Case reportDo neutralising antibodies against exogenous interferon-beta inhibit endogenous signalling pathways?
Introduction
Interferon-beta (IFNβ) is currently the most used disease-modifying treatment for relapsing-remitting (RR) multiple sclerosis (MS), decreasing the number of relapses by 30% and magnetic resonance image (MRI) activity by 70–90% (Farrell and Giovannoni, 2007). Interferons (IFNs) are endogenous cytokines produced and released by host cells in response to pathogens, that when synthesised in non-mammalian cells or genetically altered, have amino-acid or post-translational changes that may break off pre-existing immune tolerance and induce antibody production (Farrell et al., 2012). Usually they are binding antibodies (BABs) that do not affect the biological activity of the drug. The subset of BABs that bind to the drug are called neutralising antibodies (NABs), they inhibit its biological activity and are associated with decrease in treatment efficacy (Farrell et al., 2012, PRIMS Study Group, 2001).Out of the three IFNβ products available for MS treatment subcutaneous IFNβ1b is the most immunogenic (12.5–24% of patients develop NABs), followed by subcutaneous IFNβ1a, with intra-muscular IFNβ1a being the least immunogenic (PRIMS Study Group, 2001). Some patients with MS (PwMS) with low NAB titres can revert back to being NAB-negative, but those with high titres rarely revert back (Giovannoni et al., 2002).
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Clinical case
A 31 year-old lady presented to neurology in 2000 with sensory symptoms in all four limbs and Lhermitte׳s phenomenon. She had no significant past medical history other than glandular fever at 18 years old and a 20 year history of genital herpes that was well controlled at that time, with two or three reactivations per year. Neurological examination showed mild spinothalamic sensory disturbances. Brain MRI was consistent with demyelination indicating a clinically isolated syndrome.
Over the next
Discussion
NABs are clinically relevant in PwMS treated with IFNβ therapy. NAB-positive patients have more relapses, activity on MRIs and disease progression (Farrell and Giovannoni, 2007, PRIMS Study Group, 2001). In months 13–36, once NABs develop, the relapse rate in NAB-positive individuals increase by 50% compared with NAB-negative individuals and is similar to placebo-treated individuals (The IFNB Multiple Sclerosis Study Group and the University of British Columbia MS/MRI Analysis Group, 1996). But
Conclusion
IFNβ is still the most used disease-modifying treatment for RRMS and NABs seem to be clinically relevant in these patients׳ management. This case highlights that NABs influence is possibly not only limited to exogenous IFNβ decreasing treatment efficacy, but may also interfere, at least, with anti-viral properties of endogenous IFNβ (Hesse et al., 2011). Investigating patients who are treated with biological medication will allow us to better understand the biology and signalling pathways in
Conflict of Interest
We wish to draw the attention of the Editor to the following facts which may be considered as potential conflicts of interest. G. Giovannoni has declared receipt of consulting fees from AbbVie, Schering Healthcare, Biogen Idec, Genzyme, GlaxoSmithKline, GW Pharma, Merck Serono, Novartis, Protein Discovery Laboratories, Roche, Teva–Aventis, Vertex Pharmaceuticals, UCB Pharma, and Pfizer. M. Marta has received unrestricted support from Merck Serono, Biogen Idec and AbbVie. D Fine, A Dattani and I
Acknowledgements
Isabel Moreira is supported by an EFNS fellowship.
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Cited by (2)
Antigen-specific tolerization in human autoimmunity: Inhibition of interferon-beta1a anti-drug antibodies in multiple sclerosis: A case report
2021, Multiple Sclerosis and Related DisordersCitation Excerpt :During this period, mitoxantrone was also reported to cause worse fertility complications (Cocco et al., 2021) and importantly, studies emerged showing that the risk of mitoxantrone-induced leukaemia had doubled (Ellis and Boggild, 2009; Ellis et al., 2015). Therefore, even if we hypothesized that treatment could reduce infection risks associated with inhibition of endogenous IFN intrinsic pathways (Fine et al., 2015), it was not ethically justifiable to expose people to the procedure and thus the planned trial became an anecdotal case report. It is possible that loss of the neutralization response was unrelated to treatment, but this would be unlikely, as it was not found in non-tolerized individuals and those given intravenous IFNβ1a alone (Gneiss et al., 2009; Hegen et al., 2014).
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Debra Fine and Abhishek Dattani contributed equally to this case report.