the interferon and ocrelizumab groups, PIRA (rather than RAW) was responsible for 80–90% of the clinical worsening…”

  4.  “Relapse-Associated and Relapse-Independent Contribution to Overall Expanded Disability Status Scale Progression in Multiple Sclerosis Patients Diagnosed in Different Eras” by Noemi Montobbio, PhdD et al

  -”The average contribution of PIRA to overall EDSS progression, already predominant in patients diagnosed in 1980-1996 (78%)…and in 1997-2008 (76%)…was significantly increased….in patients diagnosed in later years (87%…)”

  -”However, although clinical relapses are almost completely eliminated by modern high-efficacy DMTs, the underlying disability progression independent of relapse activity is far from being halted or reversed.  Our results showed a progressive shift toward a mostly relapse-independent progression”

  January 21, 2025

  health, mental-health, ms, multiple-sclerosis, wellness

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• RAW (relapse-associated worsening) vs PIRA (progression independent of relapse activity in Multiple Sclerosis

  115)  “Harmonizing Definitions for Progression Independent of Relapse Activity in Multiple Sclerosis: A Systematic Review” by Jannis Muller, MD et al

  -”In this systematic review of 48 studies, PIRA was found to be the most common form of disability accumulation across all traditional MS phenotypes, including clinically isolated syndrome and early relapsing-remitting MS.”

  116)  “Does initial high efficacy therapy in multiple sclerosis surpass escalation treatment strategy?  A comparison of patients with relapsing-remitting multiple sclerosis in the Czech and Swedish national multiple sclerosis registries” by Tereza Hrnciarova

  -”In contrast to the previous comparison between the Swedish and Danish cohorts (Spelman et al, 2021), the primary outcome (CDW) did not show a significant difference in favor of the Swedish cohort (…p-value 0.2764)

  -”it is reasonable to ask why such a significant reduction in the risk of relapse did not translate into a change in the long-term outcome of CDW”

  117)  “Contribution of relapse-associated worsening in overall disability accrual in patients with relapsing-onset multiple sclerosis: A mediation analysis” by Bo Chen et al

  -”In relapsing-onset MS, PIRA is the major contributor to the irreversible disability accrual throughout the whole disease course…”

  -”Nonetheless,

  with more and more disease-modifying treatments (DMTs) available to

  reduce the attack frequency, substantial evidence has shown that

  disability progression in most treated patients can still develop slowly

  over time, independent of relapses and whatever medications applied, in

  whether relapsing-remitting or progressive cases (Cree et al., 2016;

  Reich et al., 2018; Signori et al., 2016).”

  -”Even in the population with

  relapsing MS who initially received ocrelizumab, a B cell-depleting

  agent, the cumulative proportion with disability progression climbed

  at a slow rate in the case of nearly complete and sustained suppression of

  new brain MRI lesion activity (Hauser et al., 2017; Hauser et al., 2020),

  with the similar findings observed in patients treated with other

  high-efficacy DMTs (Coles et al., 2012; Kapoor et al., 2018), implying

  that the neurological deterioration seems unavoidable in this life-long

  Disease.”

  -”On the other hand, compared to that in the early phase, the disability accrual in the later one is not significantly slowed by the reduced relapse frequency, suggesting that the effect of RAW on the disabled outcome may vary in different stages of the disease.“

  -”Annualized relapse rate (ARR), a marker for disease activity, cannot

  reflect the neurological deterioration in patients with MS…”

  -”The key findings were that clinical attack number partly mediated less than half (0.414) of the positive relationship between disease duration and disability worsening in the early phase (i.e., RAW accounted for 41.4% of the disability accrual while PIRA for 58.6%), whereas it was not associated with the disabled outcome in the later phase (i.e., PIRA contributed to the majority of the progression).”

  -”…supporting an immune-mediated or triggered neurodegenerative nature of MS and underlining the importance of the treatment on PIRA even in the initial phase.”

  -”A significant and partial mediator effect of clinical attack number on

  the relationship between disease duration and neurological disability

  accrual was observed in the early phase but not in the later phase herein

  (Table 3), suggesting that the role of RAW on disability accumulation

  differs in different stages of the disease, in line with previous studies

  (Leray et al., 2010; Scalfari et al., 2010; Weinshenker et al., 1989).”

  -”In previous research, when comparing untreated “natural history” and DMT-treated cohorts of patients, Tilling K et al. found that although disability progression was slowed by treatment, the treated patients still worsened considerably over time (Tilling et al., 2016).”

  -”These findings imply that RAW only partly rather than entirely contributes to the irreversible disability accumulation in relapsing MS, and disability would inevitably accrue in the long term, even the relapses are controlled, in keeping with our results that attack number partly mediates the relationship between duration and EDSS scores in the early phase.”

  -”once the patients enter the later phase, the contribution of relapse or RAW to the disabled outcome becomes negligible (indirect/total effect < 10%)…”

  -”In contrast, the disability of the individuals with NMOSD is mainly contributed by one or more severe episodes of attacks and less accumulates over time (Wingerchuk et al., 2007), which

  is one of the pivotal differences between the two diseases. This difference, on the other hand, implies that demyelination alone seems insufficient to explain the entire disability in MS.”

  -”the percent of the direct effect of disease duration on EDSS scores (PIRA) soars from 58.6% in the early phase to 90.8% in the later one (Table 3).”

  -”As demonstrated in Table 3, the significant direct effect of duration on EDSS scores in both early and later phases implies that PIRA may begin as early as the commencement

  of the disease and account for the leading cause of the irreversible disabled outcome. From this point of view, the benefit from most current DMTs may be attained with ease in the first few years and become limited in preventing the disability exacerbation in the long term, consistent with previous studies (Kingwell et al., 2019; Manouchehrinia et al., 2017; Tilling et al., 2016).”

  -”Prior studies have shown that in the early stage, patients with late-onset age are vulnerable to disability accumulation after several relapses, while the young-onset can rehabilitate with little neurological deficit (Cierny et al., 2017; D’Amico et al., 2018; Guillemin et al., 2017).  Nevertheless, we found that the disability accrual accelerated with the increase of onset age only in the early phase (significant total effect of onset age on EDSS scores with adjusting for the duration, Table 3), fully independent of clinical attack number (the direct effect was significant while the indirect effect was not), while the statistical association between onset age and disability progression was absent after that, which is also observed previously (Leray et al., 2010; Scalfari et al., 2011). The exact potential mechanisms remain elusive but may involve the

  age-related decrease in the repair capacity of the CNS (Stankoff et al., 2007) and age-related altered immune response (Ditamo et al., 2005; Weiner, 2009). Of note, although significant, the standardized total effect of onset age on EDSS scores in the early phase was merely 0.205, much smaller than that of duration (0.542) (Table 3), even the effect of attack number/RAW (0.224) or PIRA (0.318), implying that in terms of disability accrual, the cont

  118)  “Real-world evidence of ocrelizumab-treated relapsing multiple sclerosis cohort shows changes in progression independent of relapse activity mirroring phase 3 trials” by J Ingwersen et al

  -”Mean follow-up time was 29 months (range 6 to 51 months). 23.5% developed CDA under ocrelizumab therapy (n = 23). Of those, the majority developed PIRA (87.0% of CDA, n = 20) rather than RAW (13.0% of CDA, n = 3). An exploratory investigation using Cox proportional hazards ratios revealed two possible factors associated with an increased probability of developing PIRA: a shorter disease duration prior to ocrelizumab (p = 0.02) and a lower number of previous DMTs prior to ocrelizumab (p = 0.04). Our data show that in ocrelizumab-treated RRMS patients, the main driver of disability accumulation is PIRA rather than RAW.”

  -”Using data from the pivotal phase 3 randomized controlled trials (RCTs) OPERA I and OPERA II, Kappos et al. investigated RAW and PIRA contributions to the disability accumulation of ocrelizumab-treated vs. interferon-treated patients.  They found that (A) PIRA was responsible for most of the disability accumulation rather than RAW irrespective of the treatment arm (later confirmed by the findings of Lublin et al.) and (B) ocrelizumab was superior in preventing PIRA compared to interferon. However, it was less effective in preventing PIRA than RAW.”

  -”In both the interferon and ocrelizumab groups, PIRA (rather than RAW) was responsible for 80–90% of the clinical worsening…”

  -”our data contributes to the notion that in typical RRMS patients under effective, immune-directed therapy PIRA is the primary driver of disability progression rather than RAW.”

  119)  “Relapse-Associated and Relapse-Independent Contribution to Overall Expanded Disability Status Scale Progression in Multiple Sclerosis Patients Diagnosed in Different Eras” by Noemi Montobbio, PhdD et al

  -”The average contribution of PIRA to overall EDSS progression, already predominant in patients diagnosed in 1980-1996 (78%)…and in 1997-2008 (76%)…was significantly increased….in patients diagnosed in later years (87%…)”

  -”However, although clinical relapses are almost completely eliminated by modern high-efficacy DMTs, the underlying disability progression independent of relapse activity is far from being halted or reversed.  Our results showed a progressive shift toward a mostly relapse-independent progression”

  January 21, 2025

  chronic-illness, health, mental-health, ms, multiple-sclerosis

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• Lack of Efficacy of DMTs: in general and based on age and disease stage Research

  1. “Relapsing-remitting and primary progressive multiple sclerosis treated with ocrelizumab: A comparative study” by Luis A Rodriguez de Antonio et al

  -”Ocrelizumab was very effective in reducing relapses and MRI activity.  The rate of progression was slowed down; however, the effect was more evident for pwRRMS than for pwPPMS over time”

  2. “Meta-analysis of the Age-Dependent Efficacy of Multiple Sclerosis Treatments” by Ann Marie Weideman et al

  -More than 28,000 MS subjects participating in trials of 13 categories of immunomodulatory drugs are included in the meta-analysis 

  -the efficacy of immunomodulatory DMTs on MS disability strongly decreased with advancing age

  -the regression predicts zero efficacy beyond approximately age 53 years

  -high-efficacy drugs outperform low-efficacy drugs in inhibiting MS disability only for patients younger than 40.5 years

  -this meta-analysis supports the notion that progressive MS is simply a later stage of the MS disease process and that age is an essential modifier of a drug efficacy

  -higher efficacy treatments exert their benefit over lower efficacy treatments only during early stages of MS, and after, age 53, the model suggests there there is no predicted benefit to receiving immunomodulatory DMTs for the average MS patient

  3. “Effectiveness of Ocrelizumab in Primary Progressive Multiple Sclerosis: a Multicenter, Retrospective, Real-world Study (OPPORTUNITY) by Clara G Chisari et al

  -Ocrevus does not affect the B cell reconstitution and pre-existing humoral immunity

  -Ocrevus reduced the percentage of patients with 12-week confirmed EDSS disability progression

  -another recent observational comparative study of a small cohort of 13 PPMS and 29 RRMS indicated that the effect of Ocrevus on disability progression was more evident for RRMS

  -our results showed that disease activity, disease duration and EDSS at the time of Ocrevus initiation seem to not impact the disability outcomes (hard to believe; other studies have not found this to be the case; very suspicious) 

  4. “Data-driven risk/benefit estimator for multiple sclerosis therapies” by Bibiana Bielekova et al

  -current DMTs inhibit disability caused by lesion activity only

  -DMTs ineffective against PILA

  -not every CEL causes an MS relapse

  -Ocrevus has no efficacy on PILA after 12 weeks

  -DMT efficacy decreases with increasing age at treatment onset

  5. “Treatment with disease-modifying drugs for people with a first clinical attack suggestive of multiple sclerosis (Review) by Filippini G et al (Cochrane Review): 

  6. “Alemtuzumab versus interferon beta1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial”

  -”Alemtuzumab’s consistent safety profile and benefit in terms of reductions of relapses support its use for patients with previously untreated relapsing-remitting multiple sclerosis; however, benefit in terms of disability endpoints noted in previous trials was not observed here” (Dr. Cohen lead author/investigator)

  7. “Natalizumab strongly suppresses cortical pathology in relapsing-remitting multiple sclerosis”: F Rinaldi

  -Natalizumab significantly reduced accumulation of new cortical lesions (0.2±0.6,range 0-3) compared to immunomodulatory agents (1.3±1.1 togli spazio, range 1-6, p=0.001) and no treatment (2.9±1.5, range 1-8, p<0.001). The percentage of patients with new cortical lesions was also lower in natalizumab-treated patients (20%) compared to IMA-treated and untreated patients (68.0% and 74.2%; p<0.001 for both comparisons). Furthermore, the progression of cortical atrophy was significantly reduced by natalizumab (% change=1.7%) compared to IMA (3.7%, p=0.003) and no therapy (4.6%, p<0.001). Finally, a greater percentage (51.4%) of natalizumab-treated patients remained disease-free (no clinical or MRI evidence of disease activity or progression) compared to IMA-treated (18%, p=0.001) and untreated patients (5.7%, p<0.001).

  -Natalizumab treatment significantly decreases cortical lesion accumulation and cortical atrophy progression in severe relapsing-remitting MS. While supporting the inflammatory origin of cortical lesions, our results highlight the significant impact of natalizumab on cortical pathology.

  8. Regarding fingolimod

  –

  9. Regarding siponimod

  -6% difference in 3 month CDP between siponimod and placebo in SPMS (EXPAND study; *Dr Bar-Or on this study) 

  -”no treatment has consistently shown efficacy in slowing disability progression in patients with SPMS” (EXPAND study)

  10. SUNBMEM trial: Ozanimod: did not prove efficacy in delaying confirmed disability progression

  11. Ponesimod: OPTIMUM trial: did not prove efficacy in reducing confirmed disability progression but reduced brain volume loss

  12. x) “Bioavailable central nervous system disease-modifying therapies for multiple sclerosis” by Hans-Peter Hartung, Amit Bar-Or, et al

  -DMTs have limited efficacy in progressive forms of the disease where cells in the CNS play a crucial role; DMTs for relapsing MS reduce relapse rates by suppressing peripheral immune cells

  -most therapies for RMS have limited efficacy in treating progressive forms of MS and targeting peripheral inflammation is not sufficient to slow disease progression

  -for DMTs to be effective in progressive MS, they must also target chronic CNS inflammation

  -as the disease progresses, compartmentalized inflammatory mechanisms that predominantly involve microglia, B cells and other innate cells of the CNS become more prominent, leading to neurodegeneration, CNS atrophy, and disability worsening

  -CNS inflammation persists from resident innate immune cells contributing to a chronic, localized inflammatory response

  -Fingolimod: when compared with IFN Beta-1a treatment, there were no significant differences in time to disability progression or the proportion of participants with confirmed progression at 12 months

  -Ozanimod: proportions of participants with CDP at 3 and 6 months were not significantly different between treatment groups in the phase 3 clinical trials

  -ponesimod: did not impact time to 12 or 24 week confirmed disability accumulation compared with teriflunomide in participants with RMS

  -an observational, multicenter study provided Class IV evidence for aHSCT as an immunosuppressant MS therapy because treatment induced durable disease remission for over 10 years in most participants with RRMS (including extremely aggressive forms of MS) (Boffa G: “Long-term clinical outcomes of hematopoietic stem cell transplantation in multiple sclerosis”) (Class IV evidence is a classification of evidence that represents the lowest level of quality in a study)

  13.   “Disease Progression in Multiple Sclerosis”: Genentech (2024)

  -relapses were not associated with long-term disability worsening or confirmed disability worsening

  -data were consistent with 2 simultaneous processes: focal demyelinating lesions and a more diffuse process that contributes to brain and spinal cord atrophy: this is largely independent of relapses or focal lesion formation and may be the most important contributor to long-term MS disability 

  -PIRA was seen early in the MS disease course in a cohort study; 66% had at least 1 PIRA event; 31% developed PIRA within the first 5 years of the disease; 34% had all of their CDA episodes qualify for RAW; 26x greater risk of developing severe disability (EDSS 6) in patients with PIRA within the first 5 years of MS compared with patients whose first PIRA appeared later in the disease course

  -TREAT-MS study: outcome: intermediate-term risk of disability (*not significant-what needs to be measured is whether these DMTs reduce the actual disability, not the risk of it, and also, this needs to be evaluated over the long-term, not just the intermediate-term, to see whether the DMTs alter the natural history of the disease or not)

  -DELIVER-MS study: outcome: slowing brain volume (*not significant because the tolebrutinib trial showed that it slowed disability progression but not brain volume loss, as I understand it)

  14.  “Evolution of Disease-Modifying Therapy Benefits and Risks: An Argument for De-escalation as a Treatment Paradigm for Patients with Multiple Sclerosis” by Brandi L Vollmer et al

  -among those 45 years and older, there was no different between oral DMTs vs infusible DMTs in terms of odds of greater disease activity 

  -current techniques to evaluate disease activity (including markers of progressive disease) are inadequate and there is likely “silent” worsening separate from overt relapses 

  15.   “DMT Use in Progressive MS”: Cleveland Clinic

  -growing evidence suggests that relapsing and progressive MS are not distinct entities but rather gradual accumulation of disability independent of inflammatory disease activity can conceivably occur at any stage of the disease; both processes can occur simultaneously within a single patient

  -ORATORIO trial: benefit of Ocrevus in patients younger than or equal to 45 years old was not statistically significant 

  -DMT risks include: infection and malignancy 

  16. “Toxicity of Released B Cell Products in Multiple Sclerosis: Effects on Neurons and Oligodendrocytes” by Leah Zuroff, Amit Bar-Or et al

  -”Although over a dozen disease-modifying therapies are approved for the treatment of RRMS, none are meaningfully effective at limiting disease progression”

  17. From: “Defining secondary progressive  multiple sclerosis” by Johannes Lorscheider et al

  -67% of those on DMTs converted to SPMS

  -patients identified as SP spent 58-68% of their previous follow-up time on DMT

  18. “Anti-inflammatory disease-modifying treatment and short-term disability progression in SPMS” by Johannes Lorscheider et al

  -”Our pooled analysis of the currently available DMTs used after conversion to SPMS suggests that, on average, these therapies have no substantial effect on relapse-unrelated disability outcomes measured by the EDSS up to 4 years; class IV evidence that for patients with SPMS, DMT has no beneficial effect on short-term disability progression”

  19. “Disability Outcomes in Patients With Active Secondary Progressive Multiple Sclerosis” by Nathaniel Lizak et al

  -”the rate of disability progression after the onset of SPMS was not associated with the early disease course and treatment decisions”

  20. “Anti-CD20 therapies in multiple sclerosis: From pathology to the clinic”: Jerome de Seze et al

  1. Rituximab in RRMS: RIFUND-MS trial: no significant difference was observed between the groups (rituximab and tecfidera) for the EDSS, even though rituximab outperformed tecfidera in terms of reducing relapses/ARR, no new MRI activity, and reduced numbers of T2 and GD+ lesions
  2. Ocrevus, Phase II trials (OPERA I and OPERA II): results were inconclusive due to a failure of the statistical hierarchical testing procedure; in the OLE, patients switching from IFN-B-1a to Ocrevus (at 2 years) had a similar ARR at 5 years; the proportion of patients withCDP at five years was lower with Ocrevus compared to patients switching from IFN-B-1a to Ocrevus (16.1% to 21.3%, respectively); brain volume loss was unchanged in patients treated with Ocrevus for 5 years
  3. Kesimpta in RMS: ASCLEPIOS I and ASCLEPIOS II: annualized rate of brain volume loss did not differ significantly between patients treated with Kesimpta vs Aubagio, even though Kesimpta outperformed Aubagio in terms of T1 GD+ lesions; in ASCLEPIOS I, patients on Kesimpta had a lower adjusted ARR than those in the Aubagio group (similar results seen in ASCLEPIOS II)
  4. Briumvi in RMS:
  5. ULTIMATE II trial: 43% of Briumvi group showed NEDA vs 11.4% in Aubagio group; however, no significant difference in the worsening of disability at 12 weeks was found between Briumvi and Aubagio patients in the pooled analysis of the 2 trials (5.2% vs 5.9%); brain volume change was not significant between the 2 groups

  21) “Understanding multiple sclerosis as a disease spectrum: above and below the clinical threshold” by Stephen Kireger, Karin Cook and Carrie M Hersh

  -Indeed, if progressive mechanisms start early, and MS is a disease spectrum, then all RRMS trials are SPMS trials if analyzed carefully enough

  22) “Changes in disability in people with multiple sclerosis: a 10-year prospective study” by David Conradsson et al

  -The large proportion of our sample receiving immunomodulatory treatment at baseline needs to be taken into account when interpreting the study results.  The increase in EDSS scores in our study was similar to previous -1year follow-ups, monitoring cohorts, where a low proportion received immunomodulatory treatment.  The similarities in disease progression between our cohort and previous cohort studies might indicate that changes in severity of MS, as measured with EDSS, occur regardless of immunomodulatory treatment.  

  23) “Anti-inflammatory disease-modifying treatment and short-term disability progression in SPMS”: Lorscheider J et al

  -this study provides class IV evidence that for patients with SPMS, disease-modifying treatment has no beneficial effect on short-term disability progression

  -SPECTRUM and IMPACT trials

  -In line with the outcomes of most of the previous trials, our present study shows that, on average, the currently available anti-inflammatory drugs do not prevent relapse-unrelated disability accumulation of disability in patients with established SPMS in the short-term-our recent study showed that highly-effective immunotherapy mitigates predominantly relapse-dependent disability accrual over 11 years in patients with moderately advanced or advanced relapse-onset MS (regardless of their SPMS)

  24) “The Faces of “To Late”-A Surprisingly Progressive Cohort of “Stable” Relapsing Remitting Multiple Sclerosis Patients”: Alin Ciubotaru et al

  -80% of RRMS patients in this study (65% were on high efficacy DMTs) showed some type of PIRA after 12 months

  -an elevated level of PIRA was found in our cohort, with high efficacy drugs providing no supplementary protection

  25) “Disease-modifying therapies for relapsing/active secondary progressive multiple sclerosis-a review of population-specific evidence from randomized clinical trials”: Antonios Bayas et al

  -the potential of these drugs to reduce relapse-independent progression remains unclear

  -The authors suggested that anti-inflammatory DMTs have no substantial effect on relapse-independent disability progression in SPMS without a distinct inflammatory phenotype

  26) “Late-Onset MS: Disease Course and Safety-Efficacy of DMTS: Maria Chaira Buscarinu et al

  -In AFFIRM (NCT00027300) and SENTINEL (NCT00030966) studies, Natalizumab failed to reduce progression in patients with MS older than 40 years; in this case factors such as male sex, EDSS score higher than 3.5 and fewer than 9 baseline T2 lesions turn out to be predictors of non-responsiveness (30). Fingolimod showed similar results in the FREEDOMS trial (NCT00289978), being not able to reduce disability progression and relapses in patients older than 40 years, compared to placebo

  -Among the other first-line DMT, dimethyl fumarate (CONFIRM trial; NCT00451451) (26), peginterferon-β-1a (ADVANCE trial; NCT00906399) (27), and teriflunomide (TEMSO trial; NCT00134563) (28) reduced annual relapses rate (ARR) in both young and old patients (threshold of 38 years for teriflunomide and 40 years for the others); however, all these DMTs failed to reduce the risk of disability accumulation.

  -they found that IFN-β use was not statistically related with a slowing of disability progression

  -ozanimod failed to reduce both relapses and disability progression. (NCT02047734; NCT02294058)

  -Among the more recent DMTs, Ocrelizumab, a B cell-depleting anti-CD20 antibody, failed to reduce ARR in patients older than 40 years (33)

  -The age-related changes that take place in the immune system, a process known as immunosenescence generally result in a higher susceptibility to infections, a reduced response to vaccines and a higher prevalence of autoimmunity and neurodegenerative disorders. These processes may affect the safety of DMT, so that potentially severe adverse events are more common in elderly patients.

  -A pressing problem in clinical practice is the safety of certain DMT in LOMS people: especially the depleting drugs seem to pose older subjects at higher risk of serious infections or cancer.

  x)  “Clinical Outcomes of Escalation vs Early Intensive Disease-Modifying Therapy in Patients With Multiple Sclerosis”: Katharine Harding et al

  -In this cohort study including 592 people, those who received high-efficacy treatment initially had a smaller increase in Expanded Disability Status Scale score at 5 years vs those who first received moderate-efficacy disease-modifying therapy.

  -These findings suggest that real-world escalation approaches may be inadequate to prevent unfavorable long-term outcomes 

  x) “Early use of high-efficacy disease‑modifying therapies makes the difference in people with multiple sclerosis: an expert opinion”: Massimo Filippi et al

  -Growing evidence is suggesting that disability progression in MS patients is only partially secondary to the occurrence of new focal inflammatory demyelinating lesions and clinical relapses (i.e., relapse-associated worsening), whereas progression independent of relapse activity (PIRA) starts from the biological onset of MS and becomes the principal and most relevant driver of disability accumulation in the progressive forms of MS [21,22,23].

  – The neurologists of this Expert Opinion paper agreed that a drug should be defined as HE-DMT if its substantial therapeutic effect can be proven on ≥ 1 outcome of inflammation/demyelination but also on ≥ 1 outcome of disease progression (Table 1).

  x)  “A Personalized Approach in Progressive Multiple Sclerosis: The Current Status of Disease Modifying Therapies (DMTs) and Future Perspectives”:by Emanuele D’Amico

  -However, preliminary results from a phase III trial of Natalizumab in patients with SPMS (ASCEND; NCT01416181) showed no efficacy in terms of delaying disability assessed by EDSS, Timed 25-Foot Walk, and 9-Hole Peg Test [101].

  -Rituximab did not delay the disability progression compared to placebo.

  x) “Evolution of Disease Modifying Therapy Benefits and Risks: An Argument for De-escalation as a Treatment Paradigm for Patients With Multiple Sclerosis”: Brandi L Vollmer et al

  –Results: Younger patients had lower probability of disease activity on infusible vs. oral DMTs. There was no statistical difference after age 54.2 years. When dichotomized, patients <45 years on oral DMTs had greater odds of disease activity compared to patients on infusible DMTs, while among those ≥45 years, there was no difference. Literature review noted that adverse events increase with aging, notably infections in patients with higher disability and longer DMT duration

  –Conclusion: In a real-world cohort of relapsing MS patients, high efficacy DMTs had less benefit with aging but were associated with increased risks.

  1. “Multiple Sclerosis: Current and Emerging Disease-Modifying Therapies and Treatment Strategies”: Dean M. Wingerchuk, MD, MSc, FRCP(C) et al

  – Two of the greatest are lack of therapies that convincingly slow or halt progressive forms of the disease

  -Furthermore, epidemiologic studies124 and therapeutic studies in established SPMS125 suggest that there may be an important dissociation between the inflammatory and neurodegenerative phases of MS. In other words, successful elimination of early inflammation may not necessarily translate into an effect on degenerative progression, the mechanisms of which could be operative even early in relapsing disease.

  x) “The association between disability progression, relapses, and treatment in early relapse onset MS: an observational, multi-centre, longitudinal cohort study”: 

  • Valery Fuh-Ngwa et al
  • -disability worsening outcomes significantly contributed to relapse risk each year (HR = 2.96, C.I 2.91–3.02), and persisted over time (HR = 3.34, C.I 2.90–3.86), regardless of DMT treatments. 

  x) “The Effect of Disease Modifying Therapies on Disability Progression in 

  Multiple Sclerosis: A Systematic Overview of Meta-Analyses”: Suzi B Claflin et al

  -Overall, the meta-analyses included in this overview offer good evidence that, 

  in general, DMT improve short-term (≤2–3 years) disability progression 

  outcomes in adults with relapsing forms of MS compared to placebo. 

  x) “The Effect of Disease Modifying Therapies on Disease Progression in Patients 

  with Relapsing-Remitting Multiple Sclerosis: A Systematic Review and Meta-Analysis”: Georgios Tsivgoulis 

  -In subsequent subgroup analyses, neither dichotomization of DMDs as “first” and “second” line RRMS therapies [(RR = 0.72, 95% CI = 0.65–0.80) vs. (RR = 0.72, 95% = 0.57–0.91); p = 0.96] nor the route of administration (injectable or oral) [RR = 0.75 (95% CI = 0.64–0.87) vs. RR = 0.74 (95% CI = 0.66–0.83); p = 0.92] had a differential effect on the risk of disability progression

  x) “Retinal layer thinning is reflecting disability progression independent of relapse activity in multiple sclerosis”: Gabriel Bsteh et al

  -evidence is growing that even in RMS patients treated with highly efficacious DMT, long-term disability worsening is not uncommon and associated with accelerated brain atrophy but largely independent of relapse activity 

  -a high proportion of disability worsening events occur in the absence of relapses even in RMS patients treated with high efficacious DMT

  -PIRA might represent the stratum of MS-associated neurodegeneration that is largely unaffected by DMTs predominantly targeting CNS-inflammation

  x)  “Active MS is associated with accelerated retinal ganglion cell/inner plexiform layer thinning”: Ratchford JN et al

  -A relevant proportion of patients classified as RRMS experienced PIRA within a 5-year period, accounting for 59-66% of all CDW events. While highly effective DMT reduced the risk of CDW, we could not demonstrate a consistent effect on PIRA in patients with RRMS in our prospectively followed cohort study.

  x) “Macular ganglion cell-inner plexiform layer thinning as a biomarker of disability progression in relapsing multiple sclerosis”: Bsteh G et al

  -Results: Baseline mGCIPL thickness <77 µm was associated with an increased risk (hazard ratio: 2.7, 95% confidence interval (CI): 1.5-4.7, p < 0.001) of disability progression. An aLmGCIPL cut-off ⩾1 µm accurately identified clinically progressing patients (87% sensitivity at 90% specificity) and was a strong predictor of clinical progression (odds ratio: 18.3, 95% CI: 8.8-50.3).

  -Conclusion: We present evidence that cross-sectionally measured mGCIPL thickness and annualized thinning rates of mGCIPL are able to identify clinically progressing RMS with high accuracy.

  x) “Disability progression unrelated to relapses in relapsing-remitting multiple sclerosis: insights from the Swiss multiple sclerosis cohort study”: Lorscheider J et al

  -Methods: Using the Swiss Multiple Sclerosis Cohort Study, we included patients with RRMS and ≥3 prospective visits with available EDSS and Functional System (FS) scores. Confirmed disability worsening (CDW) was defined as EDSS increase of ≥1.5 steps if baseline EDSS step was 0, ≥1.0 step if 1.5-5.5, or ≥0.5 steps if >5.5, confirmed after ≥6 months. A roving baseline approach was applied to maximise sensitivity (Kappos et al., MSJ 2018), whereas re-baselining and a fixed baseline were used for a more conservative estimate. For PIRA, absence of a relapse between baseline, index event and confirmation visit was required. Influence of exposure to disease modifying treatment (DMT) was both modeled as categorical and as time-dependent covariate and analysed with Cox proportional hazards models adjusted for gender, age, disease duration, baseline EDSS and pre-baseline relapse activity. DMT was categorised in highly effective DMT, i.e. monoclonal antibodies, oral DMT and platform injectables.

  Results: We included 917 RRMS patients with a median follow-up of 4.6 years. The roving baseline approach identified 198 (22%) patients experiencing CDW. Of these, 131 fulfilled the definition for PIRA (66% of patients with CDW, 14% of all eligible patients). The number of identified PIRA and CDW decreased when using a fixed baseline (92/157, 59%) or re-baselining (93/157, 59%). Highly effective DMT was associated with a lower risk for CDW (hazard ratio [HR] 0.4, 95% confidence interval [CI] 0.2-0.7, p< 0.001) compared to no treatment. However, we observed only a trend regarding PIRA (HR 0.5, 95% CI 0.3-1.1, p=0.08), which disappeared when modelling treatment as a time-dependent covariate (HR 0.8, 95%CI 0.4-1.4, p= 0.393).

  x) “AAN Summary of Practice Guidelines for Clinicians: Practice Guideline: Disease-Modifying Therapies for Adults with Multiple Sclerosis” (April 24, 2018)

  -Nothing in this document states that DMTs slow or work on disease worsening or progression aside from Ocrelizumab for PPMS (Starting: Recommendation 17, page 3)

  -”Switching: Recommendation 1: “Now that several DMTs…have demonstrated efficacy for the prevention of clinical relapses and new MRI-detected lesions…” (page 4)

  -Switching: Recommendation 2: “None of the available DMTs is completely effective against relapses and MRI activity” (page 4)

  -Starting: Recommendation 3 (page 1): “Clinicians should counsel people with MS that DMTs are prescribed to reduce relapses and new MRI lesion activity”

  -Starting: Recommendation 9: “Multiple studies of DMTs in people with relapsing forms of MS who have had recent relapses or MRI activity or both have shown benefit of DMT in terms of reducing relapses and reducing MRI activity…Clinicians should offer DMTs to people with relapsing forms of MS with recent clinical relapses or MRI activity”

  -Starting: Recommendation 14: “…pivotal trials of alemtuzumab, fingolimod, and natalizumab showed a reduction in relapses and MRI measures in people with MS with highly active disease…Clinicians should prescribe alemtuzumab, fingolimod, or natalizumab for people with MS with highly active MS”

  -Switching: Recommendation 1: “Ongoing disease activity, measured either by clinical relapses or new MRI-detected lesions…Now that several DMTs are available and have demonstrated efficacy for the prevention of clinical relapses and new MRI-detected lesions…”

  -Stopping: Recommendation 2: “…interferon beta reduces the risk of relapse but does not delay disability progression as measured by the EDSS”

  x) “AAN Summary of Practice Guideline for Patients and their Families: Starting Disease-modifying Therapies for Multiple Sclerosis”

  -”DMTs help slow the disease process”

  -”and might help keep your condition stable”

  -”Disease-modifying therapies (DMTs) for MS help slow the disease process…”: “Lesions”; “Relapses”

  -*How come the AAN DMT Guideline document for clinicians doesn’t say anything or make any claims about DMTs slowing disease process?”-SUPER ODD! 

  “The table at the end of this sheet shows the evidence for lowering risk of relapse in relapsing-remitting multiple sclerosis”

  x) “Comprehensive systematic review summary: Disease-modifying therapies for adults with multiple sclerosis”: Alexander Rae-Grant, MD et al

  -”in-study disease progression”

  -”The following DMTs are more effective than placebo in reducing the risk of disability progression…”

  -”The following DMTs are more effective than other DMTs in reducing the risk of disability progression in people with RRMS…alemtuzumab (vs IFN-B) and ocrelizumab (vs IFN-B)

  -The following DMTs are probably more effective than placebo in reducing the risk of in-study disability progression…

  -”Cladribine is probably more effective than placebo in reducing the risk of disability progression…”

  -*everything in here uses “probably,” “possibly,” “reducing the risk,” etc*

  x) “Clinical outcomes of escalation vs early intensive disease-modifying therapy in patients with multiple sclerosis”: Harding K

  -Patients were classified according to first-line treatment strategy: high-efficacy (early intensive treatment [EIT]) or moderate-efficacy DMT (escalation [ESC]).

  – Primary outcome was 5-year change in Expanded Disability Status Scale score. Secondary outcome was time to sustained accumulation of disability (SAD)

  -After adjustment for relevant covariates, there was no difference in hazard of SAD between the groups. 

  -However, 60% of those who escalated to high-efficacy DMTs were observed to develop SAD while still receiving initial moderate-efficacy treatment before escalation.

  x)  “Association of initial disease-modifying therapy with later conversion to secondary progressive multiple sclerosis”: Brown JWL

  -Among patients with relapsing-remitting MS, initial treatment with fingolimod, alemtuzumab, or natalizumab was associated with a lower risk of conversion to secondary progressive MS vs initial treatment with glatiramer acetate or interferon beta.

  x) ”Initial high-efficacy disease-modifying therapy in multiple sclerosis: a nationwide cohort study”: 

  -We found a lower probability of 6-month confirmed EDSS score worsening and lower probability of a first relapse in patients starting a heDMT as first therapy, compared to a matched sample starting meDMT.

  -This study provides Class III evidence that for patients with MS, starting heDMT lowers the risk of EDSS worsening and relapses compared to starting meDMT.

  -*”Class III evidence”

  January 21, 2025

  health, mental-health, ms, multiple-sclerosis, wellness

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