Persistence of neutralizing antibodies after discontinuation of IFNβ therapy in patients with relapsing-remitting multiple sclerosis

2006 ◽  
Vol 12 (3) ◽  
pp. 247-252 ◽  
Author(s):  
Bodil Petersen ◽  
Klaus Bendtzen ◽  
Nils Koch-Henriksen ◽  
Mads Ravnborg ◽  
Christian Ross ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Neutralizing Antibodies ◽  
Interferon Beta ◽  
Cytopathic Effect ◽  
Serum Levels ◽  
Neutralizing Capacity ◽  
Relapsing Remitting ◽  
Long Time ◽  
Relapsing Remitting Multiple Sclerosis

Objective The main objective was to follow serum levels of neutralizing antibodies (NABs) against interferon-beta (IFNβ) after discontinuation of IFNβ therapy. Background A large proportion of patients treated with recombinant IFNβ for multiple sclerosis (MS) develop therapy-induced NABs. Knowledge of persistence of NABs after discontinuation of therapy is limited. Design/patients: A retrospective follow-up study of patients treated in Denmark for relapsing-remitting (RR) MS with IFNβ for at least 12 months. NAB-positive patients, who discontinued therapy, were followed up with measurements of NABs. Methods We measured NAB-neutralizing capacity and NAB titres a.m. Kawade using a clinically validated cytopathic effect assay. Results Thirty-seven patients were included. Mean follow-up time was 22 months. Of the 29 patients with a NAB titre at or above 25 prior to termination of therapy, only three patients reverted to a titre below 25. Of these, two had a titre below 200 and one patient a titre of 600 at the last examination before treatment stop. The longest post-treatment follow-up during which a patient maintained NAB positivity was 59 months. Conclusion NABs against IFNβ, especially with high titres, tend to persist for a long time after discontinuation of IFNβ therapy. NABs should always be measured before reinstitution of IFNβ treatment in NAB-positive patients.

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

2009 ◽  
Vol 15 (5) ◽  
pp. 601-605 ◽  
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.

Polymorphisms of innate pattern recognition receptors, response to interferon-beta and development of neutralizing antibodies in multiple sclerosis patients

2010 ◽  
Vol 16 (8) ◽  
pp. 942-949 ◽  
Author(s):  
Christian Enevold ◽  
Annette B Oturai ◽  
Per Soelberg Sørensen ◽  
Lars P Ryder ◽  
Nils Koch-Henriksen ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Pattern Recognition ◽  
Neutralizing Antibodies ◽  
Interferon Beta ◽  
Pattern Recognition Receptors ◽  
Single Nucleotide ◽  
Relapsing Remitting ◽  
Remitting Multiple Sclerosis ◽  
Multiple Sclerosis Patients ◽  
Relapsing Remitting Multiple Sclerosis

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.

Binding antibodies: Vancouver's perspective

2007 ◽  
Vol 13 (1_suppl) ◽  
pp. 36-43 ◽  
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

scholarly journals [Pegylation and interferons in multiple sclerosis]

2016 ◽  
Vol 17 (2S) ◽  
pp. 5-11
Author(s):  
Diego Centonze ◽  
Elisa Puma ◽  
Cecilia Saleri ◽  
Giulia Vestri ◽  
Sergio Iannazzo ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Neutralizing Antibodies ◽  
Interferon Beta ◽  
Linear Chain ◽  
Phase Iii ◽  
Phase Iii Clinical Trial ◽  
Pharmacodynamic Profile ◽  
Relapsing Remitting ◽  
New Treatment ◽  
Relapsing Remitting Multiple Sclerosis

Pegylation is a procedure used for drug development since the 1970s and consists of the conjugation of a polyethylene glycol molecule (PEG) to a drug. PEG has shown to be safe and effective in improving the pharmacokinetic and pharmacodynamic profile of drugs. Recently, a 20 kDa linear chain of PEG was conjugated to interferon beta-1a with the aim to offer a new treatment option to relapsing-remitting multiple sclerosis (RRMS) patients. Due to a prolonged bioavailability, this new drug can be administered less frequently (every two weeks) than the other interferons beta available, thus allowing to hypothesize a better adherence to the treatment, which, in turn, should result in better clinical and economic outcomes. A phase III clinical trial has proven its effectiveness compared to placebo in RRMS patients, as well as a safety profile comparable to that found in other interferon beta preparations. The immunogenicity of this new molecule is < 1%, thus minimizing the suppression or reduction of interferon beta biological activity that could come from the development of Neutralizing Antibodies (NAbs).[Article in Italian]

scholarly journals Interferon beta-1b in treatment-naïve paediatric patients with relapsing–remitting multiple sclerosis: Two-year results from the BETAPAEDIC study

2017 ◽  
Vol 3 (4) ◽  
pp. 205521731774762 ◽  
Author(s):  
Jutta Gärtner ◽  
Wolfgang Brück ◽  
Almuth Weddige ◽  
Hannah Hummel ◽  
Christiane Norenberg ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Standard Deviation ◽  
Interferon Beta ◽  
Expanded Disability Status Scale ◽  
Paediatric Patients ◽  
Disability Status ◽  
Relapsing Remitting ◽  
Treatment Naïve ◽  
Relapsing Remitting Multiple Sclerosis

Background and objective Study evaluating Betaferon(R)'s safety and tolerability in paediatric patients with multiple sclerosis (BETAPAEDIC) is a prospective, open-label observational multicentre study to assess the safety and effectiveness of interferon beta-1b in paediatric patients with relapsing–remitting multiple sclerosis. Methods Treatment-naïve patients (12–16 years) scheduled to start interferon beta-1b were enrolled with follow-up visits every six months for two years. Effectiveness was evaluated by annualised relapse rate, Expanded Disability Status Scale progression, cranial magnetic resonance imaging and cognitive testing. Fatigue was assessed by the Fatigue Severity Scale. Results Sixty-eight patients were screened and 67 enrolled, with mean (standard deviation) age 14.2 (1.3) years ( n=65 in the effectiveness analysis). Mean disease duration was 11 months before study enrolment; at baseline, mean (standard deviation) Expanded Disability Status Scale was 0.6 (1.0); T2 lesion number 18.3 (15.1). Mean annualised relapse rate during the study was 0.7 ( n=57), 28/57 patients (49.1%) had no relapses and for 40/52 (76.9%) no Expanded Disability Status Scale progression was observed; 23/56 (41.1%) were relapse- and progression-free to last follow-up. Neuropsychological test and fatigue scores were within normal ranges (baseline and last follow-up). Eighteen patients had fatigue at some point. New T2 and gadolinium-enhancing (Gd+) lesions were seen in 43/55 (66.2%) and 29/55 (52.7%) patients respectively. Most frequent adverse events were influenza-like illness, headache, injection-site reactions and elevated liver enzymes. Conclusion Interferon beta-1b is an effective treatment with a favourable safety profile for paediatric patients.

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