Barts-MS rose-tinted-odometer: ★
It is always nice to see evidence supporting a hypothesis you had more than a decade ago see daylight.
If you are on interferon-beta or have been on interferon-beta in the past this post is important to you. It is clear type 1 interferons, such as interferon-beta and alpha, are important antiviral cytokines and are critical in the body’s fight against coronaviruses. There are two papers in Science that show that people with errors in the interferon pathway or neutralizing anti-interferon antibodies are at high and serious risk of severe COVID-19. The reason for this is that their immune system can’t mount an appropriate antiviral response.
Why is this important to pwMS? The problem is that people on interferon-beta may generate anti-drug antibodies (ADAs) to interferon-beta that can inhibit its antiviral activity. The rate of anti-interferon-beta neutralizing antibody (NABs) production depends on the preparation of interferon-beta you are on or have been on in the past. The NAB rates vary from about 2% to 35% and higher. The reason for this is based on whether or not the interferon-beta aggregates in the vial and whether or not there are other impurities in the particular formulation that may make the interferon-beta more immunogenic (more likely to stimulate the immune system to make NABs).
Please note even if you have been treated with interferon-beta many years ago you may still have NABs. NABs may persist for many years and these will continue to inhibit your own interferon-beta’s activity.
We reported a single case, our index case (see below), who developed recurrent severe genital herpes that coincided with her developing NABs. The herpes was such a problem that this patient is now on continuous antiviral prophylaxis and has been so for about 8 years. Any attempt to stop the antiviral is followed by rapid recurrent herpetic lesions.
Based on this I suspect that pwMS who have NABs to interferon-beta may be at increased risk of getting severe COVID-19. I would urge anyone with a cohort of such patients to screen them for NABs and test this hypothesis.
It is now clear that overall pwMS on interferon-beta are at lower risk of COVID-19 and severe COVID-19 presumably because the antiviral effects of interferon are protecting them against the virus. Therefore being on interferon-beta may be a double-edged sword depending on whether or not you have NABs.
If you don’t know your NAB status ask your HCP for a test.
Would knowing that someone with MS was NAB-positive change practice? Yes, based on the science you would recommend increased vigilance and possibly self-isolation if the background risk of coronavirus infection is high.
Fine et al. Do neutralising antibodies against exogenous interferon-beta inhibit endogenous signalling pathways? Mult Scler Relat Disord 2015 Jan;4(1):88-91.
Introduction: Interferon-beta (IFNβ) is currently the most used disease-modifying treatment for relapsing-remitting multiple sclerosis (RRMS), but it can lead to the production of neutralising antibodies (NABs) against IFNβ.
Clinical case: A lady with a past history of genital herpes was diagnosed with RRMS, started IFNβ treatment with a good initial response. Three years later her treatment was interrupted to become pregnant. After delivery she restarted IFNβ; she had more reactivations of genital herpes and experienced intermittent sensory symptoms often coinciding with herpes reactivation. High NABs titres against IFNβ were found. Since the introduction of famciclovir as prophylactic antiviral therapy and a switch from IFNβ to glatiramer acetate, herpes reactivations ceased and she had no further MS relapses.
Conclusion: Exacerbations of genital herpes coinciding with MS relapses suggest a potential link between the development of NABs and inhibition of anti-viral action of endogenous IFNβ. This case highlights that NABs not only decreases exogenous IFNβ treatment efficacy but may also interfere with anti-viral properties of endogenous IFNβ. Investigating patients who are treated with biological medication will allow us to better understand the biology and signalling pathways in humans.
Bastard et al. Auto-antibodies against type I IFNs in patients with life-threatening COVID-19. Science 24 Sep 2020: eabd4585 DOI: 10.1126/science.abd4585
Interindividual clinical variability in the course of SARS-CoV-2 infection is immense. We report that at least 101 of 987 patients with life-threatening COVID-19 pneumonia had neutralizing IgG auto-Abs against IFN-ω (13 patients), the 13 types of IFN-α (36), or both (52), at the onset of critical disease; a few also had auto-Abs against the other three type I IFNs. The auto-Abs neutralize the ability of the corresponding type I IFNs to block SARS-CoV-2 infection in vitro. These auto-Abs were not found in 663 individuals with asymptomatic or mild SARS-CoV-2 infection and were present in only 4 of 1,227 healthy individuals. Patients with auto-Abs were aged 25 to 87 years and 95 were men. A B cell auto-immune phenocopy of inborn errors of type I IFN immunity underlies life-threatening COVID-19 pneumonia in at least 2.6% of women and 12.5% of men.
Zhang et al. Inborn errors of type I IFN immunity in patients with life-threatening COVID-19. Science 24 Sep 2020: eabd4570 DOI: 10.1126/science.abd4570.
Clinical outcome upon infection with SARS-CoV-2 ranges from silent infection to lethal COVID-19. We have found enrichment in rare variants predicted to be loss-of-function (LOF) at the 13 human loci known to govern TLR3- and IRF7-dependent type I interferon (IFN) immunity to influenza virus, in 659 patients with life-threatening COVID-19 pneumonia, relative to 534 subjects with asymptomatic or benign infection. By testing these and other rare variants at these 13 loci, we experimentally define LOF variants in 23 patients (3.5%), aged 17 to 77 years, underlying autosomal recessive or dominant deficiencies. We show that human fibroblasts with mutations affecting this pathway are vulnerable to SARS-CoV-2. Inborn errors of TLR3- and IRF7-dependent type I IFN immunity can underlie life-threatening COVID-19 pneumonia in patients with no prior severe infection.