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Neutralizing AntiBodies In Multiple Sclerosis 3

  1. Is the treatment effect of IFN-beta restored after the disappearance of Neutralizing Antibodies?
    Mult Scler 2008 Jul;14(6):837-42

  2. Neutralizing AntiBodies and efficacy of Interferon-beta-1a: a 4-year controlled study
    Neurology 2005 Jul 12;65(1):40-7

  3. Eight-year Immunogenicity and safety of Interferon-beta-1a-Avonex treatment in patients with Multiple Sclerosis
    Mult Scler 2005 Aug;11(4):409-19

  4. Neutralizing AntiBodies to Multiple Sclerosis treatments
    J Manag Care Pharm 2004 Jun;10(3 Suppl B):S12-9

  5. The clinical effect of Neutralizing AntiBodies against Interferon-beta is independent of the type of Interferon-beta used for patients with Relapsing/Remitting Multiple Sclerosis
    Mult Scler 2009 Mar 19

  6. Neutralizing AntiBodies to Interferon-beta: Assessment of their clinical and radiographic impact: An evidence report
    Neurology 2007 Mar 27;68(13):977-84





#1

Is The Treatment Effect Of IFN-beta Restored After The Disappearance Of Neutralizing Antibodies?

Sorensen PS, Koch-Henriksen N, Flachs EM, Bendtzen K
Mult Scler 2008 Jul;14(6):837-42
Danish Multiple Sclerosis Research Center, Department of Neurology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
PMID# 18505772
Abstract

Objective
To establish whether Multiple Sclerosis (MS) patients, who have lost the therapeutic effect of Interferon-beta (IFN-ß) owing to Neutralizing AntiBodies (NABs) and subsequently revert from a NAB-positive to a NAB-negative state.

Under continued Interferon-ß-1b therapy, regain clinical effect after reversion.

Background
Several studies have shown that a significant proportion of patients treated with IFN-ß develop NABs that hamper or abolish the therapeutic effect of IFN-ß.

However, some patients, who become NAB-positive under treatment with Interferon-ß-1b, may revert to a NAB-negative state under continuous treatment.

Methods
We identified 40 patients from the Danish IFN protocol, who fulfilled the criteria: NAB-positive status for at least 12 months followed by reversion to NAB-negative state for at least 12 months.

For comparison, we included 64 matching cases that had remained NAB-negative during an observation time of at least 36 months. The two groups were clinically and demographically alike.

We measured NAB-neutralizing capacity using a clinically validated cytopathic effect assay. A blood sample with a neutralizing capacity of 20% or more was considered as NAB-positive.

A patient was defined as NAB-positive after two consecutive blood tests separated by at least 6 months.

Reversion to a NAB-negative state required at least two consecutive negative tests. To allow for the confounding effect of time we employed a mixed Poisson model.

Results
Patients who had been NAB-positive and reverted to a NAB-negative state regained treatment effect with the relapse rate as before the NAB-positive period adjusting for the effect of time.

And the relapse rate was the same as in the permanently NAB-negative patients in corresponding time periods.

The relapse rate ratio comparing the NAB-positive with the NAB-negative periods was 1.98 (95% confidence interval: 1.32-2.97).

Conclusion
Under NAB-positive periods, the clinical effect of IFN-ß was abolished.

When NABs disappeared spontaneously under continued treatment, patients regained the full effect of INF-beta-1b therapy with no negative carry-over effect from the previous NAB-positive period.



#2

Neutralizing AntiBodies And Efficacy Of Interferon-beta-1a: a 4-Year Controlled Study

Kappos L, Clanet M, Sandberg-Wollheim M, Radue EW, Hartung HP, Hohlfeld R, Xu J, Bennett D, Sandrock A, Goelz S
Neurology 2005 Jul 12;65(1):40-7
European Interferon-beta-1a IM Dose-Comparison Study Investigators
University Hospital Basel, Department of Neurology and Research, Switzerland
PMID# 16009883
Abstract

Objective
To determine the incidence and clinical significance of Neutralizing AntiBody (NAB) formation in patients with Relapsing Multiple Sclerosis (MS) who participated in the European Interferon-ß-1a IM Dose-Comparison Study.

Methods
Patients were randomized to treatment with Interferon-beta-1a (Interferon-ß-1a) 30 microg or 60 microg IM once weekly for up to 4 years.

Serum samples obtained at baseline and every 3 months thereafter were screened for the presence of IFN binding AntiBodies by ELISA.

Patients whose results were Seropositive on ELISA were screened for the presence of NABs using an AntiViral cytopathic effect assay.

Patients were considered to be positive for NABs () if the baseline NAB titer was 0 and two or more consecutive postbaseline Titers were > or = 20.

Patients were considered to be negative for NABs (NAB-) if the baseline NAB Titer was 0 and all postbaseline NAB Titers were < 5.

Results
The proportion of patients who became NAB+ was lower in patients who received 30 microg of Interferon-ß-1a than in those who received 60 microg (7/400 [1.8%] vs 19/395 [4.8%]; p = 0.02).

    The mean time to NAB+ status was 14.5 +/- 6.2 months. Compared with patients who remained NAB-, NAB+ patients showed the following:
    1. Higher relapse rates from months 12 to 48 (p = 0.04).
    2. Higher rate of mean change (worsening) in Expanded Disability Status Scale score from baseline to month 48 (p = 0.01);
    3. Greater number of T1 Gadolinium-enhanced lesions at months 24 and 36 (p = 0.02 and 0.03).
    4. And greater accrual of new or enlarging T2 lesions from month 12 to months 24 and 36 (p = 0.05 and 0.09).

Conclusions
Neutralizing AntiBodies (NABs) to Interferon-beta-1a (Interferon-ß-1a).

As observed with other IFN-ßs used in the treatment of Multiple Sclerosis, reduce the therapeutic benefits measured by relapses and MRI activity.

Data from this study also suggest NABs to Interferon-ß-1a reduce treatment benefits as measured by change in Expanded Disability Status Scale score.



#3

Eight-Year ImmunoGenicity And Safety Of Interferon-beta-1a-Avonex Treatment In Patients With Multiple Sclerosis

Herndon RM, Rudick RA, Munschauer FE 3rd, Mass MK, Salazar AM, Coats ME, Labutta R, Richert JR, Cohan SL, Genain C, Goodkin D, Toal M, Riester K
Mult Scler 2005 Aug;11(4):409-19
University of Mississippi, VA Medical Center, Jackson, MS 39216, USA
PMID# 16042223
Abstract

An open-label extension study of the phase III trial of intramuscular Interferon-beta-1a (Interferon-ß-1a-Avonex) was conducted to evaluate the Immunogenicity and safety of IFN-ß-1a-Avonex over six years in patients with Relapsing Multiple Sclerosis (MS).

Patients who participated in the pivotal phase III study were offered enrolment; entry was also open to patients who had not participated.

All patients received Interferon-ß-1a-Avonex 30 microg intramuscularly once weekly for six years, for a treatment duration of up to eight years in patients who received IFN-ß-1a-Avonex in the phase III trial.

Serum levels of IFN-ß AntiBodies were measured every six months using a screening Enzyme-Linked Immunosorbent Assay (ELISA) followed by an AntiViral Cytopathic effect assay to detect Neutralizing AntiBodies (NABs) in Serum samples positive on ELISA.

The incidence of adverse events and laboratory test results assessed safety.

Of 382 total patients, 218 had participated in the phase III study (103 placebo, 115 Interferon-ß-1a-Avonex) and 164 had not participated; 24 of the 164 were IFN-ß-naive.

At baseline, 281 patients were negative for IFN-ß AntiBodies (NAB-).

NABs (Titer > or = 20) developed at any time over six years in 5% of these patients.

Of 140 patients who had been on Interferon-ß-1b-Betaseron, 49 were positive for NABs (NAB+) at baseline; 11 of 115 who had been on Interferon-ß-1a-Avonex were at baseline.

Thirty-nine of 49 patients who had been on Betaseron and were had Titres < 100; 36 of these 39 seroconverted to NAB- while on Interferon-ß-1a-Avonex, with a median time of approximately six months.

Ten patients who had been on Betaseron had NAB Titers > or = 100; five remained during six years on Interferon-ß-1a-Avonex and five seroconverted to NAB-, but only after at least two years.

Five patients who had been on Interferon-ß-1a-Avonex during the clinical trial were with Titers < 100 at baseline; four seroconverted to NAB-, with a median time of two to three years.

Six patients who had been on Interferon-ß-1a-Avonex had NAB Titers > or = 100; five of these remained at six years.

No patient with a NAB Titer > 1000 seroconverted to NAB-, whether initially treated with Interferon-ß-1a-Avonex or -Betaseron. Adverse events were similar to those observed in the pivotal phase III trial.

Results from this trial indicated that Interferon-ß-1a-Avonex was associated with a low incidence of NABs and was well tolerated for up to eight years.

Further, the results indicate that persistence of NABs is dependent on Titer and IFN-ß product.



#4

Neutralizing AntiBodies To Multiple Sclerosis Treatments

Rossman HS
J Manag Care Pharm 2004 Jun;10(3 Suppl B):S12-9
Multiple Sclerosis Center, Michigan Institute For Neurological Disorders, Farmington Hills 48334, USA
PMID# 15253685
Abstract

Objective
This article reviews the incidence and clinical significance of Neutralizing AntiBodies (NABs) in patients with Multiple Sclerosis (MS) undergoing treatment with Interferon-beta (IFN-ß).

Implications for practice are also discussed in light of the currently available data on the clinical consequences of NABs in patients with MS.

Summary
As with other recombinant protein drugs used for the treatment of a number of diseases, AntiBodies commonly develop to IFN-ß products during the treatment of patients with MS.

Neutralizing AntiBodies (NABs) are a subset of AantiBodies that reduce or diminish the biologic activity of IFN-ß.

Three formulations of IFN-ß are currently available for the treatment of Relapsing/Remitting MS: Interferon-ß-1b (Betaseron), intramuscular (i.m.) Interferon-ß-1a (Avonex), and subcutaneous (s.c.) Interferon-ß-1a (Rebif).

Individual phase III clinical trials and direct comparison studies have shown that NABs develop more frequently during treatment with Interferon-ß-1b than Interferon-ß-1a.

And that between the 2 Interferon-ß-1a products, NABs develop more frequently during treatment with s.c.

IFN-ß-1a than IM Interferon-ß-1a. Data from clinical trials of IFN-ß products indicate that clinical efficacy of IFN-ß is reduced in NAB-positive patients.

Conclusion
In light of these data, the Immunogenicity of IFN-ß products should be considered prior to initiating treatment with IFN-ß.

Also, ongoing laboratory monitoring of patients treated with higher-dose IFN-ß is recommended for early detection of NABs.



#5

The Clinical Effect Of Neutralizing AntiBodies Against Interferon-beta Is Independent Of The Type Of Interferon-beta Used For Patients With Relapsing/Remitting Multiple Sclerosis

Koch-Henriksen N, Sorensen P, Bendtzen K, Flachs E
Mult Scler 2009 Mar 19
University Hospital Rigshospitalet, Department of Neurology, Aarhus University Hospital in Aalborg, and The Danish MS Treatment Register, Copenhagen Copenhagen, Denmark
PMID# 19299439
Abstract

Objective
To establish whether the clinical effect of Neutralizing AntiBodies (NABs) against Interferon-beta (IFN-ß) depends on the type of IFN-ß (1a or 1b) used for treatment of patients with Relapsing/Remitting Multiple Sclerosis (MS).

Introduction
NABs against IFN-ß-1b appear faster and may be more evenly distributed on IgG subclasses.

Whereas NABs against IFN-ß-1a develop more slowly and may be devoid of IgG3. This might cause different clinical responses to NABs.

Design/Patients
All Danish MS-patients who had started first-time treatment with IFN-ß-1a 22 microg s.c tiw (Rebif 22) or IFN-ß-1b 250 microg s.c. qod (Betaferon) before January 1st 2003 were included.

Relapses were recorded at bi-annual visit.

Methods
We measured NAbs every 12 months using a clinically validated cytopathic effect assay.

A blood sample with a neutralizing capacity of 20% or more was considered as NAB-positive.

We used a mixed logistic regression analysis in which NAB-status (three levels), IFN-ß-preparation.

And time since treatment started were included as explanatory variables, and relapse rate as response variable.

Results
In 1,309 patients, who were observed for 21,958 months, 32.3% were classified as NAB-positive.

The Odds-Ratio (OR) for relapses in NAB-positive months compared with NAB-negative months was 1.25; P = 0.02. The risk of relapses was higher with Betaferon than with Rebif 22 (OR 1.26; P < 0.01).

The effect of NAB-level on relapses was independent of whether the patients were treated with Betaferon or Rebif 22 (P = 0.89) and of time (P = 0.80).

Conclusion
NABs caused by IFN-ß-1a s.c. do not differ from NABs caused by IFN-ß-1b in their detrimental clinical effect.



#6

Neutralizing AntiBodies To Interferon-beta: Assessment Of Their Clinical And Radiographic Impact: An Evidence Report

Goodin DS, Frohman EM, Hurwitz B, O'Connor PW, Oger JJ, Reder AT, Stevens JC
Neurology 2007 Mar 27;68(13):977-84
University of California, San Francisco, CA, USA
PMID# 17389300
Abstract

The clinical and radiologic impact of developing Neutralizing AntiBodies (NABs) to Interferon-beta (IFN-ß) while on this therapy for Multiple Sclerosis (MS) is assessed.

On the basis of Class II and III evidence, it is concluded that treatment of patients with MS with IFN-ß (Avonex, Betaseron, or Rebif) is associated with the production of NABs (Level A).

NABs in the Serum are probably associated with a reduction in the radiographic and clinical effectiveness of IFN-ß treatment (Level B).

In addition, the rate of NAB production is probably less with Interferon-ß-1a treatment than with IFN-ß-1b treatment, although the magnitude and persistence of this difference is difficult to determine (Level B).

Finally, it is probable that there is a difference in SeroPrevalence due to variability in the dose of IFN-ß injected or in the frequency or route of its administration (Level B).

Regardless of the explanation, it seems clear that IFN-ß-1a (as it is currently formulated for IM injection) is less ImmunoGenic than the current IFN-ß preparations (either Interferon-ß-1a (Rebif) or IFN-ß-1b) given multiple times per week subcutaneously (Level A).

However, because NABs disappear in some patients even with continued IFN-ß treatment (especially in patients with low Titers), the persistence of this difference is difficult to determine (Level B).

Although the finding of sustained high-Titer NABs (>100 to 200 NU/mL) is associated with a reduction in the therapeutic effects of IFN-ß on radiographic and clinical measures of MS disease activity.

There is insufficient information on the utilization of NAB testing to provide specific recommendations regarding when to test, which test to use, how many tests are necessary, or which cutoff Titer to apply (Level U).



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