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

2004 ◽  
Vol 10 (2) ◽  
pp. 126-138 ◽  
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.

Interferon beta in relapsing-remitting multiple sclerosis: an independent postmarketing study in southern Italy

2003 ◽  
Vol 9 (5) ◽  
pp. 451-457 ◽  
Author(s):  
Maria Trojano ◽  
Maria Liguori ◽  
Damiano Paolicelli ◽  
Giovanni Bosco Zimatore ◽  
Francesca De Robertis ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Adverse Events ◽  
Interferon Beta ◽  
Population Based ◽  
First Year ◽  
Independent Population ◽  
Disability Status ◽  
Relapsing Remitting ◽  
Remitting Multiple Sclerosis ◽  
Relapsing Remitting Multiple Sclerosis

This independent, population-based surveillance study monitored the efficacy and safety of interferon beta (IFNb) products in 1033 patients with relapsing -remitting multiple sclerosis (RRMS) from 15 centres in Italy. Relapses, Expanded Disability Status Scale (EDSS) scores, and adverse events were evaluated for up to 24 months. Data of patients with a baseline EDSS score 5-3.5 are reported. The proportions of relapse-free patients were similar among the groups at 12 and 24 months (P =0.10). IFNb products produced significant reductio ns from baseline in relapse rates at 12 and 24 months (P B-0.001), with no differences among treatments (P =0.2). There were no significant differences in mean EDSS change among groups at 12 or 24 months. The IFNb-1b group showed a higher incidence of adverse events during the first year of treatment (P B-0.05) than IFNb-1a groups, and more withdrawals (10%) compared with Avonex (5%) at 24 months. IFNb products are equally effective in low disability RRMS, but IFNb-1a may have a more favorable efficacy/tolerability ratio.

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.

The Danish National Project of interferon-beta treatment in relapsing-remitting multiple sclerosis

2000 ◽  
Vol 6 (3) ◽  
pp. 172-175 ◽  
Author(s):  
Nils Koch-Henriksen ◽  
Per Soelberg Sùrensen ◽  
Keyword(s):  
Multiple Sclerosis ◽  
Relapse Rate ◽  
Interferon Beta ◽  
Randomised Trial ◽  
Neutralizing Antibody ◽  
The European Union ◽  
Relapsing Remitting ◽  
First Relapse ◽  
Remitting Multiple Sclerosis ◽  
Relapsing Remitting Multiple Sclerosis

After approval by the European Union in 1996 of interferon-beta for treatment of relapsing-remitting multiple sclerosis (RRMS), 862 patients in Denmark have received treatment (by April 1999), and 304 of those were enrolled into an open labelled randomised trial to compare the efficacy and tolerability of treatment with interferon-beta-1b (Betaferon) 8 MIU subcutaneous every other day and interferon-beta-1a (Rebif) 6 MIU subcutaneous once a week. Primary and secondary end-points included: (1) the relapse rate, (2) tolerability, (3) neutralizing antibody formation using the same specialised laboratory and validated assay, (4) time to first relapse, (5) time to sustained progression, and (6) number of gadolinium-enhancing lesions in T1-weighted MRI and the total lesion load in T2-weighted MRI. All the records are kept in a nationwide clinical database connected with the Danish Multiple Sclerosis Registry. The randomised trial will be completed by the end of 1999, and the results are not yet available. The annual relapse rate in all treated patients until April 1999 was 0.73, the annual rate of steroid treated relapses was 0.21. By 1 April 1999 8.8% of the patients had discontinued treatment and 10.4% had changed to another interferon-beta preparation. It has been planned to extend the follow-up of all patients treated according to the Danish National Protocol for a period of several years. The continuous and nation-wide registration of the course of the disease in interferon-beta treated RRMS patients may provide valuable knowledge of the treatment-modified long-term course of the disease in a cohort of patients, selected on the basis of well-defined criteria.

scholarly journals Effects of immunomodulatory treatment with subcutaneous interferon beta-1a oncognitive decline in mildly disabled patients with relapsing—remitting multiple sclerosis

2009 ◽  
Vol 16 (1) ◽  
pp. 68-77 ◽  
Author(s):  
F. Patti ◽  
MP Amato ◽  
S. Bastianello ◽  
L. Caniatti ◽  
E. Di Monte ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Cognitive Impairment ◽  
Treatment Group ◽  
Interferon Beta ◽  
Neuropsychological Testing ◽  
High Dose ◽  
Relapsing Remitting ◽  
Disabled Patients ◽  
Remitting Multiple Sclerosis ◽  
Relapsing Remitting Multiple Sclerosis

The objective of this study was to assess the effects of subcutaneous (sc) interferon beta-1a (IFNβ-1a) on cognition in mildly disabled patients with relapsing—remitting multiple sclerosis (RRMS). Patients aged 18—50 years with RRMS (McDonald criteria; Expanded Disability Status Scale score ≤4.0) were assigned IFNβ therapy at the physician’s discretion and underwent standardized magnetic resonance imaging, neurological examination and neuropsychological testing at the baseline and regular intervals for up to three years. This analysis included 459 patients who received sc IFNβ-1a (44 mcg: n = 236; 22 mcg: n = 223; three-year follow up was available for 318 patients). The hazard ratio for cognitive impairment over three years (44 mcg versus 22 mcg) was 0.68 (95% confidence interval [CI]: 0.480—0.972), suggesting a 32% lower risk with the higher dose treatment. At year 3, the proportion of patients who were cognitively impaired increased slightly from 23.5% at the baseline to 24.8% in the IFNβ-1a 22 mcg treatment group, but remained stable at 15.2% in the IFNβ-1a 44 mcg treatment group. The proportion of patients with cognitive impairment at year 3 was significantly higher in the 22 mcg group than in the 44 mcg group (P = 0.03), although a trend was also seen at the baseline (P = 0.058). Multivariate logistic regression (corrected for baseline cognitive deficits) indicated that treatment with the higher dose of IFNβ-1a was predictive of lower cognitive impairment at three years (odds ratio: 0.51, 95% CI: 0.26—0.99) compared with the lower dose of IFNβ-1a. These findings suggest that sc IFNβ-1a may have dose-dependent cognitive benefits in mildly disabled patients with RRMS, and may support early initiation of high-dose IFNβ-1a treatment.

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

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.

Sign in / Sign up

Export Citation Format

Share Document