Wednesday, 14 October 2015

Fingolimod limits the formation of black holes



Oommen VV, Tauhid S, Healy BC, Chua AS, Malik MT, Diaz-Cruz C, Dupuy SL, Weiner HL, Chitnis T, Bakshi R.The Effect of Fingolimod on Conversion of Acute Gadolinium-Enhancing Lesions to Chronic T1 Hypointensities in Multiple Sclerosis. J Neuroimaging. 2015 Oct 8. doi: 10.1111/jon.12307. [Epub ahead of print]

BACKGROUND:Brain lesions converting to chronic T1 hypointensities ("chronic black holes" [CBH]), indicate severe tissue destruction (axonal loss and irreversible demyelination) in multiple sclerosis (MS). Two mechanisms by which fingolimod could limit MS lesion evolution include sequestration of lymphocytes in the periphery or direct neuroprotective effects. We investigated the effect of fingolimod on the evolution of acute gadolinium-enhancing (Gd+) brain lesions to CBH in patients with MS.
METHODS:This was a retrospective non-randomized comparison of patients with Gd+ brain lesions at the time of starting oral fingolimod [.5 mg/day, n = 26, age (mean ± SD) 39.2 ± 10.6 years, Expanded Disability Status Scale (EDSS) score - median (range): 1.75 (0, 6.5)] to those on no therapy [n = 30, age 41.7 ± 9.3 years; EDSS 1.0 (0, 6)]. Each lesion was classified by whether it converted to a CBH in the year following treatment.
RESULTS: In the fingolimod group, 99 Gd+ baseline lesions (mean ± SD, range: 3.8 ± 5.1; 1, 21 per patient) were identified of which 25 (25%) evolved to CBH (1.0 ± 2.0; 0, 10 per patient). The untreated group had 62 baseline Gd+ lesions (2.1 ± 2.3; 1, 13), 26 (42%) of which evolved to CBH (.9 ± 1.4; 0, 7) (P = .063). Thirteen patients (50%) receiving fingolimod and 17 untreated patients (57%) developed CBH (P = .79).
CONCLUSION: This pilot study shows a trend of fingolimod on reducing the conversion rate from acute to chronic destructive MS lesions. Such an effect awaits verification in larger randomized prospective studies.
This study suggests that fingolimod slows the conversion of lesions into T1 black holes. These are thought to be areas of damage. The authors suggests and influence on lesion development or neuroprotection. If fingolimod was such a good neuroprotective maybe we would have found that fingo would inhibit progressive MS. It didn't and so the the effect may have been to limit the damage caused by the inflammatory lesions once they had formed, such as regulating how much they evolve. This may relate to the influence on brain atrophy which fingo has an effect on.

9 comments:

  1. Why isn't this a first line therapy under NICE?

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  2. Vitamin D3 also limits the formation of black holes!

    Code: P799
    Abstract: 2154
    Vitamin D and the development and evolution of permanent black holes among patients with clinically isolated syndrome
    K.C. Fitzgerald1, K. Munger1, M.S. Freedman2, H.-P. Hartung3, X. Montalbán4, G. Edan5, F. Barkhof6, R. Sandbrink7, L. Kappos8, G. Suarez9, C. Pohl10, A. Ascherio1
    1Harvard T.H. Chan School of Public Health, Boston, MA, United States, 2University of Ottawa and Ottawa Health Research Institute, Ottawa, ON, Canada, 3Department of Neurology, Heinrich-Heine Universität, Duesseldorf, Germany, 4Hospital Universitari Vall d’Hebron, Barcelona, Spain, 5CHU-Hôpital Pontchaillou, Rennes, France, 6VU University Medical Center Amsterdam, Amsterdam, The Netherlands, 7Bayer Pharma AG, Berlin, Germany, 8University Hospital Basel, University of Basel, Basel, Switzerland, 9Bayer HealthCare Pharmaceuticals, Whippany, NJ, United States, 10University Hospital of Bonn, Bonn, Germany
    Objective: To assess the relationship between vitamin D [25(OH)D] and irreversible brain tissue damage characterized by the occurrence of persistent T1- hypointensities (permanent black holes-PBHs) in patients with clinically isolated syndrome (CIS) who were followed for 5 years.
    Methods: BENEFIT was a randomized trial comparing early versus delayed interferon beta-1b (IFNB-1b) treatment in patients with a first event suggestive of MS (CIS). Serum 25(OH)D concentrations were measured at baseline, 6, 12, and 24 months. 433 of the 468 patients had at least one 25(OH)D measurement and had lesion follow-up for at least 1 year. We calculated a season-adjusted 25(OH)D and estimated the association between the time-dependent cumulative average of 25(OH)D and the number of new PBHs after 6 months. We modeled lesion counts using negative binomial models and logistic regression models to assess the proportion of lesions evolving into PBHs accounting for intra-patient correlation using generalized estimating equations. We also assessed the association between 25(OH)D and number of lesions of a specific type at initial presentation (nodular Gd-enhancement, ring-like Gd-enhancement, T1-isointense T2 lesions or T1-hypointense lesions). Analyses were adjusted for age, sex, treatment, baseline T2 lesions and CIS onset type.
    Results: A total of 3789 new lesions developed over the 5 year follow-up period with 383 developing into PBHs. Average 25(OH)D levels were significantly inversely correlated with the number of PBHs from the 6-month to five-year MRI; patients with serum 25(OH)D levels ≥50 nmol/L experienced a 55% lower absolute rate of PBHs (95% CI: 0.29 to 0.71; P=0.006) than those < 50 nmol/L. We also observed a marginal association between serum 25(OH)D and the proportion of T2 lesions evolving into PBHs (0.71; 95% CI: 0.50 to 1.01; P=0.056, comparing patients with ≥50 nmol/L vs those < 50 nmol/L). We found generally similar associations between patients with serum 25(OH)D levels ≥50 nmol/L and the number of each of the 4 lesion types at presentation (for any T1-hypointense lesions: 0.54; 95% CI:0.54-0.91; for T1-isointense lesions: 0.63; 95% CI:0.47-0.85; for nodular Gd+ lesions: 0.67; 95% CI:0.47-0.98; for ring-like-Gd+ lesions: 0.79; 95% CI: 0.47-1.35).
    Conclusions: Our results that higher levels of 25(OH)D were associated with lesser accumulation of irreversible brain tissue damage support the importance of adequate vitamin D status in delaying MS progression.

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  3. Why neuros in UK don't order routine blood test for asses 25(OH)D levels and then to prescribe adequate doses Vit D for their patients?

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  4. Yes, why is that the case?
    I can make a long list of MS related 'PREVENTIVE' benefits.

    One could start following the recommendation of Gravin Giovannoni and at least take vitamin D3 5000 IU/day

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    Replies
    1. The Australian government is now cutting back severely on subsidised Vit D tests - which will not be good for PwMS. Their "expert advisors" have been telling them that 50nmol/L (20ng/ml) is OK and too many Vit D tests are being ordered by GPs.

      So - if my tests are not covered I will just have to find the money for them somehow - I think Vit D is too important in MS to not keep an eye on your levels. I only ask my GP for one test a year as we come out of winter.

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    2. If we (patients with MS) participate in GrassrootsHealth, we could create the world’s largest vitamin D project to prevent MS.

      Enroll and help me spread the word.

      Delete
  5. I only just learned the reason - quite rudely, I must say, and I'll be pleased to share with you all. Apparently this particular blood test for Vit D is quite costly and therefore not a covered expense under the State's program. Those able to finance their own private care likely have no trouble persuading their neuros to order such a test. Unfortunately mine ordered it due to the extreme severity of some symptoms I'd been experiencing recently. Imagine my shock then upon discovering I'd be responsible to reimburse the System upwards of £360. When I contacted them the clerk acted as though I were mental to expect the State to pay for such a thing. She couldn't be budged and refused even to discuss anything more than my handing over the full sum at that very moment. I felt I was treated very shoddily and still haven't resolved the issue.

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    Replies
    1. Are you sure they measured 25OHD?
      You can order a home Vitamin D test here:
      https://www.grassrootshealth.net/proj-welcome/?pr=95284
      and participate in their ongoing vitamin D research.

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    2. I'm sorry to hear that. My doc also promised to test me but then refused since I had been tested last year.

      The test is quite expensive outside the UK but not that much.

      Delete

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