4 Discussion
COVID-19, a pandemic respiratory infectious disease caused by severe
acute respiratory syndrome coronavirus 2(SARS-CoV-2), could lead to
autoimmune and autoinflammatory diseases10. Patients
with ARD are associated with immune dysfunction, and often treated with
immunosuppressive drugs, making them more susceptible to infection.
However, our meta-analysis showed relatively little difference between
the prevalence of SARS-CoV-2 infections in ARD patients(0.061) and the
global prevalence of SARS-CoV-2 infections(0.077) and the prevalence of
ARD patients even lower.
Among ARDs, the prevalence of PsA
was the highest. The mucosal immune system is the largest constituent of
the immune system, protecting against infectious threats at the primary
internal surface11,12. SARS-CoV-2 infection occurs
predominantly at the respiratory mucosal surfaces, and decreased mucosal
immunity must be beneficial for virus infection13. The
highest prevalence of PsA with red patches of skin topped with silvery
scales suggests that PsA patients may have some defects in mucosal
immunity, which is more prone to COVID-19
infections14.
Vasculitis patients infected with COVID-19 had the highest mortality and
hospitalization rates. COVID-19 made a life-threatening escalation from
Th2 immune response to type 3 hypersensitivity with the subsequent
deposition of antigen-antibody complexes, particularly inside the walls
of blood vessels, to such an extent as to generate a systemic vasculitis
in the context of complex immune disease15,16.
According to Gell and Coombs classification, type 3 hypersensitivity
occurs when excess or slight excess of soluble antigen leads to the
accumulation of immune complexes, and the innate immune system cannot
fully clear from the circulation. These antigen-antibody complexes
precipitate in tissues, especially in blood vessels, and induce a severe
inflammatory state through the action of complement anaphylaxis
toxins(C3a and C5a), which in turn stimulates the release of histamine
by mast cells and the recruitment of phagocytes17.
Histopathologically, the result of this process in the vascular wall is
acute necrotizing vasculitis, accompanied by neutrophil infiltration,
karyorrhexis, and fibrinoid necrosis18. Platelet
aggregation is associated with hypercoagulability and thrombosis
described during COVID-1919. To prevent C3 activation,
anaphylatoxin in this process through specific inhibitors, like
compstatin-based AMY-101, provides effective therapeutic
results15,20.
Among the ARD patients with COVID-19 infection, SLE patients had the
highest ICU admission rate. They had higher rates of hypertension,
diabetes mellitus, obesity, and sedentary lifestyle, which were
significant risk factors for hospitalization and mortality in
COVID-1921. Besides, data from the C19-GRA registry
suggested that long-term use of GC was associated with poorer
outcomes5,22. GC is frequently used to treat SLE,
potentially making these patients vulnerable to a more severe COVID-19
disease course.
The influence of drugs on the
COVID-19 infection rate of patients with ARDs is one of the biggest
concerns of medical care. We were
surprised that the prevalence of SARS-CoV-2 infection in patients with
ARDs using GC or csDMARDs or bDMARDs was lower than the global
prevalence of COVID-19 infection, indicating that these treatments did
not necessarily increase this infection rate. Among all ARD patients
infected with COVID-19, patients mainly treated with GC had the highest
prevalence. GCs have strong anti-inflammatory effects and induce the
apoptosis of lymphocytes. These immune inhibitory effects prevent
lethality by excessive inflammation, but simultaneously increase the
susceptibility to infection23,24.
Compared with the clinical outcomes of all COVID-19 patients with ARDs
treated with several therapies, we found patients using bDMARDs or
anti-TNF therapy had lower hospitalization rates, ICU admission rates,
and mortality. Besides, bDMARD monotherapy was associated with a lower
odds of hospitalization regression coefficient, and largely driven by
anti-TNF therapies. Mechanistic studies have suggested that upregulated
TNF-α may lead to inflammatory cell death, aberrant germinal center
formation, and less robust humoral immune responses in fatal COVID-19,
providing a potential biologic rationale for the protective effect of
TNF inhibitors5,25-28. In vitro studies have
demonstrated that IL-6 and TNF-α have been regulated by the recombinant
protein S of SARS-CoV 2002, indicating that TNF-α inhibitors or the IL-6
inhibitors could decrease the cytokine storm in COVID-19
patients29,30. Anti-TNF therapy has been proposed as a
potential treatment for the hyperinflammatory phase of severe
COVID-1931-33.
We found that GC monotherapy was associated with higher odds of the
hospitalization regression coefficient. Patients using csDMARDs had
higher hospitalization rates, ICU admission rates, and mortality, but
patients using GC had a higher hospitalization rate, higher ICU
admission rate, and lower mortality. In the included studies, the
csDMARDs drug used by most patients was hydroxychloroquine(HCQ). The
World Health Organization SOLIDARITY trial reported no clinical benefit
from HCQ for hospitalized patients with COVID-1934.
Abundant evidence from numerous RCTs revealed HCQ does not prevent
SARS-CoV-2 infection or improve outcomes in mild, moderate, or severe
COVID-1935. HCQ use may even be associated with lower
survival36. Therefore, csDMARDs, especially HCQ, are
not suggested in the treatment of COVID-1925.
Corticosteroids downregulate the release of cytokines, reducing the
damage caused by cytokine storms25. GC is effective in
patients with severe COVID-19-related respiratory failure, but may not
have a benefit in patients with early or mild disease. The Infectious
Diseases Society of America(IDSA) guidelines recommend dexamethasone in
patients with COVID-19, hypoxemia, and/or critical
illness37.
The effects of drugs used on clinical outcomes varied across ARDs.
SARS-CoV-2-infected SLE patients with GC treatment had the highest
hospitalization rates. sGC use(prednisone > 5 mg/day) in
SLE is a risk factor for severe COVID-19 requiring
hospitalization38. SARS-CoV-2-infected RA patients
with csDMARDs or GC treatment had higher hospitalization rates, and
those using GC had the highest mortality. Continuous GC users, on the
one hand, inhibit the immune response and delay the clearance of the
pathogen. They suppress the host inflammatory response, which in the
case of viral infections of the respiratory tract is the primary
responsible for lung damage and ARDs39. Clinic
evidence point to a predominantly negative effect of continuous
corticosteroids in managing this type of infection39.
Our study had several limitations. Meta-analyses of studies regarding
the prevalence and clinical outcomes of COVID-19 had considerable
heterogeneities. The cause of this heterogeneity could be explained by
the differences in study size, including different diseases and study
locations. Thus, we performed a subgroup analysis to assess the
prevalence and clinical outcome of COVID-19 for each disease and
performed a regression. Second, we could not obtain the specific drug
use of each patient, and most patients used multi-drug combination
therapy, which led to biases in our analysis of the impact of drugs on
the prevalence of COVID-19 and clinical outcomes. Third, the sensitivity
of RT-PCR for SARS-CoV-2 from the nasopharyngeal swab is roughly
70%40,41. Fourth, only published studies were
included in the meta-analysis, and unpublished articles were excluded;
publication and study selection bias may have affected our results.
Therefore, further studies are needed to verify our results.