The coronavirus disease-19 pandemic (COVID-19), which appeared in China in December 2019 and rapidly spread throughout the world, has forced clinicians and scientists to take up extraordinary challenges. This unprecedented situation led to the inception of numerous fundamental research protocols and many clinical trials. It quickly became apparent that although COVID-19, in the vast majority of cases, was a benign disease, it could also develop a severe form with sometimes fatal outcomes. Cytokines are central to the pathophysiology of COVID-19; while some of them are beneficial (type-I interferon, interleukin-7), others appear detrimental (interleukin-1β, -6, and TNF-α) particularly in the context of the so-called cytokine storm. Yet another characteristic of the disease has emerged: concomitant immunodeficiency, notably involving impaired type-I interferon response, and lymphopenia. This review provides an overview of current knowledge on COVID-19 immunopathology. We discuss the defective type-I IFN response, the theoretical role of IL-7 to restore lymphocyte repertoire, as well as we mention the two patterns observed in severe COVID-19 (i.e. interleukin-1β-driven macrophage activation syndrome vs. interleukin-6-driven immune dysregulation). Next, reviewing current evidence drawn from clinical trials, we examine a number of cytokine and anti-cytokine therapies, including interleukin-1, -6, and TNF inhibitors, as well as less targeted therapies, such as corticosteroids, chloroquine, or JAK inhibitors
It is not yet known whether immunomodulatory treatments used in patients with autoimmune and rheumatic diseases are associated with better or poorer outcomes over the course of COVID-19. We report the case of a recovery from COVID-19 in a 60-year-old immunocompromised man, treated with tumour necrosis factor-alpha (TNF-α) inhibitor (the soluble TNF receptor: etanercept 50mg, subcutaneous, weekly) and methotrexate (20mg subcutaneous, weekly), for spondyloarthritis. One week after the categorisation of eastern France as a new cluster of COVID-19 and 2days after the weekly subcutaneous injection of 50mg etanercept, the patient developed fever (up to 39°C), cough, myalgias and diarrhoeas. Five days after the onset of symptoms, the patient was referred to the local emergency department where the SARS-CoV2 was detected by realtime reverse transcription (RT)-PCR on a nasopharyngeal swab. There was no sign of respiratory distress and the patient did not require intensive care unit. Blood tests did not show leucopenia or lymphopenia with 4.12 x 109 /L leucocytes and 1.04 x 109 /L lymphocytes, respectively. C-reactive protein (CRP) level was 63 mg/L; procalcitonin was 0.06µg/L. The chest X-ray did not show alveolar or interstitial opacity. Thoracic CT scan was not performed. The treatment consisted of intravenous paracetamol without the need of antiviral drugs, steroids, antibiotics or intravenous immunoglobulins. In addition, no respiratory support was needed over the whole hospitalisation period. The outcome was favourable with regression of fever, cough and myalgias at day 10, along with a decrease of the CRP reaching 16mg/L.
At this stage of the epidemic and given the limited resources for RT-PCR testing, systematic viral monitoring was not performed. The patient was discharged at day 14. In our observation, the use of a TNF-α inhibitor prior to the viral infection was not associated with a severe evolution of the COVID-19.
Increased inflammatory cytokines [such as tumor necrosis factor alpha (TNFα) and interleukin-6 (IL-6)] are observed in COVID-19 patients, especially in the severe group. The phenomenon of a cytokine storm may be the central inducer of apoptosis of alveolar epithelial cells, which leads to rapid progression in severe group patients. Given the similarities of clinical features and pathogenesis between toxic epidermal necrolysis (TEN) and COVID-19, we hypothesize that the application of etanercept, an inhibitor of TNFα, could attenuate disease progression in severe group COVID-19 patients by suppressing systemic auto-inflammatory responses.
BACKGROUND: In this pandemia, it is essential for rheumatologist and patients to know the relationship between COVID-19 and inflammatory rheumatic diseases (IRD). We want to assess the role of targeted synthetic or biologic disease modifying antirheumatic drugs (ts/bDMARDs) and other variables in the development of moderate-severe COVID-19 disease in IRD.
METHODS: An observational longitudinal study was conducted (1stMar to 15thApr 2020). All patients from the rheumatology outpatient clinic from a hospital in Madrid with a medical diagnosis of IRD were included. Main outcome: hospital admission related to COVID-19. Independent variable: ts/bDMARDs. Covariates: sociodemographic, comorbidities, type of IRD diagnosis, glucocorticoids, NSAIDs and conventional synthetic DMARDs (csDMARDs). Incidence rate (IR) of hospital admission related to COVID-19, was expressed per 1,000 patients-month. Cox multivariate regression analysis was run to examine the influence of ts/bDMARDs and other covariates on IR. Results: 3,591 IRD patients were included (5,896 patients-month). Concerning csDMARDs, methotrexate was the most used followed by antimalarials. 802 patients were on ts/bDMARDs, mainly anti-TNF agents, and rituximab. Hospital admissions related to COVID-19 occurred in 54 patients (1.36%) with an IR of 9.15 [95%CI: 7-11.9]. In the multivariate analysis, older, male gender, presence of comorbidities and specific systemic autoimmune conditions (Sjoegren, polychondritis, Raynaud and mixed connective tissue disease) had more risk of hospital admissions regardless other factors. Exposition to ts/bDMARDs did not achieve statistical signification. Use of glucocorticoids, NSAIDs, and csDMARDs dropped from the final model.
CONCLUSION: This study provides additional evidence in IRD patients regarding susceptibility to moderate-severe infection related to COVID-19.
CONTEXT AND OBJECTIVE: We propose to systematically review the available evidence to evaluate if patients with immune mediated inflammatory diseases under pharmacological treatment with immunosuppressants, immunobiologics, Disease-Modifying Anti-Rheumatic Drugs (DMARD) or targeted synthetic DMARDs have better or worse outcomes when infected by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). This study is a protocol for our rapid living systematic review.
METHODS: Protocol for a rapid living systematic review methodology following the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) guidance. To conduct the rapid systematic review, we will employ abbreviated systematic review methods, including: not performing independent screens of abstracts and not searching grey literature. As this will be a living review, it will be continuously updated.
Patients on a tumor necrosis factor inhibitor for their rheumatic disease when they became infected with COVID-19 were markedly less likely to subsequently require hospitalization, according to intriguing early evidence from the COVID-19 Global Rheumatology Alliance Registry.
She presented soon-to-be-published data on the characteristics and disposition of the first 600 patients, 46% of whom were hospitalized and 9% died. A caveat regarding the registry, she noted, is that these are observational data and thus potentially subject to unrecognized confounders. Also, the registry population is skewed toward the sicker end of the COVID-19 disease spectrum because while all participants have confirmed infection, testing for the infection has been notoriously uneven. Many people are infected asymptomatically and thus may not undergo testing even where readily available.
Acute respiratory distress syndrome (ARDS) in Covid-19 patients can lead to death, owing to alveolar damage from lung inflammation, and as such, prevention of ARDS in Covid-19 patients could help decrease the mortality impact of coronavirus. A retrospective study in Wuhan, China, observed that 17% of 99 coronavirus pneumonia patients developed ARDS. Established anti-tumor necrosis factor (TNF) therapies such as Remicade (infliximab) and Humira (adalimumab) have a proven track record of decreasing inflammation in inflammatory diseases such as rheumatoid arthritis (RA) and inflammatory bowel disease (IBD), and could potentially treat coronavirus patients who develop ARDS, due to the inflammatory excess that occurs in patients with Covid-19.
There is evidence of inflammation due to capillary leakage in the lung and recruitment of cytokines and macrophages in Covid-19 patients. Patients in intensive care units have displayed an increase in the concentration of several cytokines, as Covid-19 causes an up-regulation of pro-inflammatory cytokines such as TNF, interleukin (IL)-6, interferon γ, and IL-1.
Results from pre-clinical studies of mice with severe respiratory syncytial virus (RSV) and influenza have shown that anti-TNF therapy helps to improve symptoms, which suggests a potential rationale for anti-TNF therapy in viral pneumonia. In RA patients, if TNF is blocked there is a decrease in the concentrations of cytokines such as IL-6 and IL-1, and these theories could mean that decreasing lung inflammation with anti-TNFs in Covid-19 patients could prove beneficial.
Given the preliminary evidence to date, the proposed patient group for anti-TNF therapy would be those in a clinical trial setting with moderate disease and requiring oxygen support but who will not be admitted to intensive care.
Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV-2) with the symptoms including fever, dry cough and shortness of breath. Most COVID-19 patients will develop mild to moderate symptoms, while some infected people may face to hyper-inflammation induced by massive cytokines/chemokines production, called as cytokine storm, which may lead to fatal pneumonia and acute respiratory distress syndrome.
Although, there is no specific antiviral therapy for COVID-19, understanding of cytokine storm mechanism in this disease can help to speculate possible therapeutic interventions. Current reports have presented different cytokine profiles in patients with severe COVID-19. For example, the higher levels of interleukin (IL)-2, IL-7, IL-10, tumor necrosis factor (TNF), granulocyte-colony stimulating factor (G-CSF), interferon gamma-induced protein 10 (IP-10; CXCL10), MCP-1 (CCL2) and MIP-1A (CCL3), but not IL-6, have been first shown in intensive care unit (ICU) patients compared to non-ICU patients.
In most existing reports, the elevated levels of several cytokines/ chemokine (ie., IL-6, IL-10, IFN-γ, TNF and IP-10), have been greater emphasized in severely ill (ICU) COVID-19 patients than mild to moderate (non-ICU) group.
TNF acts upstream of IL-6 and anti-TNF therapies previously revealed protective effects in lethal SARS-CoV infection. Several TNF-blocking antibodies (eg., adalimumab, etanercept, and golimumab) are successfully used to treat inflammatory diseases, and these therapies have been urgently recommended for the hospitalized COVID-19 patients.
In some countries, including Iran and Turkey, tocilizumab is a recommended therapeutic strategy for ICU patients with severe COVID-19. However, it should be note that the elevated IL-6 levels, in common with other cytokines such as TNF, have no specific pattern in all severe COVID-19 patients, so that their levels were not associated with the disease severity in some patients. Therefore, as patients with severe COVID-19 represent the differential cytokine patterns, more care should be taken before immunosuppressive therapy by cytokine blockers in COVID-19. This is important that the doctors evaluate a cytokine panel, at least including IL-6, IFN-γ, and TNF-α, to precisely identify the needs of each patient before administration of selective immunosuppressive therapy. Obviously, a combination of immunosuppressive therapy with antiviral therapies that diminish virus titer should be also into account.
OBJECTIVES: To investigate the incidence of COVID-19 in a cohort of adult and paediatric patients with rheumatic diseases receiving targeted biologic and synthetic disease modifying anti-rheumatic drugs (tDMARDs) and to explore the possible effect of these treatments in the clinical expression of COVID-19.
METHODS: A cross-sectional study comprising of a telephone survey and electronic health records review was performed including all adult and paediatric patients with rheumatic diseases treated with tDMARDs in a large rheumatology tertiary centre in Barcelona, Spain. Demographics, disease activity, COVID-19 related symptoms and contact history data were obtained from the start of the 2020 pandemic. Cumulative incidence of confirmed cases (SARS-CoV-2 positive PCR test) was compared to the population estimates for the same city districts from a governmental COVID-19 health database. Suspected cases were defined following WHO criteria and compared to those without compatible symptoms.
RESULTS: 959 patients with rheumatic diseases treated with tDMARDs were included. We identified 11 confirmed SARS-CoV-2 positive cases in the adult cohort and no confirmed positive cases in the paediatric cohort. All patients had a successful recovery and only one patient required admission in the intensive care unit. When using the same classification criteria (only COVID-19 positive cases with pneumonia), COVID-19 incidence rates of the rheumatic patient cohort were very similar to that of the general population [(0.48% (95% CI 0.09 to 8.65%)] and [0.58% (95% CI 5.62 to 5.99%)], respectively. We found significant differences in tDMARDs proportions between the suspected and non-suspected cases (p=0.002).
CONCLUSION: Adult and paediatric patients with rheumatic diseases on tDMARDs do not seem to present a higher risk of COVID-19 or a more severe disease outcome when compared to general population. Our exploratory analysis suggests that the proportion of COVID-19 suspected cases differs between tDMARDs.