key: cord-0949052-xmts6or4
authors: Ehrenfeld, Michael; Tincani, Angela; Andreoli, Laura; Cattalini, Marco; Greenbaum, Assaf; Kanduc, Darja; Alijotas-Reig, Jaume; Zinserling, Vsevolod; Semenova, Natalia; Amital, Howard; Shoenfeld, Yehuda
title: Covid-19 and autoimmunity
date: 2020-06-11
journal: Autoimmun Rev
DOI: 10.1016/j.autrev.2020.102597
sha: c204d329e0796c5207557b5186597fa7d6096a5d
doc_id: 949052
cord_uid: xmts6or4

nan

Though the exact etiology of autoimmune diseases still remains unknown, there are various factors which are believed to contribute to the emergence of an autoimmune disease in a host including the genetic predisposition, the environmental triggers such as bacterial infections, including the gut microbiota, viral fungal and parasitic infections, as well as physical and environmental agents, hormonal factors and the hosts immune system dysregulation. All these factors interplay was (12) (13) . Suggested mechanisms of induction of the autoimmunity include both molecular mimicry (14) as well as "bystander activation" whereby the infection may lead to activation of antigen presenting cells that may in turn activate pre-primed auto-reactive T-cells, thus leading to the production of pro-inflammatory mediators, which in turn may lead to tissue damage (15) .

Alternative suggested mechanisms include epitope spreading as well as presentation of cryptic antigens (16) .

Corona viruses represent a major group of viruses mostly affecting human beings through zoonotic transmission. In the past two decades, this is the third instance of the emergence of a novel accompanied by hyperferritinemia and multiple organ involvement including hematological, gastrointestinal, neurological and cardiovascular complications leading to death (19) (20) (21) (22) (23) . The ARDS described in up to 20% of Covid-19 cases, is reminiscent of the cytokine release syndromeinduced ARDS and secondary hemophagocytic lymphohistiocytosis (sHLH) observed in patients with SARS-CoV and MERS-CoV as well as in leukemia patients receiving engineered T cell therapy. These cases with Covid-19 are those who develop through the excessive cytokine release and the uncontrolled immune activation, the multiorgan failure with a grave prognosis (24) (25) .

It has been suggested that the shared pathogenetic mechanisms and clinical-radiological aspects between the hyper-inflammatory diseases and Covid-19 may suggest that SARS-CoV-2 could act as a triggering factor for the development of a rapid autoimmune and / or autoinflammatory dysregulation, leading to the severe interstitial pneumonia, in genetic predisposed individuals (26) .

Furthermore, in an online pre-published study from Germany the authors studied prospectively a group of 22 patients for the possible role of autoimmunity in SARS-CoV-2 -associated respiratory failure. Based on serological, radiological and histomorphological similarities between Covid-19associated ARDS and acute exacerbation of connective tissue disease induced interstitial lung disease, the authors suggest that SARS-CoV-2 infection might trigger or simulate a form of organ specific autoimmunity in predisposed patients (27) . In a similar retrospective study from China of 21 patients with critical SARS-CoV-2 pneumonia, the authors showed a prevalence of between 20-50% of autoimmune disease related autoantibodies, suggesting the rational for immunosupression in such cases of Covid-19 (28) .

Immune thrombocytopaenic purpura (ITP) is an autoimmune systemic disease manifested by the presence of low blood platelets count (<10(5)/µl) and the production of autoantibodies against through molecular mimicry (29) (30) . . The association between ITP and Covid-19 has been   suggested in a single case report of a 65-year-old female patient with a background history of   hypertension, autoimmune hypothyroidism, and positive swab for Covid-19 who presented with fever, dry cough and signs of pneumonia. Laboratory studies were within normal limits and she was treated by intra-venous amoxicillin-clavulanic acid, low-molecular weight heparin and oxygen. The normal platelet count on admission had gradually dropped to 66,000 and later to 8,000 per cubic millimeter on day seven accompanied by classical lower-extremity purpura and epistaxis. Both heparin and the antibiotics were discontinued. She was treated by two rounds of IVIG while the platelets had drooped even further to 1,000 per cubic millimeter followed by the onset of right frontal headache, with a CT of the head demonstrating subarachnoid microhemorrhage. A platelet transfusion was administered with concurrent starting of 100 mg of prednisolone. On day 10, the headache had resolved with no new neurologic findings, and the platelet count had gradually increased to 139,000 on day 13 with a complete resolution of the purpura. The temporal sequence in this case suggests, but does not prove, that the ITP was triggered by the Covid-19 especially in view of the history of autoimmune hypothyroidism which is often associated with ITP. There are however other potential causes for the thrombocytopenia in this case such as the treatment with amoxicillin-clavulanic acid as well as the known heparininduced-thrombocytopenia (HIT) (31) (32) . Another report by Tsao et al currently online, describes a case of SARS-CoV-2 positive pediatric patient with ITP and raises the awareness of ITP as a possible pediatric presentation of the virus (33).

The first is a report of five out of 1200 patients hospitalized between February 28 th and March 21 st , 2020 in Northern Italy hospitals. The onset of neurological symptoms began 7-10 days after the initial respiratory symptoms. Four out of the 5 patients had lower-limb weakness and paresthesia and one was with facial diplegia followed by ataxia and paresthesia. Generalized, flaccid tetraparesis or tetraplegia evolved over a period of 36 hours to 4 days in 4 of the patients. Three of them required mechanical ventilation. Anti-ganglioside antibodies were either negative or not done. All patients received IVIG (1 of then required 2 cycles) and one had started plasma exchange. The second report from Iran describes a 65 year old male patient admitted to hospital because of acute progressive symmetric ascending quadriparesis, two weeks after a history of cough, fever and dyspnea. Covid-19 was diagnosed by RT-PCR. The patient was treated by hydroxychloroquine, Lopinavir/Ritonavir, and Azithromycin. GBS was confirmed by EMG. The patient was treated by IVIG for 5 days. Another early report of a single GBS patient came from China during the SARS-CoV-2 epidemic, although there is some concern regarding the causality in this particular case (38) .

MFS is a rare, acquired disease that is considered to be a mild variant of Guillain-Barré syndrome, and is observed in about 5% of all cases of GBS. It is characterized by a triad of ataxia, areflexia, and ophthalmoplegia. Acute onset of external ophthalmoplegia is a cardinal feature. Ataxia tends to be out of proportion to the degree of sensory loss. Patients may also have mild limb weakness, ptosis, facial palsy, or bulbar palsy. Occasionally generalized muscle weakness and respiratory failure may develop. Patients have reduced or absent sensory nerve action potentials and absent tibial H reflex. Like GBS, symptoms may be preceded by a viral illness. The majority of individuals with MFS have unique antibodies that characterize the disorder, which are Anti-GQ1b and anti-GD1b antibodies.

Dense concentrations of GQ1b ganglioside are found in the oculomotor, trochlear, and abducens nerves, which may explain the relationship between anti-GQ1b antibodies and ophthalmoplegia. Treatment for MFS is identical to treatment for GBS:

intravenous immunoglobulin (IVIG) or plasmapheresis. A group from Spain reported of two patients infected with SARS-CoV-2 who acutely presented with MFS and polyneuritis cranialis respectively. Both patients presented with the typical neurological symptoms. One of the two patients was found to be positive for anti-GD1b-IgG antibodies and was treated with IVIG and the J o u r n a l P r e -p r o o f Journal Pre-proof second patient with acetaminophen. Two weeks later, both patients made a complete neurological recovery, except for residual anosmia and ageusia in the first case (39) .

Deep vein thrombosis, pulmonary embolism and stroke have been observed in patients affected by severe forms of COVID-19 (40) (41) . These vascular events, particularly strokes, were mostly recorded in elderly patients (41) . However, 5 cases of stroke were recently reported in relatively young patients (age range: 33-49 years), in association with prolonged activated partialthromboplastin time (aPTT) in 2 cases (42) . with COVID-19. CAPS is usually preceded by a precipitating factor, which is an infection in the majority of the cases (45) . The link between infection and aPL was first observed when patients with different autoimmune conditions were found to be positive for the serological test of syphilis, whose antigen was described as a mixture of phospholipids, including cardiolipin (46) . Nowadays, the detection of aPL is performed by anticardiolipin (aCL) and anti-beta2glicoprotein I (anti-b2GPI) immunoassays and by the functional coagulation test lupus anticoagulant (LA), according to the international consensus APS classification criteria (47) .

Three cases of COVID-19 patients with severe thrombotic events associated with aCL and anti-b2GPI were recently reported (48) . Specifically, aCL of IgA isotype and anti-b2GPI of IgG and

IgA isotype were detected, raising the hypothesis that the mucosal damage induced by SARS-J o u r n a l P r e -p r o o f

CoV-2 could preferentially stimulate the IgA immune response. LA was found to be negative in these 3 patients.

On the other hand, LA was found to be positive in 25 out of 56 (44.6%) consecutive COVID-19

patients, while IgG/IgM aCL and/or anti-b2GPI were positive only in 5 (8.9%). No specific relation with thrombosis was mentioned in this cohort (49) .

In addition, LA was studied in patients with prolonged aPTT, a finding that has been frequently reported in COVID-19. More than 90% of patients with prolonged aPTT, with or without clinical evidence of thrombosis, resulted positive for LA (50) .

Another study investigated patients with acute respiratory distress syndrome and COVID-19 from intensive care units. In this study, 50 out of 59 (84.7%) tested patients had LA positive, strongly associated with high D-dimers and thrombosis, particularly if the test was performed early in the disease course. In this series only one patient had positive aCL of IgM isotype (51) .

Therefore, we can assume that aPL can be frequently detected in patients with SARS-CoV-2

infection. Certainly, this finding is not surprising (52) . In fact, the occurrence of transient aPL was (67) Children with SARS-CoV-2 infection usually have a benign course (67) . Differently from what we usually see in Kawasaki Disease, which has a predilection for asian countries, PeCOHS has not been described so far in those countries, suggesting that both the genetic predisposition of the host and differences in the viral genome may play a role in this disease.

To our knowledge, the majority of patients with PeCOHS respond to a variable combination of steroids and IVIG. The discussion about the immunomodulatory effects of both steroids and IVIG is beyond the scope of this review, but it is interesting to highlight that one of the many effects of IVIG is the down modulation of superantigens (80) . Of note, IVIG is the therapy of choice in the capillary leak syndrome, whose main features are similar to KSS and PeCOHS (81) . Finally, the efficacy of anti-IL-1 treatment as "rescue therapy" for cases resistant to IVIG+steroids points out the relevance of this pro-inflammatory cytokine in the hyperinflammatory state, similar to what already shown in adults with COVID-19 and hyperinflammation (82) .

In conclusion, although SARS-CoV-2 infection appears to occur as a oligo-symptomatic form in the majority of children, there is mounting evidence that it can cause a systemic hyperinflammatory syndrome that mimics KSS, but has some peculiar features. The role of host and virus genetics and the exact immune mechanisms leading to the disease are far from been understood, and case collection would help us in better characterization of the clinical phenotype.

As light has been shed on the interaction between SARS-CoV-2 and the immune system, we will gain hints also at Kawasaki Disease pathogenesis, almost 50 years from its first description by Tomisaku Kawasaki.

Since Patients with SLE had posed a serious concern during the Covid-19 pandemia. This group of patients is well known to bear an increased risk of severe infections, due to both their immune system and the related organ damage as well as due to the therapies used including immunosuppressive drugs. In a report of 19 SLE patients from France who were clinically quiescent on a long-term treatment with Hydroxychloroquine (HCQ) and were infected by the Covid-19 virus, the authors were able to conclude that the clinical course of these lupus patients did not show any signs of the disease exacerbation, except for a single case of tenosynovitis (85) . administration was not associated with either a greatly lowered or an increased risk of intubation or death (107) . Many similar reports came to the same conclusions (108) (109) (110) , to the extent that the FDA has issued a safety alert and the American College of Physicians has as well recommended against the use of chloroquine or HCQ for COVID-19 (111) (112) . Furthermore, an attempt to evaluate HCQ serum or plasma levels from various rheumatic disease patients receiving this treatment, found that these plasma or serum levels were unlikely to achieve the concentration 

Anakinra is a recombinant human IL-1 receptor antagonist. It is approved to treat rheumatoid arthritis and cryopyrin-associated periodic syndromes, and it is also used off-label for a variety of inflammatory conditions and severe chimeric antigen receptor T cell (CAR-T)-mediated cytokine release syndrome (CRS) and macrophage activation syndrome (MAS)/secondary hemophagocytic lymphohistiocytosis. A case series of anakinra use in moderate to severe COVID-19 pneumonia has recently been published (118) . This small study of 9 patients with moderate to severe Covid-19 pneumonia, who did not reach respiratory failure and were given anakinra (Anti-IL-1), serves as a proof of concept since all 9 patients had dropped their fever, CRP levels had dropped and normalized in 5 out of 8 patients at day 11. CT scans did not deteriorate and all were alive at the last follow up. Similar results were reached in a retrospective study from Italy of 16 patients with Covid-19 and adult respiratory distress syndrome who were J o u r n a l P r e -p r o o f managed with non-invasive ventilation outside of the ICU. Treatment with high-dose anakinra was found to be safe and associated with clinical improvement in 72% of the patients (119).

Notwithstanding the current wave of intensive worldwide research, the ethiopathology of the diseases induced by the SARS-CoV-2 infection is the central question that remains obscure. One likely explanation is that the heterogeneity and multitude of the disorders induced by the current pandemic derive from molecular mimicry phenomena between the virus and human proteins. The scientific rationale is that, following the infection, the immune responses raised against SARS-CoV-2 may cross-react with human proteins that share peptide sequences with the virus, in this way leading to autoimmune pathologic sequelae (120) . Actually, a recent report (121) militates in this direction and likely explains lungs and airways dysfunctions through the sharing of peptides between SARS-CoV-2 glycoprotein and alveolar lung surfactant proteins (121) . Moreover, in the clinical context exposed above, it is of note to report that Histone-lysine N-methyltransferase 2C SSSGWTA Transmembrane protein KIAA1109 Data on protein function/disease from Uniprot (https://www.uniprot.org/).

The extent of the molecular mimicry between SARS-CoV-2 and the human proteome should be carefully analyzed as a mandatory step preliminarily to any vaccine formulation As a matter of fact, because of the pathogen-host peptide commonality, a potential consequence of vaccination might consist of a specific autoimmune reactions hitting self-antigens such as the already analyzed alveolar surfactant protein (121) . Only peptide sequences uniquely belonging to the virus can represent the basis for safe and specific vaccinations protocols (125) (126) (127) .

J o u r n a l P r e -p r o o f Based upon the possibility to detect autoimmune reactions by morphological methods we analyzed autopsies from 18 deceased patients from COVID-19. The pathological investigation was done by using bright lineage of immunohistochemistry (CD2, 3, 5, 7, 8, 20, 31, 34, 69) . Our study allowed us to demonstrate the role of different mechanisms of death (128) . Of special interest was the diffuse infiltration of the lungs, along with focal infiltration of the kidney, liver, intestine, adrenals, pancreas and pericard by lymphocytes, which were seen in different grade in all our cases. In order to understand its nature we were able to prove that the infiltrate was dominated by T lymphocytes (CD3+), and the most numerous of them were CD8+ suppressors, observed in the lungs (fig1a), adrenals (fig1b), liver (fig1c), intestine (fig1d) and other organs partly accompanied by tissue lesions. Taking in to consideration that one of the most important mechanisms of autoimmune reactions is CD8+ T Cell mediated cytotoxicity, we assumed that the findings confirm an autoimmune process. Further complex studies will hopefully allow us to optimize the strategy of treatment as well.

J o u r n a l P r e -p r o o f 

The mosaic of autoimmunity

Reshaping the mosaic of autoimmunity

Hepatitis C virus, autoimmunity and rheumatic disease

The viral autoimmunity relationship

Viral infection can induce the production of autoantibodies

The environment in autoimmune diseases

Epstein-Barr virus and cytomegalovirus in autoimmune diseases are they truly notorious? a preliminary report

Hepatitis B virus (HBV) and autoimmune disease

Clinical and Molecular Evidence for Association of SLE with parvovirus B19

Infections as a cause of autoimmune rheumatic diseases

The autoimmunologist: geoepidemiology, a new center of gravity, and prime time for autoimmunity

Mechanisms of environmental influence on human autoimmunity: a National Institute of Environmental Health Sciences expert panel workshop

Environmental basis of autoimmunity

The role of infections in autoimmune diseases

Molecular mimicry, bystander activation, or viral persistence: infections and autoimmune disease

The role of viral infections in the development of autoimmune diseases

Epidemiology and cause of severe respiratory syndrome (SARS) in Guangdong, People's Republic of China in

Middle East respiratory syndrome coronavirus (MERS-CoV): A review

Clinical characteristics of Coronavirus disease 2019 in China

Review of the 2019 novel coronavirus (SARS-CoV-2) based on current evidence

Hyperferritinemia in autoimmunity

COVID-19 Corona Virus-disease of year 2019

Covid-19 gone bad: A new character in the spectrum of the hyperferritinemic syndrome?

Cytokine release syndrome in severe COVID-19

On the alert for cytokine storm: Immunopathology in COVID-19

Could Sars-coronavirus-2 trigger autoimmune and / or autoinflammatory mechanisms in genetically predisposed subjects?

COVID-19-induced acute respiratory failure-an exacerbation of organ-specific autoimmunity?

Clinical and autoimmune characteristics of severe and critical cases with COVID-19

Immune Thrombocytopaenic Purpura: An autoimmune cross-link between infections and vaccines

Viruses, anti-viral therapy and viral vaccines in children with immune thrombocytopenia

Immune thrombocytopenic purpura in a patient with Covid-19

Thrombocytopenia is associated with severe coronavirus disease 2019 (COVID-19) infections: a meta-analysis

Immune thrombocytopenia (ITP) in a SARS-CoV-2 positive pediatric patient

Guillain-Barrė Syndrome-A classical autoimmune disease triggered by infection or vaccination

Guillain-Barre as an autoimmune disease

Guillain-Barrė syndrome associated with SARS-CoV-2. 2020; NEJM

Guillain-Barrė syndrome associated with COVID-19 infection: A case report

Guillain-Barrė syndrome associated with SARS-CoV-2 infection: causality or coincidence?

Miller Fisher syndrome and polyneuritis cranialis in COVID-19

COVID-19 Complicated by Acute Pulmonary Embolism

Acute Cerebrovascular Disease Following COVID-19: A Single Center, Retrospective, Observational Study

Large-Vessel Stroke as a Presenting Feature of Covid-19 in the Young

Antiphospholipid syndrome

Catastrophic antiphospholipid syndrome: an update

Catastrophic antiphospholipid syndrome: lessons from the 'CAPS Registry' A tribute to the late Josep Font

A new serologically active phospholipid from beef heart

International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS)

Coagulopathy and Antiphospholipid Antibodies in Patients with Covid-19 NEJM April

Lupus anticoagulant is frequent in patients with Covid-19

Lupus Anticoagulant and Abnormal Coagulation Tests in Patients with Covid-19

Clinical Research in Intensive Care and Sepsis Trial Group for Global Evaluation and Rese arch in Sepsis). High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study

Antiphospholipid antibodies, antiph ospholipid syndrome and infections

Viral infections and antiphospholipid antibodies

Antiphospholipid Antibodies and Their Relationship With Infections, Vaccines, and Drugs in Cervera R

Bacterial induction of autoantibodies to beta-2-glycoprotein-I accounts for the infectious etiology of antiphospholipid syndrome

A peptide that shares similarity with bacterial antigens reverses thrombogenic properties of antiphospholipid antibodies in vivo

Antiphospholipid syndrome: antibodies to Domain 1 of β2-glycoprotein 1 correctly classify patients at risk

Clinical characterization of antiphospholipid syndrome by detection of IgG antibodies against β2 -glycoprotein i domain 1 and domain 4/5: ratio of antidomain 1 to anti-domain 4/5 as a useful new biomarker for antiphospholipid syndrome

Antiphospholipid antibody syndrome. From bench to bedside

Infectious origin of the antiphospholipid syndrome

Tomisaku Kawasaki's original report of fifty patients in 1967

Diagnosis, treatment, and long-term management of Kawasaki disease: A scientific statement for health professionals from the

Epidemiologic features of Kawasaki disease in Japan: Results of the 2009-2010 nationwide survey

Hospitalizations for Kawasaki syndrome among children in the United States

Describing Kawasaki shock syndrome: results from a retrospective study and literature review

COVID-19 epidemic: disease characteristics in children

The immune system of children: the key to understanding SARS-CoV-2 susceptibility?

Royal College of Pediatrics and Child Health Guidance: Paediatric multisystem inflammatory syndrome temporally associated with COVID-19

Pediatric Intensive Care Society PICS Statement: Increased number of reported cases of novel presentation of multisystem inflammatory disease

Hyperinflammatory shock in children during COVID-19 pandemic

Classification criteria for macrophage activation syndrome complicating systemic juvenile idiopathic arthritis: A European league against Rheumatism/American college of Rheumatology/Paediatric rheumatology international trials organisation collaborative initiative

An outbreak of severe Kawasaki -like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study

COVID-19 and Kawasaki Disease: Novel Virus and Novel Case

Understanding toxic shock syndrome

Kawasaki disease shock syndrome : Clinical characteristics and possible use of IL-6, IL-10 and IFN-γ as biomarkers for early recognition

Antibody-dependent SARS coronavirus infection is mediated by antibodies against spike proteins

B cells and antibodies in kawasaki disease

Diagnosis of Systemic Capillary Leak Syndrome in a Young Child Treated with Intravenous Immunoglobulin in the Acute Phase

Interleukin-1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study

Are my patients with rheumatic diseases at higher risk of COVID-19?

What does the COVID-19 pandemic mean for rheumatology patients?

Role of immunosuppressive therapy in rheumatic diseases concurrent with covid-19

Clinical course of coronavirus disease 2019 (COVID-19) in a series of 17 patients with systemic lupus erythematosus under long-term treatment with hydroxychloroquine

Rheumatic disease and COVID-19: initial data from the COVID-19 global rheumatology alliance provider registries

Covid-19 infection in a northern-Italian cohort of systemic lupus erythematosus assessed by telemedicine

Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72314 cases from the Chinese center for disease control and prevention

Clinical characteristics of coronavirus disease 2019 in China

Covid-19 in immune-mediated inflammatory diseases-Case series from New York

COVID-19 with rheumatic diseases: a report of 5 cases

Clinical course of Covid-19 in a series of patients with chronic arthritis treated with immunosuppressive targeted therapies

Incidence and clinical course of COVID-19 in patients with connective tissue diseases: a descriptive observational analysis

COVID-19 pneumonia in a large cohort of patients with biological and targeted synthetic antirheumatic drugs

Rituximab for granulomatosis with polyangiitis in the pandemic of covid-19: lessons from a case with severe pneumonia

Impact of COVID-19 pandemic on patients with large-vessel vasculitis in Italy: a moncentric survey

Correlation of chest CT and RT-PCR testing in coronavirus disease 2019 (COVID-19) in China: a report of 1014 cases

Novel COrona Virus Disease 2019 (COVID-19) epidemic: What are the risks for systemic sclerosis patients

Systemic sclerosis and the COVID-19 pandemic: World Scleroderma Foundation preliminary advice for patient management

COVID-19 in a patient with systemic sclerosis treated with tocilizumab for SSc-ILD

COVID-19) Treatment Guidelines. National Institutes of Health

American College of Rheumatology guidance for the management of adult patients with rheumatic disease during the COVID-19 pandemic

Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro

Chloroquine is a potent inhibitor of SARS coronavirus infection and spread

Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro

Continuous hydroxychloroquine or colchicines therapy does not prevent infection with SARS-CoV-2: Insights from a large healthcare database analysis

Observational study of hydroxychloroquine in hospitalized patients with Covid-19

The urgency of care during the Covid-19 pandemic-Learning as we go

Association of treatment with hydroxychloroquione or azithromycin with in-hospital mortality in patients with Covid-19 in New York State

Should clinicians use chloroquine or hydroxychloroquine alone or in combination with azithromycin for the prophylaxis or treatment of COVID-19? Living practice points from the American College of Physicians (Version 1) Ann Intern Med 2020

Hydroxychloroquine in patients with rheumatic disease complicated by COVID-19: Clarifying target exposures and the need for clinical trials

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

Clinical features of patients infected with 2019 novel coronavirus in Wuhan

Clinical features of 69 cases with coronavirus disease

Effective treatment of severe COVID-19 patients with tocilizumab

Targeting the inflammatory cascade with anakinra in moderate to severe Covid-19 pneumonia: case series

Interleukin-1 blockade with high-dose anakinra in patients with Covid-19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study

Molecular mimicry: its evolution from concept to mechanism as a cause of autoimmune diseases

On the molecular determinants of the SARS-CoV-2 attack

ITPKC functional polymorphism associated with Kawasaki disease susceptibility and formation of coronary artery aneurysms

Disrupted intricacy of histone H3K4 methylation in neurodevelopmental disorders

IL-7 and lymphopenia

Peptide cross-reactivity: the original sin of vaccines

Self-nonself" peptides in the design of vaccines

From HBV to HPV: Designing vaccines for extensive and intensive vaccination campaigns worldwide

Issues of pathology of a new coronavirus infection COVID-19