Interferon-2a Reduces MRI Disease Activity In Relapsing/Remitting Multiple Sclerosis
Norwegian Study Group on Interferon- in Multiple Sclerosis
Myhr KM, Riise T, Green Lilleas FE, Beiske TG, Celius EG, Edland A, Jensen D, Larsen JP, Nilsen R, Nortvedt MW, Smievoll AI, Vedeler C, Nyland HI
Neurology 1999 Mar 23;52(5):1049-56
Univ of Bergen, Dept of Neurology, Haukeland Univ Hospital, Norway
PMID# 10102427; UI# 99200550
To evaluate the efficacy and safety of Interferon-alpha2a (IFN-2a) in Relapsing/Remitting MS (RRMS).
Several immune-modulating therapy regimens of IFN- have shown varying results in MS.
A recent pilot study suggested benefits from IFN-2a.
Ninety-seven patients were randomized to receive subcutaneous injections of placebo (33 patients) or 4.5 million international units (mIU) (32 patients) or 9.0 mIU (32 patients) of IFN-2a three times weekly for 6 months, with a further 6 months of follow-up.
Monthly Gadodiamide-enhanced MRI was the primary method of evaluating efficacy.
IFN-2a treatment resulted in fewer new MRI lesions during the treatment period (p < 0.003).
The probability of no new lesions during treatment was >2.5 times higher with 9.0 mIU IFN-2a than with placebo (p < 0.005).
The median number of lesions at the end of treatment was lower with IFN-2a treatment than with placebo (p = 0.0004), but the difference disappeared during follow-up.
The total number of lesions (mean) increased by 4.78 with placebo, 0.86 with 4.5 mIU IFN-2a, and 0.28 with 9.0 mIU IFN-2a during treatment (p = 0.030).
No treatment effect on exacerbation rate, progression of disability, or quality of life was detected. Nine patients discontinued treatment, five because of adverse events.
IFN-2a treatment significantly reduced disease activity as measured by MRI.
But, the efficacy disappeared within 6 months after discontinuation of treatment.
A long-term study of more patients using disability as a primary outcome measure is needed to evaluate the clinical impact.
Short-Term Evolution Of Individual Enhancing MS Lesions Studied With Magnetization Transfer Imaging
Filippi M, Rocca MA, Sormani MP, Pereira C, Comi G
Magn Reson Imaging 1999 Sep;17(7):979-84
Univ of Milan, Dept of NeuroScience, Scientific Institute, Ospedale San Raffaele, Italy
PMID# 10463647; UI# 99391288
We performed serial monthly Magnetization Transfer (MT) imaging to evaluate the prevalence and evolution of structural changes in individual enhancing lesions from patients with Multiple Sclerosis (MS).
Every 4 weeks for 3 months, we obtained Dual Echo, (MT) imaging and, 5 min after SD (0.1 mmol/kg) Gadolinium-DTPA injection, T1-weighted scans from 10 patients with early Relapsing/Remitting MS.
We measured the MT Ratio (MTR) of enhancing lesions seen on the entry scans on co-registered quantitative MTR images at entry and during the follow up.
Fourty-two enhancing lesions were identified on the entry scans.
According to the "maximal random fluctuation" detected for the Normal-Appearing White Matter MTR values, 16 (38%) lesions were classified as "increasing MTR" lesions, 21 (50%) as "stable MTR" lesions, and 5 (12%) as "decreasing MTR" lesions.
The classification of the lesions after the first month of follow up strongly predicted the classification at the end of the follow up (chi squared = 20.35, p = 0.0004).
These results indicate that the enhancing lesion population in MS is heterogeneous.
And, that reparative mechanisms occurring after Blood-Brain Barrier opening are not efficient in only a minority of the enhancing lesions from patients with early Relapsing/Remitting MS.
Clinical Worsening In Multiple Sclerosis Is Associated With Increased Frequency And Area Of Gadopentetate Dimeglumine-Enhancing MRI Lesions
Smith ME, Stone LA, Albert PS, Frank JA, Martin R, Armstrong M, Maloni H, McFarlin DE, McFarland HF
Ann Neurol 1993 May;33(5):480-9
National Institutes of Health, National Institute of Neurological Disorders and Stroke, NeuroImmunology Branch, Bethesda, MD
PMID# 8498825; UI# 93270445
It is now well established that clinically stable patients with Relapsing/Remitting Multiple Sclerosis have ongoing disease activity when evaluated by serial Gadolinium-enhanced (Gd-DTPA) Magnetic Resonance Imaging (MRI) scans.
Despite this, the relationship between clinical disease and MRI lesions, though suspected, has not been extensively documented.
The relationship between Gd-DTPA MRI lesions and clinical disease was examined in this study of 9 patients with mild Relapsing/Remitting Multiple Sclerosis (Expanded Disability Status Scale [EDSS] < 3.5).
Who had 24 to 37 monthly Gd-DTPA MRI scans, Neurological Examinations, and EDSS score assignments.
The area and frequency of Gd-DTPA lesions were examined during months with and without clinical worsening as measured by EDSS. Forty-one episodes of clinical worsening were noted during the study.
A significant association was observed between these periods of clinical worsening and MRI parameters, including increases in total number, number of new lesions, and the total area of enhancement.
Logistic regression analysis showed a significant effect of the number and area of Gd-DTPA MRI lesions on both the onset and continuation of clinical worsening.
Confirming an important relationship between clinical disease and an increase in Cerebral Gd-DTPA MRI activity.
A relationship with long-term disability was suggested, but cannot be confirmed without longer follow-up of these patients.
Randomized Double-Blind Placebo-Controlled Study Of Interferon-ß-1a In Relapsing/Remitting Multiple Sclerosis
Lancet 1998 Nov 7;352(9139):1498-504
PRISMS (Prevention of Relapses and Disability by Interferon-ß-1a Subcutaneously in Multiple Sclerosis) Study Group
PMID# 9820297; UI# 99036183
Previous trials of Interferon-ß in Multiple Sclerosis (MS) have shown efficacy, but the degree of clinical benefit remains uncertain, and the optimum dose is not known.
We undertook a double-blind, placebo-controlled study in Relapsing/Remitting MS to investigate the effects of subcutaneous Interferon-ß-1a.
560 patients with Kurtzke Expanded Disability Status Scale (EDSS) scores of 0-5.0, from 22 centers in nine countries.
Were randomly assigned subcutaneous recombinant (Rebif) Interferon-ß-1a 22 microg (n=189), or 44 microg (n=184), or placebo (n=187) three times a week for 2 years.
Neurological examinations were done every 3 months. All patients had MRI twice yearly and 205 had monthly scans in the first 9 months of treatment. Analysis was by intention to treat.
Clinical data on 533 (95%) patients were available at 2 years.
The relapse rate was significantly lower at 1 and 2 years with both doses of Interferon-ß-1a than with placebo.
Mean number per patient 1.82 for 22 microg group, 1.73 for 44 microg group vs 2.56 for placebo group: risk reductions 27% [95% CI 14-39] and 33 [21-44].
Time to first relapse was prolonged by 3 and 5 months in the 22 microg and 44 microg groups respectively, and the proportion of relapse-free patients was significantly increased (p<0.05).
Interferon-ß-1a delayed progression in disability, and decreased accumulated disability during the study.
The accumulation of burden of disease and number of active lesions on MRI was lower in both treatment groups than in the placebo group.
Subcutaneous Interferon-ß-1a (Rebif) is an effective treatment for Relapsing/Remitting MS.
In terms of relapse rate, defined disability, and all MRI outcome measures in a dose-related manner, and it is well tolerated.
Longer-term benefits may become clearer with further follow-up and investigation.
Predictive Value Of Gadolinium-Enhanced MRI For Relapse Rate And Changes In Multiple Sclerosis Disability Or Impairment - A Meta-Analysis
Gadolinium MRI Meta-Analysis Group
Kappos L, Moeri D, Radue EW, Schoetzau A, Schweikert K, Barkhof F, Miller D, Guttmann CR, Weiner HL, Gasperini C, Filippi M
Lancet 1999 Mar 20;353(9157):964-9
Kantonsspital, Dept of Neurology, Basel, Switzerland
PMID# 10459905; UI# 99387661
Reliable prognostic factors are lacking for Multiple Sclerosis (MS). Gadolinium enhancement in Magnetic Resonance Imaging (MRI) of the Brain detects with high sensitivity disturbance of the Blood-Brain Barrier, an early event in the development of Inflammatory lesions in MS.
To investigate the prognostic value of Gadolinium enhanced MRI, we did a meta-analysis of longitudinal MRI studies.
From the members of MAGNIMS (European Magnetic Resonance Network in Multiple Sclerosis) and additional centers in the USA, we collected data from five natural-course studies and four placebo groups of clinical trials completed between 1992 and 1995.
We included a total of 307 patients, 237 with Relapsing disease course and 70 with Secondary/Progressive disease course.
We investigated by regression analysis the relation between initial count of Gadolinium-enhancing lesions and subsequent worsening of disability or impairment as measured by the Expanded Disability Status Scale (EDSS) and Relapse Rate.
The relapse rate in the first year was predicted with moderate ability by the mean number of Gadolinium enhancing lesions in monthly scans during the first 6 months (relative risk per five lesions 1.13, p=0.023).
The predictive value of the number of Gadolinium enhancing lesions in one baseline scan was less strong.
The best predictor for relapse rate was the variation (SD) of lesion counts in the first six monthly scans which allowed an estimate of relapse in the first year (relative risk 1.2, p=0.020) and in the second year (risk ratio=1.59, p=0.010).
Neither the initial scan nor monthly scans over six months were predictive of change in the EDSS in the subsequent 12 months or 24 months.
The mean of Gadolinium-enhancing-lesion counts in the first six monthly scans was weakly predictive of EDSS change after 1 year (odds ratio=1.34, p=0.082) and 2 years (odds ratio=1.65, p=0.049).
Although disturbance of the Blood-Brain Barrier as shown by Gadolinium enhancement in MRI is a predictor of the occurrence of relapses, it is not a strong predictor of the development of cumulative Impairment or Disability.
This discrepancy supports the idea that variant PathoGenetic mechanisms are operative in the occurrence of relapses and in the development of long-term disability in MS.
Adams AB, Tyor WR, Holden KR
Pediatr Neurol 1999 Jul;21(1):481-3
Medical Univ of South Carolina, College of Medicine, Dept of Neurology, Charleston, USA
PMID# 10428435; UI# 99355389
The long-term treatment with Interferon-ß-1b of a 7-year-old male with Relapsing/Remitting Multiple Sclerosis is documented.
Thirty-two months after initiating treatment, he demonstrates dramatic clinical improvement, without relapse, despite high titers of Neutralizing AntiBodies to Interferon-ß-1b. It appears reasonable to attribute a role in his improvement to Interferon-ß-1b.