Development of interferon beta-neutralising antibodies in multiple sclerosis—a systematic review and meta-analysis

Govindappa, Karthik; Sathish, Jean G.; Park, Kevin; Kirkham, Jamie J; Pirmohamed, Munir

doi:10.1007/s00228-015-1921-0

Cited by 16 publications

(4 citation statements)

References 56 publications

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“…The reported ranges for the rate of NAb positivity have generally been 27–53% in patients treated with subcutaneous IFN-β-1b, 15–35% in those treated with subcutaneous IFN-β-1a, and 2–19% in those treated with intramuscular IFN-β-1a. 14 15 Our results are comparable with those of previous studies investigating subcutaneous IFN-β-1b and IFN-β-1a, which have been prescribed in Korea since 1998 and 2000, respectively. The prescription of intramuscular IFN-β-1a for MS patients in Korea was approved very recently (2013); therefore, only five patients undergoing this particular treatment could be enrolled in the current study; none of them exhibited NAb positivity.…”

Section: Discussionsupporting

confidence: 87%

Neutralizing Antibodies Against Interferon-Beta in Korean Patients with Multiple Sclerosis

Hyun

Kim

et al. 2018

J Clin Neurol

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Background and PurposePatients treated with interferon-beta (IFN-β) can develop neutralizing antibodies (NAbs) against IFN-β that can negatively affect the therapeutic response. This study assessed the prevalence of NAbs and the impact of NAb positivity on the therapeutic response to IFN-β in Korean patients with multiple sclerosis (MS).MethodsThis was a multicenter study involving 150 MS patients from 9 Korean medical centers who were treated with IFN-β for at least 6 months. Sera that had not been influenced by acute treatment were assessed for NAbs using a luciferase reporter gene assay. To evaluate the association between persistent positivity for NAbs and disease activity, NAbs were tested at 2 different time points in 75 of the 150 patients. Disease activity was defined as the presence of clinical exacerbations and/or active MRI lesions during a 1-year follow-up after NAb positivity was confirmed.ResultsNAbs were found in 39 of the 150 (26%) MS patients: 30 of the 85 (35%) who were treated with subcutaneous IFN-β-1b, 9 of the 60 (15%) who were treated with subcutaneous IFN-β-1a, and 0 of the 5 (0%) who were treated with intramuscular IFN-β-1a. Thirty of the 39 patients exhibiting NAb positivity were tested at different time points, and 20 of them exhibited persistent NAb positivity. Disease activity was observed more frequently in patients with persistent NAb positivity than in those with transient positivity or persistent negativity [16/20 (80%) vs. 4/55 (7%), respectively; p<0.001]. When disease activity was compared between patients with persistent and transient NAb positivity, the difference was unchanged and remained statistically significant [16/20 (80%) vs. 2/10 (20%), p=0.004].ConclusionsThese results further support that persistent NAb positivity is associated with disease activity in MS patients treated with IFN-β.

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Section: Discussionsupporting

confidence: 87%

Neutralizing Antibodies Against Interferon-Beta in Korean Patients with Multiple Sclerosis

Hyun

Kim

et al. 2018

J Clin Neurol

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“…The prevalence rates of both BABs (78%) and NABs (28%) were comparable to those published elsewhere. 16 Among subjects with high titres of NABs, we also observed differences in clinical and MRI responses. This is consistent with the proposed detrimental effect of NABs on treatment efficacy, and a recommendation to switch therapy should be made.…”

Section: Discussionmentioning

confidence: 73%

Prevalence of neutralising antibodies to interferon-beta and clinical response in Chinese patients with relapsing multiple sclerosis

Lau

et al. 2017

Multiple Sclerosis Journal - Experimental, Translational and Cl

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BackgroundThere are no data on neutralising antibodies to interferon-beta and its clinical implications in Chinese patients with multiple sclerosis (MS).ObjectivesThe objectives of this study were to investigate the prevalence of neutralising antibodies among Chinese patients with relapsing MS receiving interferon-beta (1a or 1b) and to study the association between neutralising antibodies and the clinical-radiological response.MethodsWe performed a cross-sectional study on MS patients who received interferon-beta for 9 months or more, and evaluated the clinical response by relapses and magnetic resonance imaging lesions. Blood samples were evaluated for myxovirus resistance protein A (MxA) gene expression by polymerase chain reaction, anti-interferon-beta binding antibodies by enzyme-linked immunosorbent assay, and neutralising antibodies by cell-based MxA protein induction and luciferase reporter gene assays. Assay performances were evaluated by receiver operating characteristic analysis.ResultsAmong 78 subjects recruited, 61/77 (79%) had anti-interferon-beta binding antibodies, and 22/78 (28%) had neutralising antibodies by MxA protein induction assay. The presence of high-titre neutralising antibodies was associated with poor clinical outcome (odds ratio 6.1, 95% confidence interval 1.5–25.6, P = 0.013). The sensitivity and specificity for neutralising antibodies using MxA gene expression assay (cut-off 0.20) was 80% and 68%, respectively (area under the curve 0.71).ConclusionsNeutralising antibodies are associated with poor clinical outcome in Chinese patients with relapsing MS. MxA gene expression and protein induction assays are complimentary assays for neutralising antibody detection.

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“…Although the exact causes of increased disease activity are not investigated in this retrospective real-world cohort study, there are several other possible reasons that could be investigated further, including the development of neutralising antibodies, which were shown in a European prospective multicentre centre study to develop in almost a quarter of patients on any IFN β-based regimen at a median of 23.8 months on treatment. The development of neutralising antibodies may abrogate treatment effectiveness, leading to clinical and radiological disease progression [27]. …”

Section: Discussionmentioning

confidence: 99%

Reasons for discontinuation of subcutaneous interferon β-1a three times a week among patients with multiple sclerosis: a real-world cohort study

Sabidó-Espin¹,

Munschauer

2017

BMC Neurol

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BackgroundContinuation of interferon (IFN) β-based therapies is important for maximum treatment effectiveness in patients with multiple sclerosis (MS); however, few real-world data are available on discontinuation from IFN β. The aim of this cohort analysis was to estimate real-world discontinuation rates up to 3 years among MS patients in the United States taking subcutaneous (sc) IFN β-1a three times a week (tiw) and to identify whether the factors associated with discontinuation change over time.MethodsPatient data were pooled from the MarketScan© Commercial and Medicare Supplemental healthcare claims databases. Patients with ≥1 multiple sclerosis diagnosis who were sc IFN β-1a tiw naïve, had ≥1 year of continuous eligibility before treatment, and ≥1 prescription were followed from first prescription (index date) until date of discontinuation, switch, or end of observation. Treatment status was analysed at exactly 1, 2 or 3 years after index. Multivariable models were used to identify drivers of discontinuation.ResultsData from 5956 patients were included; 2862 patients (48.1%) discontinued therapy. Discontinuation rates were 36.9% (1 year), 49.5% (2 years) and 55.8% (3 years). A greater proportion of discontinuing patients had poor adherence (<80% [94.0%] versus ≥80% [51.7%]) or were taking additional medication at follow-up versus the overall population. Factors independently associated with discontinuation irrespective of time on therapy were increasing number of magnetic resonance imaging scans (1 year adjusted odds ratio 1.45, 95% confidence interval 1.26–1.67; 2 years 1.18, 1.06–1.32; 3 years 1.20, 1.07–1.34) and adherence <80% versus ≥80% (1 year 180.95, 135.84–241.03; 2 years 135.80, 100.10–184.23; 3 years 174.89, 115.27–265.38). Factors associated only with early discontinuation (at 1 year) were ≥3 sets of laboratory investigations versus none (2.54, 1.20–5.38), and anxiolytic use at follow-up (1.40, 1.06–1.82). Factors associated only with later discontinuation (at 2 years and/or at 3 years) were antidepressant use at follow-up (2 years 1.46, 1.10–1.94) and greater number of relapses (2 years 1.60, 1.11–2.30; 3 years 2.31, 1.27–4.22).ConclusionsPotential drivers of discontinuation change over time. Improved awareness of the drivers of discontinuation could lead to targeted interventions to improve adherence.Electronic supplementary materialThe online version of this article (doi:10.1186/s12883-017-0831-4) contains supplementary material, which is available to authorized users.

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Development of interferon beta-neutralising antibodies in multiple sclerosis—a systematic review and meta-analysis

Abstract: Our data show that 2.0-18.9% of patients developed NAbs to Avonex™, 16.5-35.4% of patients developed NAbs to Rebif™ and 27.3-53.3% of patients developed NAbs to Betaferon/Betaseron™.

Cited by 16 publications

References 56 publications

Neutralizing Antibodies Against Interferon-Beta in Korean Patients with Multiple Sclerosis

Neutralizing Antibodies Against Interferon-Beta in Korean Patients with Multiple Sclerosis

Prevalence of neutralising antibodies to interferon-beta and clinical response in Chinese patients with relapsing multiple sclerosis

Reasons for discontinuation of subcutaneous interferon β-1a three times a week among patients with multiple sclerosis: a real-world cohort study

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