Neurology -- Correspondence for Goodin et al., 68 (13) 977-984

Correspondence published:

Neutralizing antibodies to interferon beta: Assessment of their clinical and radiographic impact: Per Soelberg Sorensen, Antonio Bertolotto, Orbassano, Italy (25 July 2007)

Reply from the author to Sorensen and Bertolotto: Douglas S. Goodin, MD (25 July 2007)

Neutralizing antibodies to interferon beta: Assessment of their clinical and radiographic impact:: Chris H. Polman, Chris H Polman, Florian Deisenhammer, Gavin Giovannoni, Joep Killestein, Huub Schellekens (25 July 2007)

Reply from the author to Polman et al: Douglas S. Goodin, MD (25 July 2007)

Neutralizing antibodies to interferon beta: Assessment of their clinical and radiographic impact: Andrew R. Pachner (25 July 2007)

Reply from the author to Pachner: Douglas S. Goodin, MD (25 July 2007)

Neutralizing antibodies to interferon beta: Assessment of their clinical and radiographic impact 25 July 2007

Per Soelberg Sorensen,
Danish Multiple Sclerosis Research Center
Copenhagen University Hospital, Rigshospitalet, 2100 Copenhagen, Denmark,
Antonio Bertolotto, Orbassano, Italy
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Re: Neutralizing antibodies to interferon beta: Assessment of their clinical and radiographic impact

pss{at}rh.dk Per Soelberg Sorensen, et al.

In this issue of Neurology, Goodin et al present a Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology (AAN) on Neutralizing antibodies to interferon-beta: Assessment of their clinical and radiographic impact. [1]
We served as the only European members of the task force and the only members with experience in the use of neutralizing antibodies in daily practice. We concur with most of the contents, but we withdrew our authorship of the final version of the manuscript because in our opinion, parts of it are not evidence based and we disagree with two of the recommendations in the report.
The contents of the paragraph: "Are NAbs to IFNBeta associated with an increase in the activity or the severity of MS (measured either clinically or radiographically) in IFN-beta-treated patients?" ignore important clinical evidence.
There is abundant evidence from the literature [2-10] that persistently high NAb titers to IFN-beta will abolish the biological response to IFN-beta and have a deleterious effect on the clinical and radiographic efficacy of IFN-beta. The traditional classification of clinical therapeutic trials based on blinded randomization to different interventions is not appropriate for the assessment of the impact of NAbs on clinical efficacy.
The only blinding that is appropriate in a trial dealing with the impact of NAbs is the blinding of the people that perform the NAb measurements and blinding of the clinicians, who evaluate the patients, to the results of NAb testing. If these blinding procedures have been implemented correctly, and the quality of the study complies with requirements of a controlled study of NAb effects, then the study is a class I study.
One essential requirement of a study of NAb effects is that the duration of the study should be sufficient to show clinical consequences of NAbs. Hence, only studies of > 2 years with blinding of investigators as to the patients' NAb status are classified as adequate studies and other studies as inadequate studies. When all of the evidence is assembled, the presence of NAbs does seem to impact on efficacy, especially on clinical relapses and disease activity assessed by MRI.
All pivotal studies [6-10] but one [11] reported that the relapse and MRI outcomes are better�although not always statistically significantly�in the NAb-negative group compared to the NAb-positive group. Thus, the larger trials with duration of two years or more such as the PRISMS-4, the European SPMS, and the North American SPMS studies demonstrated a significant NAb-associated increase in relapse rate (p=0.05-0.01). It is reasonable to conclude that the long-term presence of NAbs is deleterious.
We disagree with conclusion 2: "It is very probable that the presence of NAbs, especially in persistently high-titer, is associated with a reduction in both the clinical and radiographic effectiveness of IFNBeta treatment (Level B). We also disagree with conclusion 5: "Although the finding of sustained high-titer NAbs (>100 NU/ml) is associated with a reduction in the therapeutic effects of IFN-beta on clinical and radiographic 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)". In the report and in our view there is evidence to suggest the following:
The presence of NAbs, especially in persistently high-titers, is associated with a reduction in the radiographic and clinical effectiveness of IFN-beta treatment (Level A).
Based on the evidence that high-titer NAbs (>100-200 NU/ml) is associated with a reduction or abolition of the therapeutic effects of IFN-beta] on radiographic and clinical measures of MS disease activity, testing for the presence of NABs should be performed during the first 24 months of therapy. In patients with NAbs, measurements should be repeated after 3-6 months. Therapy with IFN-beta should be discontinued in patients with high titres of NAbs sustained at repeated measurements with 3-6 months intervals (Level A).
These conclusions are in accordance with the European guidelines on use of anti-IFN-beta antibody measurements in multiple sclerosis. [2]
Disclosures: The authors report no conflicts of interest.

Reply from the author to Sorensen and Bertolotto 25 July 2007

Douglas S. Goodin, MD,
University of California, San Francisco
San Francisco, CA
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Re: Reply from the author to Sorensen and Bertolotto

Douglas.Goodin{at}ucsf.edu Douglas S. Goodin, MD

Drs. Sorensen and Bertolotto were an important part of our expert panel and it was with considerable regret that, at the final stage of document development, they removed their names due to what might be construed as a relatively minor difference of opinion. Thus, our panel concluded that high-titer-NAbs were probably associated with poor clinical outcomes (Level B conclusion). [1]
By contrast, Drs. Sorensen and Bertolotto argue that this statement should have been a more definitive (Level A) conclusion. Nevertheless, in a comment modified specifically by Dr. Sorensen during our deliberations and assented to by Dr. Bertolotto at the time, our committee noted that �because patients can never be randomized with respect to their ultimate NAb-status�one can never exclude the possibility that there are patient-specific factors, which both predispose certain patients to the development of NAbs and, in an unrelated manner, make them either more or less susceptible to MS attacks. If so, this will make NAbs artificially appear to increase or decrease the MS attack rate, underscoring the fact that evidence of an association cannot prove causation.�
This is precisely the reason why all of the available data is not Class I evidence (even by the new AAN criteria for establishing causation) and why, therefore, a more definitive statement is not possible. Add to this problem the other deficiencies in the current evidence such as the very small sample size of most studies, the frequent lack of statistical significance, and the highly variable definitions of NAb-positivity and high-titer, and it becomes abundantly clear that any Level A conclusion is unwarranted.
Not surprisingly, without the possibility of a more definitive conclusion about the clinical impact of NAbs, any statement suggesting that therapy for an individual patient be terminated solely on the basis of an unvalidated surrogate measure is unsupportable.
References
1. Goodin DS, Frohman EM, Hurwitz B, et al. Neutralizing antibodies to interferon beta: Assessment of their clinical and radiographic impact: An evidence report: Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology Neurology 2007; 68: 977-984.
2. Sorensen PS, Deisenhammer F, Duda P, et al. Guidelines on use of anti-interferon-beta antibody measurements in multiple sclerosis - Report of an EFNS Task Force on IFN-beta antibodies in multiple sclerosis. Eur J Neurol 2005;12:817-827.
3. Sorensen PS, Ross C, Clemmesen KM, et al. Clinical importance of neutralising antibodies against interferon beta in patients with relapsing-remitting multiple sclerosis. Lancet 2003;362:1184-1191.
4. Francis GS, Rice GP, Alsop JC. Interferon beta-1a in MS: results following development of neutralizing antibodies in PRISMS. Neurology 2005 Jul 12;65:48-55.
5. Kappos L, Clanet M, Sandberg-Wollheim M, et al. Neutralizing antibodies and efficacy of interferon beta-1a: a 4-year controlled study. Neurology 2005 Jul 12;65:40-47.
6. The IFNB Multiple Sclerosis Study Group: Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology 1993;43:655-661.
7. PRISMS Study Group: PRISMS-4: Long-term efficacy of interferon-beta-1a in relapsing MS. Neurology 2001;56:1628-1636.
8. Polman C, Kappos L, White R, et al. Neutralizing antibodies during treatment of secondary progressive MS with interferon beta-1b. Neurology 2003 Jan 14;60:37-43.
9. SPECTRIMS. Randomized controlled trial of interferon-beta-1a in secondary progressive MS: clinical results. Neurology 2001;56:1496-1504.
10. Panitch H, Miller A, Paty D, Weinshenker B. Interferon beta-1b in secondary progressive MS: results from a 3-year controlled study. Neurology 2004 Nov 23;63:1788-1795.
11. Rudick RA, Simonian NA, Alam JA, et al. Incidence and significance of neutralizing antibodies to interferon beta-1a in multiple sclerosis. Multiple Sclerosis Collaborative Research Group (MSCRG). Neurology 1998;50:1266-1272.
Disclosures: Dr. Goodin has participated in (or is currently participating in) several industry-sponsored clinical trials in multiple sclerosis. The sponsoring pharmaceutical companies for these trials have included (or do include) Ares-Serono, Bayer Healthcare, Bayer-Schering, Berlex Laboratories, Biogen-Idec, Teva-Neuroscience, BioMS, and Novartis. Dr. Goodin has also lectured at both medical conferences and in public on various aspects of the diagnosis and management of MS. In many cases these talks have been supported either directly or indirectly by educational grants from one of the above listed companies.

Neutralizing antibodies to interferon beta: Assessment of their clinical and radiographic impact: 25 July 2007

Chris H. Polman,
Department of Neurology, VU Medical Centre
PO Box 7057, 1007 MB, Amsterdam, The Netherlands,
Chris H Polman, Florian Deisenhammer, Gavin Giovannoni, Joep Killestein, Huub Schellekens
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Re: Neutralizing antibodies to interferon beta: Assessment of their clinical and radiographic impact:

Ch.polman{at}vumc.nl Chris H. Polman, et al.

We acknowledge the efforts of the AAN Therapeutics and Technology Assessment Subcommittee to provide both practical and evidence-based guidelines on neutralizing antibodies (NAb) against interferon beta in MS. [1] European guidelines have been previously published by the European Federation of Neurological Societies (EFNS). [2] Even though there are differences between the two guidelines, there is a general consensus that sustained high-dose Nab-positivity is associated with a clear reduction in the therapeutic effect of IFNb. We believe the discrepancies between both reports are because in many studies, NAb-related outcomes were only secondary and that there still is some controversy which assay system to apply.
In contrast to the Therapeutic and Technology Assessment subcommittee (TTA), we consider the nationwide Danish study the most authoritative in this field. [3] It presents unique long-term information in a large cohort (n = 541) of unselected MS patients treated in daily practice. Because this study has been prospectively designed to follow the development and clinical importance of NAbs for up to 5 years of IFNb treatment, and judgment of clinical activity and Nab-assessment were clearly separated, we are unclear why the evidence derived from this study was only allocated as class III evidence by the AAN Subcommittee. The results from this study strongly suggest that the presence of Nabs should prompt consideration about change in treatment.
We were pleased to recognize that all TTA recommendations for future research correspond to the aims of the Specific Targeted Research Project, Neutralizing antibodies on interferon beta in multiple sclerosis (NABINMS), as established by the European Commission under its 6th Framework Programme (also see www.nabinms.eu).
On behalf of the members of the NABINMS consortium, CH Polman, F Deisenhammer, G Giovannoni, J Killestein, H Schellekens.
Disclosures
Professor Polman reports having received the following: consulting fees from Biogen Idec, Schering AG, Teva, Serono, Novartis, GlaxoSmithKline, Astra Zeneca and Antisense Therapeutics; lecture fees from Biogen Idec, Schering AG, Novartis and Teva; and grant support from Biogen Idec, Schering AG , Serono, Teva, Wyeth, Novartis, UCB and GlaxoSmithKline.
Dr Deisenhammer has participated in meetings sponsored by and received honoraria from pharmaceutical companies marketing treatments for multiple sclerosis. His institution has received financial support for participation in randomised controlled trials of products manufactured by Schering, Biogen, Teva, and Elan. He has also received honoraria for acting in the capacity as adviser to various pharmaceutical companies who have drug development programmes for multiple sclerosis.
Professor Giovannoni reports having received the following: consulting fees from Biogen-Idec, Schering AG, Schering-Healthcare, Teva, Serono, Novartis, GlaxoSmithKline and Protein Discovery Laboratories; lecture fees from Biogen Idec, Schering AG, Schering Healthcare and Teva; and grant support from Biogen-Idec, Schering AG , Schering-Healthcare, Merck-Serono, Teva, Novartis, UCB and Merz.
Dr Killestein worked with companies that market drugs for MS (Schering, Biogen Idec, Serono, Teva) and with some companies that have development programmes for future drugs in MS.
Professor Schellekens has been a speaker at meetings organized by Schering AG, Serono, Teva and Biogen-Idec.

Reply from the author to Polman et al 25 July 2007

Douglas S. Goodin, MD,
University of California, San Francisco
San Francisco, CA
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Re: Reply from the author to Polman et al

Douglas.Goodin{at}ucsf.edu Douglas S. Goodin, MD

Dr. Polman et al consider the paper by Sorensen et al [3] as authoritative and question its classification (by the TTA) as Class III evidence. The issue is the likelihood of bias being introduced by the study design.
In this context, it is worthwhile to consider this paper [3] in some detail. Thus, the new AAN criteria for either a Class I or a Class II study assessing causation require (among other things) that �comparison groups are matched for known possible confounding risk factors, or the effects of such confounders are controlled in the study analysis.� Neither of these conditions is satisfied in the Sorensen study. [3] There are many potential confounders which might impact post-treatment relapse rates including disease duration, EDSS, pre-treatment relapse rate, age, gender, MRI appearance, ethnicity, and genotype.
Presumably, some combination of these factors led to the actual treatment decisions made for these patients. In this circumstance, it is not surprising to find that these baseline characteristics differ between the treatment groups (table 1 in reference 3). Because each of the different therapies has different NAb-rates, different NAb-titers, different NAb-persistence, and different efficacy such an imbalance could easily introduce bias.
In addition, many of these same baseline factors might influence NAb-rates and NAb-titers and, if so, these factors would again be imbalanced between NAb-positive and NAb-negative groups and would confound group comparisons. There could also be interactions between the imbalances introduced by treatment factors and those introduced by a differing propensity to produce NAbs. In this regard, it is only partially reassuring that Table 5 [3] indicates that relapse rates, �progression indices� and disease duration (when dichotomized, apparently, at arbitrary cut-points) were similar between groups at baseline.
Importantly, the authors of this study [3] did not even attempt to adjust or control for any of these potential sources of bias. It is for this reason that the TTA graded this study [3] as Class III. We graded the data from the RCTs as Class II because, in these studies, both NAb-positive and NAb-negative patients received the same treatment. Therefore, treatment-decision factors and interactions were not possible.
However, even if this study was upgraded to Class II, our recommendations would not change. Without a Level A conclusion based on consistent Class I evidence, any statement suggesting that therapy be altered solely on the basis of NAb-positivity would be unsupportable.
References
1 Goodin DS, Frohman EM, Hurwitz B, et al. Neutralizing antibodies to interferon beta: Assessment of their clinical and radiographic impact: An evidence report: Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2007;68: 977-984.
2. Sorensen PS, Deisenhammer F, Duda P, et al. EFNS Task Force on Anti-IFN-beta Antibodies in Multiple Sclerosis. Guidelines on use of anti-IFN-beta antibody measurements in multiple sclerosis: report of an EFNS Task Force on IFN- beta antibodies in multiple sclerosis. Eur J Neurol 2005;12:817-827.
3. Sorensen PS, Ross C, Clemmesen KM, et al and the Danish Multiple Sclerosis Study Group. Clinical importance of neutralizing antibodies against interferon beta in patients with relapsing-remitting multiple sclerosis. Lancet 2003;362:1184-1191.
Disclosures: Dr. Goodin has participated in (or is currently participating in) several industry-sponsored clinical trials in multiple sclerosis. The sponsoring pharmaceutical companies for these trials have included (or do include) Ares-Serono, Bayer Healthcare, Bayer-Schering, Berlex Laboratories, Biogen-Idec, Teva-Neuroscience, BioMS, and Novartis. Dr. Goodin has also lectured at both medical conferences and in public on various aspects of the diagnosis and management of MS. In many cases these talks have been supported either directly or indirectly by educational grants from one of the above listed companies.

Neutralizing antibodies to interferon beta: Assessment of their clinical and radiographic impact 25 July 2007

Andrew R. Pachner,
UMDNJ-New Jersey Medical School
185 South Orange Ave., Newark, NJ
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Re: Neutralizing antibodies to interferon beta: Assessment of their clinical and radiographic impact

pachner{at}umdnj.edu Andrew R. Pachner

We read the recent article by Goodin et al on the effect of neutralizing antibodies (NAbs) to IFN�. [1] Goodin et al seemingly minimize that NAbs do neutralize; they neutralize in vitro and they neutralize in vivo. The degree of impairment of bioactivity is proportional to the level of NAbs: low titer Nabs (less than 100TRU) impair bioactivity while high titer NAbs abolish bioactivity. [2] MS patients cannot derive full clinical benefit of IFN� if the drug is not fully bioactive. The impairment or complete abolition of biological therapies induced by NAbs is known throughout other medical specialties. [3]
Goodin et al should not denigrate data from bioactivity analyses using IFN�-upregulated genes, by claiming that �binding (to the IFN receptor) could be distorted by NAbs in such a way that some functions, but not others, are impacted.� Available data indicates the opposite�that upregulation of all IFN�-responsive genes is equally blocked by Nabs. [2]
Goodin et al did not consider the 2005 Report of the EFNS Task Force on IFN� antibodies in MS. [4] The conclusions in the EFNS report conflict with those in the Goodin et al article. The EFNS report makes practical recommendations, including advising that �tests for the presence of NABs should be performed during the first 24 months of therapy� and that �therapy with IFN� should be discontinued in patients with (sustained)high titers of NABs�.
Goodin et al infer that NAbs are not a concern because, in some patients, they eventually disappear. However, reversion rates to NAb-negativity after becoming NAb- positive are very low in IFN�-1a treated patients [5], a group that represents the vast majority of IFN�-treated MS patients in the US. Furthermore, during the time that patients are NAb-positive, their response to IFN� is abolished or impaired, and reversion to NAb-negativity may take years.
Finally, Goodin asserts that �some individuals can have an apparently excellent response to IFN� despite having very high NAb titers�. It is apparent that patients with very high NAb titers injecting themselves with IFN� are taking a placebo since when NAb levels are high, the injected drug loses bioactivity as soon as it is injected.
Disclosure: The author reports no conflicts of interest.

Reply from the author to Pachner 25 July 2007

Douglas S. Goodin, MD,
Univsersity of California, San Francisco
505 Parnassus Avenue, San Francisco, CA 94143
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Re: Reply from the author to Pachner

douglas.goodin{at}ucsf.edu Douglas S. Goodin, MD

Our committee--including members on both sides of the public debate--concluded that high-titer NAbs were probably associated with poor clinical outcomes. [1] A more definitive statement was not possible due to deficiencies in the current evidence. Thus, there is a substantial risk of random error due to the small size of most current studies, definitions of NAb-positivity and high-titer vary widely between reports, samples are non-randomized, and patient factors that might influence both NAb-titers and relapse-rates are generally neither considered nor controlled.
In his comments, Dr. Pachner buttresses his case for a NAb-impact by stating that "upregulation of all IFNB-responsive genes is equally blocked by NAbs". Nevertheless, despite IFNB upregulating hundreds of proteins (reflecting numerous, non-anti-viral, IFNB-actions), the cited-study only measured NAb-impact on three anti-viral biomarkers. [2] Dr. Pachner's sweeping generalization is not justified by the available data. More importantly, even if his generalization were correct, Dr. Pachner has not validated MxA or any other biomarker as a surrogate for assessing clinical outcome in MS. As a direct consequence of this failure, the impact of NAbs on clinical outcome in MS cannot even be addressed using these biomarkers, regardless of whether they are measured in vitro or in vivo. A non-validated-surrogate is simply a non-validated surrogate, period.
Dr. Pachner also claims that "the degree of impairment of bioactivity is proportional to the level of NAbs". Dr. Pachner�s previous study [2], however, characterized the correlation between low/moderate NAb-titers and gene expression as "not good". Of necessity, such a poor correlation should dampen considerably our enthusiasm for using non-validated surrogates.
Dr. Pachner previously asserted that "the effects [of NAbs] are generally not evident in... patients treated for less than 2 years." [6] Currently, he argues that, because "reversion to NAb-negativity may take years", any such reversion is clinically meaningless. Nevertheless, if one assumes that NAb-positivity becomes clinically important only after year two, then reversions to NAb-negative status after year two must be equally important.
Finally, Dr. Pachner mentions our omission of the EFNS NAb report. [4] The AAN process, however, differs in an important way from that used by the EFNS. Thus, the EFNS assessment preparation guidelines state that in "important clinical areas for which no high class evidence is available...[it is]...possible to recommend best practice based on the experience of the guideline development group". [7] By contrast, the AAN-process uses evidence, not consensus.
References
1. Goodin DS, Frohman EM, Hurwitz B, et al. Neutralizing antibodies to interferon beta: assessment of their clinical and radiographic impact: an evidence report: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2007;68:977-984.
2. Pachner A, Narayan K, Pak E. Multiplex analysis of expression of three IFN�-induced genes in antibody-positive MS patients. Neurology 2006;66:444-446.
3. Schellekens H. Bioequivalence and the immunogenicity of biopharmaceuticals. Nature Reviews 2002;1:457-462.
4. Sorensen PS, Deisenhammer F, Duda P, et al. Guidelines on use of anti- IFN-beta antibody measurements in multiple sclerosis: report of an EFNS Task Force on IFN-beta antibodies in multiple sclerosis. Eur J Neurol 2005;12:817-827.
5. Soelberg Sorensen P, Koch-Henriksen N, Ross C, Clemmesen KM, Bendtzen K, Danish Multiple Sclerosis Study Group. Appearance and disappearance of neutralizing antibodies during interferon-beta therapy. Neurology 2005; 65:33-39.
6. Pachner AR. Anti-IFN�] antibodies in IFN�]-treated MS patients: Summary Neurology 2003;61: S1-5.
7. Brainin M, Barnes M, Baron JC, et al. Guidance for the preparation of neurological management guidelines by EFNS scientific task forces--revised recommendations 2004. Eur J Neurol. 2004;11:577-581.
Disclosures: Dr. Goodin has participated in (or is currently participating in) several industry-sponsored clinical trials in multiple sclerosis. The sponsoring pharmaceutical companies for these trials have included (or do include) Ares-Serono, Bayer Healthcare, Bayer-Schering, Berlex Laboratories, Biogen-Idec, Teva-Neuroscience, BioMS, and Novartis. Dr. Goodin has also lectured at both medical conferences and in public on various aspects of the diagnosis and management of MS. In many cases these talks have been supported either directly or indirectly by educational grants from one of the above listed companies.