Silent progression in disease activity-free relapsing multiple sclerosis. Cree BAC, Hollenbach JA, Bove R, Kirkish G, Sacco S, Caverzasi E, Bischof A, Gundel T, Zhu AH, Papinutto N, Stern WA, Bevan C, Romeo A, Goodin DS, Gelfand JM, Graves J, Green AJ, Wilson MR, Zamvil SS, Zhao C, Gomez R, Ragan NR, Rush GQ, Barba P, Santaniello A, Baranzini SE, Oksenberg JR, Henry RG, Hauser SL. Ann Neurol. 2019;85(5):653-666.
OBJECTIVE: Rates of worsening and evolution to secondary progressive multiple sclerosis (MS) may be substantially lower in actively treated patients compared to natural history studies from the pretreatment era. Nonetheless, in our recently reported prospective cohort, more than half of patients with relapsing MS accumulated significant new disability by the 10th year of follow-up. Notably, “no evidence of disease activity” at 2 years did not predict long-term stability. Here, we determined to what extent clinical relapses and radiographic evidence of disease activity contribute to long-term disability accumulation. METHODS:Disability progression was defined as an increase in Expanded Disability Status Scale (EDSS) of 1.5, 1.0, or 0.5 (or greater) from baseline EDSS = 0, 1.0-5.0, and 5.5 or higher, respectively, assessed from baseline to year 5 (±1 year) and sustained to year 10 (±1 year). Longitudinal analysis of relative brain volume loss used a linear mixed model with sex, age, disease duration, and HLA-DRB1*15:01 as covariates.RESULTS:Relapses were associated with a transient increase in disability over 1-year intervals (p = 0.012) but not with confirmed disability progression (p = 0.551). Relative brain volume declined at a greater rate among individuals with disability progression compared to those who remained stable (p < 0.05).INTERPRETATION: Long-term worsening is common in relapsing MS patients, is largely independent of relapse activity, and is associated with accelerated brain atrophy. We propose the term silent progression to describe the insidious disability that accrues in many patients who satisfy traditional criteria for relapsing-remitting MS. Ann Neurol 2019;85:653-666.
Relapses Are Associated with Short‐Term but Not Confirmed or Long‐Term Disability Worsening
White Matter Lesions Contribute to MS Relapses.
CRAB drugs were 2.4‐fold more likely to be associated with relapses compared to high‐potency therapies (natalizumab, mitoxantrone, rituximab, cyclophosphamide).
Radiographic disease activity as defined by new brain lesions on T2‐weighted imaging correlated strongly with clinical relapses. However, the development of new T2 lesions did not correlate with EDSS worsening measured, but I guess EDSS is dominated by spinal cord events so brain MRI is not going to be totally informative
Long‐Term Brain Volume Loss and Disability Progression
Rates of relative brain volume loss for participants with either relapses or increasing disability are significantly greater than the rate found in clinically quiescent participants. Significant differences were found for comparisons between the “stable disability without relapse” and “increased disability without relapse,” “increased disability with relapse,” and “stable disability with relapse” groups.
Although relapses may contribute to relative brain volume loss in subjects without increasing disability (p = 0.027), there was no apparent additional impact of relapses in the group of subjects with worsening disability (p = 0.486). Similarly, there was no apparent additional impact of increased disability in the group of subjects with relapses (p = 0.999).
Results indicated that age‐adjusted baseline brain atrophy was associated with both an increased risk of long‐term disability
So people continue to deterirorate as there brain shrinks. But remeber…life makes you loose 0.15% a year
The analyses showed that treatment with CRAB therapy reduced brain atrophy compared to no treatment and that escalation to natalizumab is potentially associated with further stabilization of brain volume loss despite natalizumab‐treated participants having lower baseline brain volumes, which they interpret as a marker of disease severity. Therefore treatment is beneficial and being on a high efficay is what you want.
So this is not news you want to hear, in that people continue to deteriorate despite being treated to inhibit relapses. They call this silent progression. I call it ineffective disease control because we are not learning from biology. MS is inflammatory from beginnning to end and MS is neurodegenerative from beginning to end and the factors that drive these pathologies need different treatments. Monotherapies to target one or the other will not work effectively…it is not rocket science. If you are not new to the blog we have been saying this for years. But the great and the good need to say this before people wake up. Monotherapies should be a thing of the past, but they are not. We continue to put people on ineffective therapy.
Whilst hunting for neuroprotective agents we continue to do the same, as we are doing monotherapy trials, but if you do not deal with the inflammation properly then you are not targeting the problem biology.
Ibudilast was it a FLuke?
AAN 2019. Effect of Ibudilast on Neurofilament-light Chain in Progressive MS: Analysis from a Phase II Trial Fox R et al.
Objective: To report the effect of ibudilast on serum and CSF neurofilament-light (NfL) from the phase II trial of ibudilast in progressive MS.
Background: Serum NfL is a candidate biomarker of treatment response in multiple sclerosis (MS) clinical trials. Ibudilast 100 mg/d was found to slow the progression of brain atrophy in SPRINT-MS, a 255-patient randomized, placebo-controlled 96-week phase II trial of progressive MS. We evaluated the effect of ibudilast on serum and CSF NfL in SPRINT-MS.
Design/Methods: Serum samples were collected at screening, 8, 48, and 96 weeks. In an optional sub-study, 75 patients consented to CSF sampling, which was collected at screening, 48, and 96 weeks. NfL was assayed using the SIMOA immunoassay.
Results: Mean baseline serum NfL was 33.5+22.4 and 40.3+54.1 pg/ml in ibudilast and placebo groups, respectively. Mean baseline CSF NfL was 1616.7+1474.4 and 1301.2+822.2 pg/ml in ibudilast and placebo groups, respectively. Over the course of the study, there was no between-group difference in NfL in either serum (P=0.35) or CSF (P=0.62). In some subjects, changes in NfL were observed concomitantly with new/enlarging T2 lesions, which suggests confounding by active inflammation.
Conclusions: Ibudilast treatment was not associated with a decline in either serum or CSF NfL. Inflammatory activity may have confounded the intended use of NfL to measure neurodegeneration.
We have been hoping that neurofilament would be a biomarker surrogate for nerve damage in MS. Here they looked at the effect of neuroafilament after Ibudilast treatment and found no effect. Does this mean that idudilast is not affecting progression? It rather suggests that the inflammation is not under-control suffieicnetly. Although the people in the trial were allowed to use CRAB drugs until, in my opinion, we start highly-efffective treatments straight away we will continue to lose brain.
Using ibudilast without effective control of inflammation is the same as controling inflammation without effective neuroprotection
What’s lost is lost and so by not controling disease (PPMS above, RRMS below) properly you loose nerves. Above it was placebo versus ocrelizumab and the all are switched to orelizumab.
Below people were treated with beta interferon and ocreliumab. By being on beta interferon the people lost 2 years worth of brain (0.15% a year is normal brain loss) before they switched. I just don’t get this approach:-(