The Cost of Patients With Relapsing-Remitting Multiple Sclerosis Who Develop Neutralizing Antibodies While Treated With Interferon Beta

Background: Interferon-beta therapy of patients with relapsing—remitting multiple sclerosis involves repeated ‘immunizations’ with exogenous protein solutions. Innate pattern recognition receptors play an important role in immune responses towards foreign substances and may thus be related to treatment outcome. Objective: To determine the genotypes at 42 single nucleotide polymorphism loci in selected pattern recognition receptors for 567 prospectively followed relapsing—remitting multiple sclerosis patients treated with recombinant interferon-beta, and test for relationships to several outcome parameters, including formation of interferon-beta neutralizing antibodies. Results: The results suggest an association between the rs5743810 polymorphism (Ser249Pro) of TLR6 and development of neutralizing antibodies after 24 months of therapy in males ( p = 0.00002), but not in females ( p = 0.2). This association survived crude Bonferroni correction ( pcorrected = 0.02). Additional associations were observed in carriers of the TLR2-rs5743708 and NOD2-rs3135499 SNPs (time to relapse), the TLR7-rs179008 and NOD1-rs2075820 SNPs (time to disease progression) and the TLR4-rs7873784, TLR9-rs5743836, and NOD2-rs2066842 SNPs (frequency of neutralizing antibodies development). All of these, however, failed to survive correction for multiple testing. There were no significant differences between interferon-beta responders and non-responders for any of the investigated single nucleotide polymorphisms. Conclusions: The rs5743810 polymorphism of TLR6 may be involved in development of anti-interferon-beta antibodies in males, although further studies are required to firmly establish this.

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Binding antibodies: Vancouver's perspective

Multiple Sclerosis Journal ◽

10.1177/1352458507076989 ◽

2007 ◽

Vol 13 (1_suppl) ◽

pp. 36-43 ◽

Cited By ~ 2

Author(s):

J. Oger ◽

E. Gibbs

Keyword(s):

Multiple Sclerosis ◽

Clinical Outcomes ◽

Therapeutic Efficacy ◽

Biological Effect ◽

Neutralizing Antibodies ◽

Interferon Beta ◽

Relapsing Remitting ◽

Remitting Multiple Sclerosis ◽

Relapsing Remitting Multiple Sclerosis ◽

Different Characteristics

Binding antibodies (BAbs) and neutralizing antibodies (NAbs) develop following the use of interferon beta (IFNβ) in patients with relapsing-remitting multiple sclerosis (RRMS). The appearance of anti-IFNβ antibodies has been associated with reduction of the therapeutic efficacy of IFNβ therapy; however, while BAbs and NAbs arise from exposure to IFNβ, they have different characteristics and different impacts on clinical outcomes. Not all patients develop BAbs and NAbs, and patients who do may revert to seronegative status for each of these antibodies, even with continued IFNβ treatment. This review examines the potential clinical and biological effect of BAbs and NAbs on therapeutic efficacy in the treatment of RRMS. Multiple Sclerosis 2007; 13: S36—S43. http://msj.sagepub.com

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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

Multiple Sclerosis Journal ◽

10.1177/1352458508101946 ◽

2009 ◽

Vol 15 (5) ◽

pp. 601-605 ◽

Cited By ~ 17

Author(s):

N Koch-Henriksen ◽

PS Sorensen ◽

K Bendtzen ◽

EM Flachs

Keyword(s):

Multiple Sclerosis ◽

Neutralizing Antibodies ◽

Interferon Beta ◽

Clinical Effect ◽

Explanatory Variables ◽

Time Treatment ◽

Neutralizing Capacity ◽

Relapsing Remitting ◽

Remitting Multiple Sclerosis ◽

Relapsing Remitting Multiple Sclerosis

Objective To establish whether the clinical effect of neutralizing antibodies (NAbs) against interferon-beta (IFNβ) depends on the type of IFNβ (1a or 1b) used for treatment of patients with relapsing-remitting multiple sclerosis (MS). Introduction NAbs against IFNβ-1b appear faster and may be more evenly distributed on IgG subclasses, whereas NAbs against IFNβ-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 IFNβ-1a 22 μg s.c tiw (Rebif22) or IFNβ-1b 250 μg 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), IFNβ-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 Rebif22 (OR 1.26; P < 0.01). The effect of NAb-level on relapses was independent of whether the patients were treated with Betaferon or Rebif22 ( P = 0.89) and of time ( P = 0.80). Conclusion NAbs caused by IFNβ-1a s.c. do not differ from NAbs caused by IFNβ-1b in their detrimental clinical effect.

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Longitudinal analyses of the effects of neutralizing antibodies on interferon beta-1b in relapsing-remitting multiple sclerosis

Multiple Sclerosis Journal ◽

10.1191/1352458504ms1004oa ◽

2004 ◽

Vol 10 (2) ◽

pp. 126-138 ◽

Cited By ~ 66

Author(s):

A John Petkau ◽

Richard A White ◽

George C Ebers ◽

Anthony T Reder ◽

William A Sibley ◽

...

Keyword(s):

Multiple Sclerosis ◽

Neutralizing Antibodies ◽

Interferon Beta ◽

Neutralizing Antibody ◽

High Dose ◽

Exacerbation Rate ◽

Disability Status ◽

Relapsing Remitting ◽

Remitting Multiple Sclerosis ◽

Relapsing Remitting Multiple Sclerosis

We have analysed data on exacerbation rates, Expanded Disability Status Scale (EDSS) scores, and lesion burdens using the results of two neutralizing antibody (NA B) assays (C PE and MxA) from the pivotal relapsing-remitting multiple sclerosis (MS) trial of interferon beta-1b (IFNB) with a longitudinal appro ach, where the influence of NA Bs in individual patients is assessed by comparing responses during NAB- positive and NA B-negative periods. There are apparent influences on exacerbation rate related to dose of IFNB, titer level, and duration of positivity. With the MxA assay, exacerbation rates after switching to NA B-positive status are estimated to be 28% higher [95% confidence interval (CI): (-15%, 92%)] and -2% higher [95% CI: (-21%, 21%)] on the low- and high-dose IFNB arms, respectively. When compared with all NA B-negative periods, exacerbation rates during NA B-positive periods are estimated to be 29% higher [95% C I: (0%, 67%)] and 18% higher [95% CI: (0%, 40%)] on the low- and high-dose IFNB arms, respectively. When NA B-positive patients again become NA B-negative, no evidence of increased exacerbation rates could then be demonstrated. More detailed exploratory analyses indicate that the effects are most evident in the approximately 20% of patients developing high titers. In these patients, the influence of NABs may be self-limited, as titers often diminish or NA Bs become undetectable with time.

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