key: cord-0946624-skydt0yb
authors: Sattui, Sebastian E.; Crow, Mary K.; Navarro-Millán, Iris
title: The role of immunomodulatory medications in the treatment of COVID-19
date: 2021-07-08
journal: Curr Opin Rheumatol
DOI: 10.1097/bor.0000000000000817
sha: aed9bdb19701a0461eb7fb499ecb3e812197b5ba
doc_id: 946624
cord_uid: skydt0yb

Given the role of inflammation in severe forms of COVID-19, glucocorticoids and disease-modifying antirheumatic drugs (DMARDs) have been assessed as potential COVID-19 therapies. RECENT FINDINGS: Randomized controlled trials (RCTs) have shown that glucocorticoids reduce mortality in severe COVID-19. RCTs of DMARDs have shown mixed results varying on intervention and inclusion criteria. DMARDs, including colchicine or biologic agents, may improve COVID-19 outcomes in specific patient populations. SUMMARY: Glucocorticoids are an effective treatment for the management of severe COVID-19. Further studies are needed to better define the patient populations who could benefit from DMARD use, as well as provide guidance regarding the timing of these interventions.

The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory coronavirus (SARS-CoV-2), has led to an unprecedented global health crisis with over 170 million confirmed cases and over 3.7 million deaths as of June 2021 [1] . The severe forms of COVID-19, a hyperinflammatory syndrome characterized by lymphopenia and elevated transaminases, lactate dehydrogenase (LDH), ferritin, D-dimers, as well as elevated inflammatory markers such as C-reactive protein (CRP), interleukin-6 (IL-6), tumor-necrosis factor (TNF)-" and IL-8 have been described [2,3 & ,4]. Some of these features have been identified as poor prognostic factors in patients with COVID-19, independent of other wellestablished risk factors such as older age, male sex, obesity, and increased comorbidity burden.

Given the resemblance to other hyperinflammatory conditions such as macrophage activation syndrome (MAS), also known as secondary hemophagocytic lymphohistiocytosis (HLH), or chimeric antigen receptor (CAR) T-cell induced cytokine release syndrome (CRS), several immunosuppressive therapies have been and are currently being investigated for the treatment of severe COVID-19. The aim of this review is to summarize data, primarily from randomized clinical trials, regarding the use of immunosuppressive treatments, including glucocorticoids, and disease-modifying antirheumatic drugs (DMARDs) for the treatment of COVID-19 up to May 30th, 2021.

Infection of cells expressing angiotensin-converting enzyme 2 receptors by SARS-CoV-2 represents the initial phase of the disease [5] . The later stage, which is characterized by increased production of proinflammatory cytokines and chemokines such as IL-1, IL-6, TNF-a, and IL-8, mediates organ damage and failure leading to death in severe COVID-19 [6 & ,7] . It is important to note that this two-phase approach is simplistic and that these processes occur concomitantly, resulting in infection of endothelial cells,

The initial therapeutic approach to COVID-19 hyperinflammatory state was based on previous experiences with other hyperinflammatory syndromes such as MAS/HLH. However, recent studies comparing characteristics between these two conditions have highlighted some differences. Compared to MAS/ HLH, which is characterized by activation of an IL-18-interferon-g axis, COVID-19 hyperinflammatory state is characterized by elevation of IL-1 receptor antagonist, intracellular adhesion molecule 1, and IL-8, as well as reduced levels of soluble Fas ligand [10] . Also, a study evaluating patients with COVID-19 hyperinflammation showed that they did not fulfill MAS/HLH classification criteria such as the HScore and 2004-HLH diagnostic criteria, despite having evident hyperinflammation features [11] .

Two different sets of criteria for COVID-19 hyperinflammatory states have been proposed and validated (Table 1) [12 && ,13 && ]. In both studies, criteria identified patients at increased risk of prolonged hospitalization, mechanical ventilation, or death. Further studies are needed to better understand the ability of these criteria to discriminate potential benefits of anti-inflammatory therapy. Recently, these criteria have shown an association with hyperinflammation and worse outcomes in patients with rheumatic diseases [14 & ].

Glucocorticoids Given the lack of benefits of glucocorticoids in infection-associated syndromes such as influenza, septic shock, and acute respiratory distress syndrome (ARDS), there was significant hesitancy regarding their use in patients with SARS-CoV-2 infection [15] . However, glucocorticoids were used from very early in the pandemic and observational studies showed mixed results [16] . Beneficial effects of dexamethasone for the treatment of severe COVID-19 were initially shown by the RECOVERY trial [17 & ] . In this open-label

In patients with COVID-19 infection and oxygen requirements, glucocorticoids are associated with improved outcomes including mortality.

Most recent randomized trials using IL-6 inhibitors have shown improvement in outcomes in patients with severe COVID-19 infection.

Further studies are needed to clarify the role of other DMARDs for the treatment of COVID-19, including the specific patient populations that would benefit from such interventions. [23 & ]. It is important to note that despite this encouraging data, registry studies of patients with autoimmune disease and baseline glucocorticoid use have shown an increased risk of severe COVID-19 with higher doses of glucocorticoids. Data from the COVID-19 Global Rheumatology Alliance (GRA) showed increased risks of both hospitalization and death in patients with baseline prednisone doses of 10 mg or higher [24,25 && ]. Limitations to these registries, such as confounding by indication, limit the ability to fully disentangle these associations. However, these data, especially in conjunction with the RECOVERY findings in patients not on ventilatory support, may suggest that timing of intervention might be critical and that use of glucocorticoids could have a different effect depending on the phase of the disease.

Due to its ability to inhibit the NLRP3 inflammasome, leading to suppression of IL-1b, IL-18, and IL-6, colchicine has been proposed as a potential therapeutic for noncritically ill patients with COVID-19 [26] . An Italian cohort study using historical comparators receiving SOC, showed that patients treated with colchicine had a lower risk of death (hazard ratio (HR) 0.15 [95% CI 0.06-0.37]) [27] . Similar results were observed in another Italian single-center propensity score-matched cohort study, showing improving odds of discharge at day 28 and decreased overall mortality (9.1% vs 33.3%, OR 0.20 [95% CI 0.05-0.80]) [28] .

An initial open-label RCT from Greece, the Greek Effects of Colchicine in COVID-19 trial, compared colchicine vs SOC in 105 hospitalized COVID-19 patients [29] . The primary outcome, time to deterioration by 2 points in World Health Organization-Clinical Progression Scale (WHO-CPS), was longer in the colchicine arm compared to SOC (20.7 days vs 18.6 days, P ¼ 0.03). No difference was observed in the other primary endpoints, including peak high-sensitivity troponin or resolution of CRP levels. Note that more clinically relevant outcomes would have been 30 and 60-day survival as the course of the disease was very heterogeneous and none of these parameters helped predict those at high risk of dying. Most recently, results from the Colchicine for community-treated patients with COVID-19 (COLCORONA) trial, were published [30 & ]. In this multicenter RCT of 4488 patients with suspected or confirmed COVID-19 diagnosis, colchicine was administered at a dose of 0.5 mg twice per day for 3 days and later 0.5 mg daily for 27 days vs placebo. In the primary composite outcomes of hospitalization or death, a nonstatistically significant difference was observed (4.7% vs 5.8%, OR 0.79 [95% CI 0.61-1.03]). However, in the prespecified subgroup analysis of 4159 patients with PCR-confirmed COVID-19, a significant decrease in the primary endpoint was observed in patients treated with colchicine (4.6% vs 6.0%, OR 0.75 [95% CI 0.57-0.99]). This yielded a number needed to treat (NNT) of 70 (95% CI 36-1842). Except for a higher incidence of pulmonary embolism in the treatment arm, there were no differences in serious adverse events. The trial was terminated early due to logistical issues therefore potentially underpowering the conclusions. Although its use in high-risk patients might be convenient due to simple route of administration, low cost and relatively safe profile, the potential benefit on mortality is still unclear and will be hopefully clarified by several ongoing trials.

The initial associations between IL-6 elevation and COVID-19 severity sparked interest in the use of IL-6 inhibitors for the treatment of severe COVID-19. Initial observational studies showed promising results, and a meta-analysis including 16 studies showed a decreased risk of death (pooled OR 0.57 [95% CI 0.36-0.92]) associated with the use of tocilizumab (TCZ) compared to SOC [31] . Significant heterogeneity among studies was noted. Importantly, several of these studies focused on specific selection criteria that included documented infection with respiratory failure and markers of inflammation (e.g., CRP, ferritin) [32] .

Despite encouraging data from observational studies, early RCTs did not confirm these earlier (Table 3 ). The CORIMUNO-19 and COVACTA trials, which did not include inflammatory criteria for inclusion, failed to meet their primary endpoints [33, 34] . The RCT-TCZ-COVID-19 and BACC BAY trials, which did include inflammatory criteria for inclusion, were potentially underpowered due to early stoppage or an unexpected low number of events, respectively [35, 36] . More recent and larger RCTs, where most patients enrolled were also receiving background glucocorticoid treatment, have shown more positive results with regards to the use of IL-6 inhibition in severe COVID-19. The EMPACTA trial, which included 389 patients, showed a 44% decreased risk (HR 0.56 [95% CI 0.33-0.97]) of the composite outcomes of mechanical ventilation or death associated with the use of TCZ [37] . No improvement in all-cause death was observed. In the REMAP-CAP trial, that randomized patients to either TCZ, sarilumab or placebo, an improvement in organ support-free days and increased survival at 90 days were seen for both IL-6 inhibitors [38 & ]. These results have been also confirmed by more recent trials including the RECOVERY trial. In the TCZ intervention arm from the RECOVERY adaptive platform, where 4116 patients were randomized to either TCZ or SOC, the risk of all-cause death was lower in patients treated with TCZ (adjusted RR 0.85 [95% CI 0.76-0.94]) [39 && ]. Decrease in time to discharge and composite of mechanical ventilation and death was also lower in the intervention arm. These new findings, therefore, suggest benefits from the use of IL-6 inhibition, in addition to background glucocorticoid treatment, in patients with elevated markers of inflammation.

Transcriptomic analysis of whole blood of COVID-19 patients showed increasing expression IL-1a and IL-1b prior to the nadir of respiratory function, unlike other proinflammatory cytokines [40] . Also, given the clinical similarities between cytokine storm syndromes and COVID-19 hyperinflammation, use of IL-1 inhibitors for the treatment of severe COVID-19 was considered early in the pandemic [41] [42] [43] [44] .

Early case series and cohort studies suggested improvement in clinical outcomes of severe COVID-19 with anakinra, an IL-1 receptor antagonist. In a meta-analysis of two large cohort studies, anakinra was associated with a lower risk of mortality (pooled HR 0.2 [95% CI 0.1-0.4]) [16] . Despite these encouraging results, RCTs have not supported these observations ( Table 4 ). The CORIMUNO-ANA-1 trial, a French multicenter open-label study, randomized patients to intravenous anakinra (200 mg BID on days 1-3, 100 mg BID on day 4, and 100 mg once on day 5) Role of immunomodulatory medications Sattui et al. ]. The study was stopped early by recommendation of the data safety monitoring board, and no differences were found in the primary outcomes of improvement in clinical status at day 4 or need for mechanical ventilation or death at day 14. The Anakinra for COVID- 19 Respiratory Symptoms (ANACONDA) study was also stopped early due to concern for worse outcomes in the intervention arm [46] . Results of this study are not available. Interestingly, a Greek open-label interventional study that allocated treatment with anakinra to patients with COVID-19 and elevated levels of soluble urokinase plasminogen activator receptor (suPAR) showed a decrease in mechanical ventilation in patients treated with anakinra [47] .

Treatment with canakinumab, an ILb inhibitor, has also been assessed in small case series and in larger studies. The CAN-COVID study, a phase 3 trial, randomized patients to either canakinumab or SOC [48] . Although results of the study have not been published, a press release in November 2020 announced that the study did not achieve its primary endpoint of improvement in survival without mechanical ventilation at day 28. Currently, the role of IL-1 inhibitors for the treatment of COVID-19 is not clear, and hopefully ongoing phase 3 clinical trials will better clarify this point.

Based on observations of elevated TNF-" levels in patients with severe COVID-19, there is growing interest regarding the use of TNF-inhibitors for the treatment of COVID-19 [49] . In fact, a role for TNF inhibition in animal models of other viral lung diseases such as influenza has been proposed [50] . These mechanistic observations have also been reinforced by lower odds of severe COVID-19 in patients on baseline TNF-inhibitors such as rheumatic and inflammatory bowel disease patients [51 & ]. Currently, five ongoing trials utilizing infliximab in hospitalized COVID-19 patients and one using adalimumab in ambulatory COVID-19 patients are ongoing (Table 5 ). 

For the treatment of COVID-19 infection, JAK inhibitors have two proposed mechanisms of action: inhibition of viral entry to cells through disruption of AAK1 and decreased signaling of pro-inflammatory cytokines, such as IL-2, IL-6, and IFN-g, through inhibition of the JAK-STAT pathway [9, 52] . A metaanalysis of observational studies using baricitinib and ruxolitinib for the treatment of COVID-19 showed lower odds of mortality, ICU admission, and higher odds of discharge associated with treatment. It is important to note that studies included were observational and presented significant heterogeneity [53] . The Adaptive COVID-19 Treatment Trial 2 was the first published double-blind RCT comparing baricitinib against placebo (with background remdesivir) [54 && ] . In this trial of 1033 hospitalized patients, those treated with baricitinib had a shorter time to recovery (7 vs 8 days, P ¼ 0.03) and higher odds of clinical improvement (OR 1.3 [95% CI 1.0-1.6]). A nonsignificant trend toward lower mortality at day 28 was also noted. Most recently, the preprint results of a large global RCT of 1525 hospitalized patients showed no difference in its primary outcome of reduction of disease progression (OR 0.86 [95% CI 0.67-10.8]) [55] . However, a 38.2% reduction in mortality was observed in all prespecified groups. In both trials, no difference in venous thromboembolic events was noted.

Interestingly, similar to glucocorticoids, baseline use of JAK inhibitors has been associated with worse COVID-19 outcomes. A recent analysis of a large cohort of rheumatoid arthritis (RA) patients showed that use of JAK inhibitors was associated with a higher risk of worse COVID-19 severity (OR 1.52 [95% CI 1.02-2.28]) compared to TNF inhibitors [56 & ]. These findings may be associated with inhibition of the interferon pathway which is necessary for the clearance of viral infections, and may also speak to the importance of timing of the intervention. Results from the ongoing trial will provide further information regarding the use of these drugs for the treatment of COVID-19 (Table 6 ).

Granulocyte-monocyte colony stimulating factor (GM-CSF) inhibiting therapies are currently being studied for the treatment of rheumatic diseases such as RA and giant cell arteritis [57, 58] . GM-CSF has been associated with severe COVID-19, and elevated levels have been associated with markers of endothelial injury and thrombosis [59] . Bronchoalveolar lavage fluid analysis from patients with severe COVID-19 has shown high levels of Th-17 cells associated with an overexpression of GM-CSF and IL-17A [60] .

An initial study with lenzilumab (600 mg IV for three doses) in 12 patients with severe COVID-19 showed a faster improvement in clinical outcomes when compared to a matched control cohort receiving SOC (5 days vs 11 days, P ¼ 0.06) [61] . Although clinical improvement was similar in both groups, the proportion of patients with ARDS was also reduced with lenzilumab treatment. The first published RCT assessing the use of a GM-CSF inhibitor, mavrilimumab, randomized patients to mavrilimumab vs SOC [62] . The Mavrilumab in patients with severe COVID-19 pneumonia and systemic hyperinflammation (MASH-COVID) study included hospitalized patients with COVID-19 pneumonia, hypoxemia, and CRP > 5 mg/dl. The primary outcome of survival without supplementary oxygen at day 14 was not different between the two groups (57% vs 47%, OR 1.48 [95% CI 0. 43-5.16] . The results of this study were underpowered due to early termination after slow recruitment. Preprint results of two larger trials, LIVE-AIR (with lenzilumab) and OSCAR (otilimab), and ongoing studies will further clarify the role of GM-CSF inhibitors as treatment options for severe COVID-19 [63, 64] .

Complement activation has been shown to play a central role in the pathophysiology of both ARDS and macrovascular thrombosis. Endothelial injury secondary to activation of anaphylatoxins (C3a, C4a, and C5a) is a key component in the pathway of both of these complications [65 & ]. Even more so, increased complement activation seems to be a distinctive feature of severe COVID-19 as shown by significant elevation of circulating markers of complement activation when compared to patients with other critical conditions, including influenza infection [66] .

Use of eculizumab, a C5 inhibitor, for the treatment of severe COVID-19 has been described in several case reports. Eculizumab (900 mg, 2 doses) in addition to SOC was associated with recovery of four patients with severe COVID-19 [67] . In a nonrandomized controlled study of 80 patients with severe COVID-19, 35 patients treated with eculizumab vs 45 patients receiving SOC, patients treated with eculizumab had a higher survival at day 15 (82.9% vs 62.2%, P ¼ 0.04) [68] . A phase 2 trial of IFX-1, a C5a inhibitor, showed no difference in its primary outcome of percentage change in PaFIO2, but showed a nonsignificant trend toward improved survival and decreased pulmonary embolisms [69] . Further knowledge of anticomplement therapies, including identification of biomarkers of patients who would benefit from these, are needed.

The unprecedented challenge of the global COVID-19 pandemic has rightfully monopolized the attention of the entire medical field. The hyperinflammatory features of severe COVID-19, somehow resembling those of rheumatic and cytokine storm syndromes, have placed both rheumatologists and the immunomodulatory medications used for the treatment of rheumatic diseases in a unique position. The successful use of glucocorticoids such as dexamethasone for the ]. Challenges to research during the COVID-19 pandemic have also left several valuable lessons that should be incorporated in future scenarios. As shown in this review, discordant results of trials assessing the same drug could be potentially explained by lack of uniform selection criteria, changes in definitions of SOC or changes in timing, dosages or duration of interventions. Understandably, the dynamic nature of the pandemic and knowledge generated has led to some of these limitations. However, coordinated efforts such as the RECOVERY adaptive trial platform have led to invaluable knowledge.

Although glucocorticoids have an established role in the treatment of severe COVID-19, other immunomodulatory therapies such as JAK inhibitors, particularly baricitinib, and IL-6 might require further studies despite some encouraging results. Particularly, studies are needed to better identify patients who would benefit from these interventions. Hopefully, ongoing RCTs or studies utilizing proposed COVID-19 hyperinflammatory phenotypic criteria will shed some light on this matter as well the role of other DMARDs such as IL-1, GM-CSF and complement inhibitors. Although approved vaccines are helping to mitigate the pandemic, the need to identify better treatment options for patients with severe COVID-19 and complications such as COVID-19 hyperinflammation remains crucial.

Financial support and sponsorship None. 

Cytokine storms: understanding COVID-19

COVID-19 illness in native and immunosuppressed states: a clinical-therapeutic staging proposal

Distribution of ACE2, CD147, CD26, and other SARS-CoV-2 associated molecules in tissues and immune cells in health and in asthma, COPD, obesity, hypertension, and COVID-19 risk factors

Clinical and immunological features of severe and moderate coronavirus disease

This article describes the differences in immunological features between moderate and severe COVID

Cytokine release syndrome in severe COVID-19

COVID-19 cytokine storm: the interplay between inflammation and coagulation

Baricitinib, a drug with potential effect to prevent SARS-COV-2 from entering target cells and control cytokine storm induced by COVID-19

Discrimination of COVID-19 from inflammation-induced cytokine storm syndromes by disease-related blood biomarkers

Cytokine release syndrome is not usually caused by secondary hemophagocytic lymphohistiocytosis in a cohort of 19 critically ill COVID-19 patients

Preliminary predictive criteria for COVID-19 cytokine storm

Proposed set of criteria and validation for evaluation of COVID-19 cytokine storm

Clinical criteria for COVID-19-associated hyperinflammatory syndrome: a cohort study

Proposed set of criteria and validation for evaluation of COVID-19 cytokine storm

Laboratory trends, hyperinflammation, and clinical outcomes for patients with a systemic rheumatic disease admitted to hospital for COVID-19: a retrospective, comparative cohort study

Study evaluating features of hyperinflammation and association with outcomes in patients with rheumatic diseases

On the use of corticosteroids for 2019-nCoV pneumonia

Antirheumatic disease therapies for the treatment of COVID-19: a systematic review and meta-analysis

Dexamethasone in hospitalized patients with Covid-19

RECOVERY trial showing benefit of glucocorticoids in the treatment of COVID-19

Effect of hydrocortisone on mortality and organ support in patients with severe COVID-19: The REMAP-CAP COVID-19 corticosteroid domain randomized clinical trial

Methylprednisolone in adults hospitalized with COVID-19 pneumonia: An open-label randomized trial (GLUCOCOVID)

Effect of hydrocortisone on 21-day mortality or respiratory support among critically ill patients with COVID-19: a randomized clinical trial

Methylprednisolone or dexamethasone, which one is superior corticosteroid in the treatment of hospitalized COVID-19 patients: a triple-blinded randomized controlled trial

Effect of dexamethasone on days alive and ventilator-free in patients with moderate or severe acute respiratory distress syndrome and COVID-19: The CoDEX Randomized Clinical Trial

Association between administration of systemic corticosteroids and mortality among critically ill patients with COV-ID-19: a meta-analysis

Systematic review and meta-analysis of RCT showing benefit of glucocorticoids for the treatment of COVID-19

Epidemiology and outcomes of novel coronavirus 2019 in patients with immune-mediated inflammatory diseases

Factors associated with COVID-19-related death in people with rheumatic diseases: results from the COVID-19 Global Rheumatology Alliance physician-reported registry

Study describing poor prognostics factors for patients with rheumatic diseases from the COVID-19 GRA registry

Anti-inflammatory therapy for COVID-19 infection: the case for colchicine

Association between treatment with colchicine and improved survival in a single-centre cohort of adult hospitalised patients with COVID-19 pneumonia and acute respiratory distress syndrome

Colchicine to weather the cytokine storm in hospitalized patients with COVID-19

Effect of colchicine vs standard care on cardiac and inflammatory biomarkers and clinical outcomes in patients hospitalized with coronavirus disease

Colchicine for community-treated patients with COVID-19 (COLCORONA): a phase 3, randomised, doubleblinded, adaptive, placebo-controlled, multicentre trial

RCT using colchicine for the community-treated patients with COVID-19

Addition of tocilizumab to the standard of care reduces mortality in severe COVID-19: a systematic review and meta-analysis

Interleukin-6 blockade with sarilumab in severe COVID-19 pneumonia with systemic hyperinflammation: an open-label cohort study

Effect of tocilizumab vs usual care in adults hospitalized with COVID-19 and moderate or severe pneumonia: a randomized clinical trial

Tocilizumab in hospitalized patients with severe Covid-19 pneumonia

Efficacy of tocilizumab in patients hospitalized with Covid-19

Effect of tocilizumab vs standard care on clinical worsening in patients hospitalized with COVID-19 pneumonia: a randomized clinical trial

Tocilizumab in patients hospitalized with Covid-19 pneumonia

Interleukin-6 receptor antagonists in critically ill patients with Covid-19

REMAP-CAP trial showing benefit of IL-6 inhibition for the treatment of COVID-19

Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

RECOVERY study showing benefit of addition to tocilizumab for the treatment of COVID-19

A dynamic immune response shapes COVID-19 progression

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

Anakinra for severe forms of COVID-19: a cohort study

Blockage of interleukin-1b with canakinumab in patients with Covid-19

Use of anakinra to prevent mechanical ventilation in severe COVID-19: a case series

Effect of anakinra versus usual care in adults in hospital with COVID-19 and mild-to-moderate pneumonia (COR-IMUNO-ANA-1): a randomised controlled trial

RCT showing lack of efficacy of anakinra in the treatment of COVID-19

Anakinra for COVID-19 Respiratory Symptoms (ANACONDA)

Novartis provides update on CAN-COVID trial in hospitalised patients with COVID-19 pneumonia and cytokine release syndrome (CRS)

Cytokine release syndrome: inhibition of pro-inflammatory cytokines as a solution for reducing COVID-19 mortality

Inhibition of tumor necrosis factor reduces the severity of virus-specific lung immunopathology

The potential for repurposing anti-TNF as a therapy for the treatment of COVID-19

Article highlighting rationale for the use of TNF-inhibitors in COVID-19

Baricitinib restrains the immune dysregulation in patients with severe COVID-19

JAK-inhibitor and type I interferon ability to produce favorable clinical outcomes in COVID-19 patients: a systematic review and meta-analysis

Baricitinib plus remdesivir for hospitalized adults with Covid-19

RCT showing benefit of baricitinib in treatment of COVID-19

Baricitinib plus standard of care for hospitalized adults with

Associations of baseline use of biologic or targeted synthetic DMARDs with COVID-19 severity in rheumatoid arthritis: Results from the COVID-19 Global Rheumatology Alliance physician registry

Study showing baseline use of JAK inhibitors associated with worse COVID-19 outcomes in patients with rheumatic diseases

Targeting granulocyte-monocyte colonystimulating factor signaling in rheumatoid arthritis: future prospects

Efficacy, patient-reported outcomes, and safety of the antigranulocyte macrophage colony-stimulating factor antibody otilimab (GSK3196165) in patients with rheumatoid arthritis: a randomised, phase 2b, dose-ranging study

Inflammatory profiles across the spectrum of disease reveal a distinct role for GM-CSF in severe COVID-19

Granulocyte-macrophage colony stimulating factor in COVID-19: friend or foe?

GM-CSF neutralization with lenzilumab in severe COVID-19 pneumonia: a case-cohort study

Mavrilimumab in patients with severe COVID-19 pneumonia and systemic hyperinflammation (MASH-COVID): an investigator initiated, multicentre, double-blind, randomised, placebo-controlled trial

A randomized trial of otilimab in severe COVID-19 pneumonia (OSCAR)

Lenzilumab efficacy and safety in newly hospitalized COVID-19 subjects: results from the LIVE-AIR phase 3 randomized double-blind placebo-controlled trial

The complement system in COVID-19: friend and foe?

Increased complement activation is a distinctive feature of severe SARS-CoV-2 infection

Eculizumab treatment in patients with COVID-19: preliminary results from real life ASL Napoli 2 Nord experience

Eculizumab as an emergency treatment for adult patients with severe COVID-19 in the intensive care unit: A proof-of-concept study

Anti-C5a antibody IFX-1 (vilobelimab) treatment versus best supportive care for patients with severe COVID-19 (PANAMO): an exploratory, open-label, phase 2 randomised controlled trial

Autoantibodies against type I IFNs in patients with life-threatening COVID-19

Study showing association between specific type I IFN antibodies and association with severe COVID-19

Study showing association between specific IFN gene mutations and severe COVID-19

Methylprednisolone as adjunctive therapy for patients hospitalized with coronavirus disease

a randomized, double-blind, phase IIb

Effect of tocilizumab on clinical outcomes at 15 days in patients with severe or critical coronavirus disease 2019: randomised controlled trial

Sarilumab in patients admitted to hospital with severe or critical COVID-19: a randomised, double-blind, placebo-controlled, phase 3 trial

Tocilizumab plus standard care versus standard care in patients in India with moderate to severe COVID-19-associated cytokine release syndrome (COVINTOC): an open-label, multicentre, randomised, controlled, phase 3 trial

Anakinra in hospitalized patients with severe COVID-19 pneumonia requiring oxygen therapy: Results of a prospective, open-label, interventional study