In the past year, considerable gains in our understanding of the immunobiology of
COVID-19 have provided key insights into the centrality of interferons in the immune
response against severe acute respiratory syndrome coronavirus 2. Several studies
attest to the involvement of interferons. For instance, Zhang and colleagues
1
screened a large cohort of patients with severe COVID-19 for the presence of predicted
loss-of-function variants in 13 genes associated with Toll-like receptor signaling
molecules and the type I interferon pathway identified in cases of severe influenza
and other viral infections. Of 659 patients with severe COVID-19, 23 (3·5%) harbored
known or new mutations in eight of the genes, attesting to the importance of these
pathways in viral defense. In a second study, Bastard and colleagues
2
reported a remarkable finding that 135 (13·7%) of 987 patients with life-threatening
COVID-19 harboured autoantibodies against type I interferons (mostly against interferon
[IFN]-α2 and IFN-ω) with most showing neutralising capacity in vitro. Such antibodies
were only detected in 4 (0·3%) of 1227 unexposed, healthy individuals.
These papers add to a growing body of literature affirming the importance of interferons
in COVID-19, which has direct and indirect implications for the field of rheumatology.
Of particular and immediate importance is how these data might affect the development
programme of a new class of biological agents designed to therapeutically target the
type I interferon pathway in patients with systemic lupus erythematosus (SLE) and
allied conditions.
The documentation of naturally occurring autoantibodies against a cytokine is not
remarkable, as low concentrations of such antibodies have been reported in studies
of healthy blood donors, which showed most of the donors to have trace amounts.
3
In the largest study examining the prevalence of antibodies against five cytokines
including type I interferons in 8972 blood donors, high concentrations of antibodies
to type I interferons were found in less than 1% of participants, with no epidemiological
associations with variables such as age, sex, or smoking,
3
similar to findings in control populations (type I interferon antibodies in <1%) in
the COVID-19 study.
2
These autoantibodies have also been found in intravenous immunoglobulin preparations
and in patients undergoing therapy with type I interferon for infections such as hepatitis
C.
4
The biological role of such antibodies is uncertain, and whether they are deterministic
(ie, have an immunoregulatory function) or stochastic (ie, appear in response to physiological
elevations) is debated. Under some circumstances, naturally occurring anti-cytokine
antibodies have been shown to be pathogenic across a range of haematological, pulmonary,
and infectious diseases.
5
Such immune dysregulatory syndromes can be monogenic (eg, defects in the AIRE gene)
or polygenic (eg, antibodies against interleukin [IL]-17, IL-22, IFN-γ, and granulocyte-macrophage
colony-stimulating factor), with polygenic syndromes now classified as inborn errors
of immunity, although no specific genes have been identified.
6
Autoantibodies against type I interferon might be clinically important, as they have
been associated with a history of severe viral infections in patients with RAG1/2
gene deficiency, an inborn error of immunity associated with diseases with prominent
autoimmune features.
7
Autoantibodies against one or more cytokines have been reported in a number of rheumatological
conditions, but their biological role remains undefined. The notable exception is
SLE, in which autoantibodies against numerous cytokines, including type 1 interferon,
have been reported in 27% and 42% of individuals in two studies.
8
These antibodies have varying capacity to neutralise type I interferon bioactivity,
depending on the study and assay used, but their presence has been associated with
reduced type I interferon in serum and lowered disease activity.
9
However, no clear evidence shows that in the absence of immunosuppression or comorbidities,
patients with SLE are at increased risk of developing severe COVID-19 due to subclinical
immunodeficiency, and more robust epidemiological studies are needed.
10
Absence of evidence of de novo vulnerability to viral infections in patients with
SLE, despite the high prevalence of neutralising autoantibodies to type I interferons,
perhaps should not be surprising. In the study by Bastard and colleagues,
2
the presence of such antibodies appeared to antedate illness with COVID-19, and none
of the patients had a history of severe influenza or other severe viral illnesses
before COVID-19. This observation suggests that in individuals with subclinical immunodeficiency
and anti-type I interferon antibodies, infection with COVID-19 might, in some unique
way, tip the balance to the advantage of the pathogen, whereas this might not happen
in response to other common viral infections. Prospective studies examining the potential
influence of autoantibodies against type I interferons on the incidence and severity
of viral infection in patients with SLE and other rheumatological disorders is needed.
Finally, what might these data forecast regarding the development programmes for biological
therapeutics targeting type 1 interferons? Previous clinical trials of monoclonal
antibodies directed against type 1 interferons have largely been unsuccessful on the
basis of efficacy. By contrast, anifrolumab, an IgG1 monoclonal antibody that targets
the type I interferon receptor—allowing it to neutralise the entire family of type
I interferons, including IFN-α, IFN-β, IFN-δ, and IFN-ω—has completed two large phase
3 trials (NCT02446912, NCT02446899). Despite some inconsistency in trial outcomes,
anifrolumab showed efficacy across clinical, laboratory, and quality of life domains
in SLE.
11
One limitation is that all drugs directed at type I interferons share a safety concern
of increased risk of herpes zoster infection, which has been as high or higher than
that seen with Janus kinase (JAK) inhibitors. However, most infections observed in
clinical trials have been non-serious.
12
Although risk of simple upper respiratory infections might also be increased with
anifrolumab, no evidence to date shows an increased risk of other serious viral infections.
Careful monitoring of outcomes in patients on this drug (and other drugs capable of
inhibiting type I interferon) who contract COVID-19 should be of the highest priority.
Small molecules, particularly JAK inhibitors, are also of concern given their capacity
to broadly inhibit interferon signaling and associated risk of herpes zoster infection.
Many JAK inhibitors are currently in clinical trials for COVID-19, a logical step
given their potent anti-inflammatory capacity, and baricitinib was granted emergency
use authorisation in the USA (Nov 19, 2020) in combination with the antiviral drug
remdesivir for hospitalised patients with COVID-19. Yet concerns remain over the countervailing
effects of these drugs on interferon pathways.
12
Moving forward, if drugs targeting interferons and interferon pathways advance to
approval in SLE and other autoimmune diseases, clinicians should consider the broader
implications of anti-type I interferon therapies on protective immune responses to
other viral infections. Ultimately, some form of heightened risk mitigation might
be required. Monitoring for viral complications will be wise with the future use of
these drugs. As new immune-based therapeutics are developed that target new molecules
and pathways for immune diseases, clinicians should return to lessons learned from
inborn errors of immunity, which might help us to prepare for future discoveries.
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