Interferons In Multiple Sclerosis

Objective
The ability of recombinant human Interferon-beta-1a (rh-IFN-ß-1a) to suppress Multiple Sclerosis activity, evaluated from MRI, was assessed across a range of lesions enhancing at different Gadolinium-DTPA (Gd) doses and with different sizes.

Methods
Every 4 weeks, standard dose (Sd; 0.1 mmol/kg Gd) and triple dose (Td; 0.3 mmol/kgGd) MRI were obtained from 18 patients with Relapsing/Remitting Multiple Sclerosis for 3 months before and 4 months after starting treatment with 44 mug rh-IFN-ß-1a subcutaneously, once a week.

Results
The total numbers of enhancing lesions were 145 and 126 on Sd scans and 278 and 192 on the Td scans obtained before and after treatment.

The introduction of treatment decreased, on average, the rate of appearance of new enhancing lesions seen on Sd and Td scans by 37% (p<0.001).

Treatment effects on new enhancing lesions seen on Td scans was, on average, 28% higher than on those seen on Sd scans.

The distribution of lesion sizes on Td scans changed significantly during the treatment period (p=0.05), due to a marked decrease in the number of small lesions.

Conclusion
The effect of 44 mug rh-IFN-ß-1a in reducing Multiple Sclerosis disease activity, as monitored by Gd enhanced MRI, is not homogeneous, but graduated according to the pathological characteristics and size of the lesions.

We investigated whether Interferon-ß-1a modifies the course of new enhancing lesions in Relapsing/Remitting Multiple Sclerosis.

Sixty-eight patients were studied by monthly Magnetic Resonance Imaging (MRI) in a pre-test/post-test design including 6 months of observation and 6 months of treatment.

We examined the course of new Gd-enhancing lesions on two consecutive scans during observation and during treatment.

Lesions detected during treatment were also analyzed by MRI 1 year later for persistence of enhancement, persistence of T₂ HyperIntensity, development of T₁ HypoIntensity, or disappearance.

Among the enhancing lesions detected by observation and treatment MRI, respectively, Gd-enhancement persisted at 2 months in 20% and 3% (P < 0.001), T₂ HyperIntensity persisted in 86% and 63% (P < 0.03), and T₁ HypoIntensity developed in 49% and 15% (P < 0.01).

Progression to T₁ HypoIntensity was significantly more frequent in larger lesions during both the observation and treatment periods (P < 0.01).

No re-enhancement of plaques was present at 1-year follow-up; a further reduction in T₂ HyperIntensity (63% vs. 39%) was observed while T₁ HypoIntensity remained unchanged.

Both the duration of Gd enhancement and the short-term MRI course of new enhancing lesions benefited by treatment with recombinant Interferon-ß-1a treatment.

Fifty-three patients with Relapsing/Remitting Multiple Sclerosis who had monthly Gd (Gadolinium) enhanced MRI (Magnetic Resonance Imaging) and clinical evaluation, were divided into two subgroups:

1. Patients with a clinical relapse, treated with IVMP (IntraVenous MethylPrednisolone) and at least one enhancing lesion on MRI

2. Patients who did not have a clinical relapse but with at least one enhancing lesion on MRI

In group 1, we evaluated the number and volume of enhancing lesions on the scan before and three scans after IVMP therapy; in group 2, we considered the first scan with enhancing lesions and the subsequent three scans.

The mean number and volume of enhancing lesions on the first scan was significantly higher in patients with clinical relapse compared to patients without clinical relapse.

In group 1, we found a consistent reduction in the first scan following Steroid treatment which returned to initial levels at the following scan.

Both volumetric and numerical evaluation are appropriate MRI outcome measures in monitoring therapeutic trials.

The aim of the study was to evaluate the predictive power of baseline Gadolinium (Gd) enhanced MRI in relation to subsequent clinical and MRI activity.

Sixty eight patients with Clinically Definite Relapsing/Remitting Multiple Sclerosis had a baseline Gd enhanced MRI and were followed up clinically and by monthly Gd enhanced MRI for six months.

The occurrence of relapses during the follow up period was predicted by the presence of at least one enhancing lesion on the baseline MRI (P < 0.05).

The number and volume of enhancing lesions at baseline were significantly associated with both enhancing lesions observed during the follow up period (P < 0.0001) and the accumulation of abnormality on T₂ weighted images (P < 0.0001).

Moreover, the presence of three or more enhancing lesions at baseline scan was consistently associated with the development of permanent abnormalities on T₂ weighted images six months later.

The study suggests that the number and volume of Gd enhancing lesions at a single examination are strong short term predictors of subsequent clinical and MRI activity.

This study assessed whether dysfunction of the Blood-Brain Barrier is an obligatory early event in lesion formation in Multiple Sclerosis.

Dual-echo and T₁-weighted Magnetic Resonance Imaging (MRI) after the injection of a triple dose (0.3 mmol/kg) of Gadolinium-DTPA were obtained from ten patients with Relapsing/Remitting Multiple Sclerosis every week for 2 months.

Sixty-four newly active lesions were detected by the two techniques.

All the 44 new lesions seen on dual-echo scans enhanced during the early phases of their formation: 33 at their first appearance, 10 1 week before their appearance on the dual-echo scans, and one the week thereafter.

When the every fourth (monthly) scan was analyzed, a total of 55 newly active lesions were detected (i.e., 14% active lesions would have been missed compared to the number found on weekly scanning).

Thirty-one of them were detected by both dual-echo and triple-dose scans, 15 only by enhanced scans, and nine only by dual-echo scans.

This study confirms that with highly sensitive Magnetic Resonance Imaging techniques dysfunction of the Blood-Brain Barrier is an obligatory early event in new lesion formation in Relapsing/Remitting Multiple Sclerosis.

We performed 15 dynamic Gadolinium-DTPA (Gd-DTPA)-enhanced MRI studies in 8 patients with Relapsing and Remitting Multiple Sclerosis; 7 were follow-up studies.

We measured the time course of enhancement in 102 enhancing lesions for up to 384 minutes, with rest breaks. Immediate postcontrast MRIs demonstrated many different patterns of enhancement.

We observed both uniformly enhancing and ring enhancing lesions.

The enhancing regions were often less extensive than the corresponding high signal on T₂-weighted images.

Three lesions were seen with Gd-DTPA but not on unenhanced scans; 1 was seen on unenhanced scans 10 days later, suggesting that Blood-Brain Barrier disturbance may precede other MRI signs of MS lesions.

Three months later, some high-signal areas on T₂-weighted scans had decreased in size to resemble the areas previously outlined by Gd-DTPA. This technique provides useful information about the PathoGenesis and behavior of MS lesions.

Objective
To evaluate the efficacy and safety of Interferon-alpha2a (IFN-2a) in Relapsing/Remitting MS (RRMS).

Background
Several immune-modulating therapy regimens of IFN- have shown varying results in MS.

A recent pilot study suggested benefits from IFN-2a.

Methods
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.

Results
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.

Conclusion
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.

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.

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.

Background
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.

Methods
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.

Findings
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.

Interpretation
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.

Background
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.

Methods
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.

Findings
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).

Interpretation
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.

The long-term treatment with Interferon-ß-1b of a 7-year-old male with Relapsing/Remitting Multiple Sclerosis is documented.