Dear Editor,
Coronavirus disease 2019 (COVID-19) is a newly recognized systemic condition due to
the SARS-CoV-2 infection. As rheumatologists, we often found analogies between vascular
inflammation, endothelial dysfunction and lung manifestations of COVID-19 and inflammatory
autoimmune diseases. In the management of COVID-19 infection seems sensible to distinguish
viral and host inflammatory phase since about one patient in twenty develops an uncontrolled
inflammatory response with multiple organ failure. Fever, cough, dyspnoea, fatigue
and myalgia are the most common symptoms and high creatine-phosphokinase, and inflammatory
markers (ferritin, C-reactive protein, D-dimers, interleukin-6) are associated with
a poor prognosis [1]. In this regard, several pieces of evidence point toward a central
role of massive and dysfunctional endothelial activation, leading to diffuse thrombotic
disease, both as a specific effect of SARS-CoV-2 and as a consequence of systemic
inflammation. The so-called “cytokine storm” is the production of large amounts of
mediators of inflammation that can be triggered by SARS-CoV-2 infection [2] but is
also described in autoimmune and autoinflammatory diseases. Vasculopathy and thrombotic
manifestations seem to characterize the more aggressive cases of COVID-19 infection
[3], especially in the lungs and skin [4]. In many autoimmune diseases vascular abnormalities
are associated with systemic inflammation, lung disease [5] and heart damage [6],
but the clinical course is often chronic. Intriguingly, in terms of clinical picture,
some epidemiologic aspects, biomarkers and pathological aspects of tissue damage,
COVID-19 shows many similarities with the subset of dermatomyositis associated with
anti-melanoma differentiation-associated gene 5 (MDA5) (Table 1
). Anti-MDA5 dermatomyositis is a serologically-defined subtype of dermatomyositis
that is characterized by a high risk of rapidly progressive interstitial lung disease,
little evidence of clinical muscle inflammation, typical rashes and high prevalence
of systemic symptoms. Viral infections have been considered as a possible trigger
to the uncontrolled innate and adaptive immune response of anti-MDA5 dermatomyositis.
Anti-MDA5 dermatomyositis has a poor prognosis but low recurrence rate in survivors
and, while it is a very rare condition globally, it is reported much more frequently
in East Asia, suggesting a genetic or environmental modulation of the onset of the
disease. Even if direct evidence of a specific viral pathogen is lacking, this hypothesis
is supported by the recognition of IFN induced with helicase C domain protein 1 (IFIH1)
gene as a target of anti-MDA5 antibodies [7]. IFIH1 is indeed required for the normal
immune response against some classes of viruses, including coronavirus, promoting
the production of cytokines such as IFNγ, TNF-α, IL-1β, IL-6 and IL-18 and stimulation
of TH1 cells and macrophages. In case of a defective anti-inflammatory counterbalance,
the result is the development of a cytokine storm with the overexpression of pro-inflammatory
mediators, sustaining rapidly progressive forms of interstitial lung disease [8].
Not surprisingly, systemic symptoms like fever are particularly frequent in these
patients compared to the ones with other connective tissue diseases, and hyperferritinemia
is an almost invariable finding with very high levels associated with a more severe
disease course and a poor prognosis [9]. Manifestations of hypercoagulability with
various degrees of thromboembolism, are also a recognized risk in inflammatory myopathies
and thrombotic alterations of small and medium-sized arteries represent a histopathological
hallmark in skin biopsies [10]. Radiologic appearance on chest CT of anti-MDA5 disease
is very close to the one of COVID-19 (Fig. 1
), with a bilateral distribution of ground-glass opacities with or without consolidation
in posterior and peripheral lungs and - in a substantially different way from other
myositis related interstitial lung disease - with prevalent peribronchovascular consolidations
[11,12]. Spontaneous pneumomediastinum is not a rare finding in both severe COVID-19
and anti-MDA5 positive dermatomyositis related interstitial lung disease while is
less common in anti-MDA5 negative myositis. In the above depicted context, anti-MDA5
antibodies formation may be a simple epiphenomenon due to antigen release from infected
or damaged cells or may have a pathogenetic role, directly promoting tissue damage.
Consistently with this last speculation, anti-MDA5 titre correlates with disease activity,
prognosis and therapeutic response [13], and B-cells depletion treatment has shown
to be useful in refractory cases. The significant role of humoral immunity in anti-MDA5
myositis could appear distinctive from COVID-19. To date, a pathogenetic effect of
antibodies targeted against SARS-CoV-2 cannot be excluded since their neutralizing
effect is still debated and the anti-IgG response has been associated with disease
severity and higher proinflammatory cytokines level [14]. The possibility of secondary
antibody-mediated organ damage would represent another common point between COVID-19
and anti-MDA5 dermatomyositis, at least in the subgroup of patients who develop an
uncontrolled immunoinflammatory response after SARS-CoV-2 infection. Notably, a cross-reactivity
between anti-SARS-CoV-1 (a form of coronavirus close to the one responsible of COVID-19)
antibodies and lung epithelial cells has been described [15]. The analogies between
these two conditions allow speculations about the rationale of targeted therapies
with promising results in anti-MDA5 positive interstitial lung disease in COVID-19.
High dose corticosteroids, intravenous human immunoglobulin, JAK-inhibitors and T-cell
modulating drugs reported efficacy in small case series and are currently under investigation
in clinical trials for the treatment of COVID-19. A therapeutic role of direct B cells
depletion seems unlikely in COVID-19 due to their crucial protective role against
viral infections, unless a direct pathogenic effect of SARS-CoV-2 induced antibodies
in severe COVID-19 systemic disease is proven. Other pharmacological strategies, including
inhibition of IL-6 (tocilizumab, sarilumab, siltuximab and clazakizumab), IL-1 (anakinra
and canakinumab), anti-GM-CSF (gimsilumab) or IFNγ (emapalumab) - rarely or neither
used in the treatment of anti-MDA5 interstitial lung disease - are currently being
tested for COVID-19 treatment, given the crucial role of these cytokines in the disease,
but with understandable concerns on the possible interference with the host response
to the virus. In COVID-19, appears crucial that a structured approach to clinical
phenotyping is undertaken, in order to distinguish the phase where the viral pathogenicity
is dominant by the phase in which host inflammatory response prevails.
Table 1
Comparison between COVID-19, anti-MDA5 dermatomyositis and classic dermatomyositis.
Table 1
COVID-19
Anti-MDA5 dermatomyositis with ILD
Classic dermatomyositis with ILD
Epidemiology
Prevalence
More than two million cases globally
Rare
Rare
Geographic clusters
First reports in China, (now in all continents)
Mainly reported in east Asia
None
Sex predominance
None
None
Female predominance
Natural history
Severe and rapidly progressive disease in about 20% of cases
Rapidly progressive
Slowly progressive
Recurrence
Unknown
Rare
Relapsing-remitting
Mortality rate
High
Very high
High
Pathogenesis
Association with viral infection
Proven association with SARS-CoV-2 infection
Possible trigger of picoRNA- or other viruses
Debated triggering role of viruses
Inflammatory state
High grade systemic inflammation
High grade systemic inflammation
Low-moderate grade systemic inflammation
Prothrombotic state and endothelial dysfunction
Hallmark of the disease
Hallmark of the disease
Hallmark of the disease
Autoantibody mediated injury
Possible cross-reactivity of induced antibodies
Postulated direct role of anti-MDA5
Debated direct pathogenetic role
Lung histopathology
DAD and microangiopathy
DAD and microangiopathy
NSIP and OP
Clinical manifestations
Lung disease
Almost always present
Almost always present
Common
Myositis
Mild-absent
Mild-absent
Almost always present
Skin and peripheral vascular involvement
Common
Almost always present
Almost always present
Fever
Almost always present
Very common
Uncommon
Association with cancer
Absent
Rare
Possible
Diagnosis and monitoring
CK
Mild-moderate high
Mild-moderate high
Very high
Ferritin
High
High
Normal or slightly increased
Lymphocytes
Commonly low
Occasionally low
Occasionally low
CRP
Very high
Very high
Usually normal
ESR
High
High
High
Antinuclear Antibodies
Unknown
Negative
Usually positive
Antiphospholipid antibodies
Possibly positive
Possibly positive
Possibly positive
CT scan of the chest
Bilateral GGO or consolidation in posterior and peripheral lungs
Bilateral GGO or consolidation in posterior and peripheral lungs
Bilateral peribronchovascular GGO or consolidation
Nailfold capillaroscopy
Unknown
Enlarged capillaries, hemorragias, neovascularization
Enlarged capillaries, hemorragias, neovascularization
Treatment
Corticosteroids
Under investigation
Commonly used
Commonly used
Anti-IL6
Under investigation
Unknown efficacy
Unknown efficacy
Anti-IL1
Under investigation
Unknown efficacy
Unknown efficacy
JAK-inhibitors
Under investigation
Under investigation
Under investigation
Anti-CD20
Not suitable
Rescue therapy
Rescue therapy
ILD interstitial lung disease, DAD diffuse alveolar damage, NSIP nonspecific interstitial
pneumonia, OP organizing pneumonia, CK creatine kinase, CRP C reactive protein, ESR
erythrocyte sedimentation rate, CT computed tomography, GGO ground glass opacities,
IL interleukin, JAK Janus kinase.
Fig. 1
Similarities in CT scans findings of two patients with anti-MDA5 dermatomyositis (A*,
C**) and two patients with COVID-19 (B, D).
The images show bilateral subpleural areas of patchy ground glass opacities and consolidation
accompanied by traction bronchiectasis and perilobular linear opacities.
*Courtesy of Prof. Noriho Sakamoto, Nagasaki University Graduate School of Biomedical
Sciences.
**Courtesy of Prof. Juan González-Moreno, Internal Medicine Department, Hospital Son
Llàtzer, Palma.
Fig. 1
In conclusion - in early phases of COVID-19 - the eradication of SARS-CoV-2 should
be the goal to prevent the subsequent inflammatory storm while in the established
phases of the inflammatory response the aim should be to extinguish effectively the
inflammatory-immune response. In a context where the key therapeutic targets have
to be fully understood, we believe that looking at the experience with autoimmune
diseases of rheumatological interest, such as anti-MDA5 related lung disease could
guide and stimulate the development of useful therapeutic strategies. Moreover, even
if the long-term impact of COVID-19 is not yet established, as rheumatologist we deeply
expect that the medical efforts to extinguish the burden of inflammation in severe
COVID-19 as soon as this occurs, may help to contain the number of patients that will
develop chronic damage and functional impairment, especially in the respiratory compartment.
Funding info
No specific funding was received from any bodies in the public, commercial or not-for-profit
sectors to carry out the work described in this article.
Ethical approval information
Non applicable.
Data sharing statement
There are no data in this work (letter to the Editor).
Contributorship
All the authors gave substantial contributions to the conception or design of the
work, acquisition, analysis or interpretation of data, drafting the work or revising
it critically for important intellectual content and final approval of the version
published.
Uncited references
[13], [14], [15]
Declaration of Competing Interest
There are no competing interests for any author.