Table 1.

Overarching principles and points to consider on COVID-19 pathophysiology and immunomodulatory treatment from the rheumatology perspective, with levels of evidence (LoE) and levels of agreement (LoA)

Overarching principles	LoA mean (SD); % of votes ≥8/10
A. The phenotype of SARS-CoV-2 infection is heterogeneous ranging from asymptomatic to lethal disease due to multiorgan damage.	9.92 (0.3); 100
B. SARS-CoV-2 infection may need different treatment approaches, including antiviral, oxygen therapy, anticoagulation and/or immunomodulatory treatment at different stages of the disease.	9.92 (0.3); 100
Points to consider
COVID-19 pathophysiology
1. Genetically determined differences including, but not limited to, immune gene pathways may contribute to the variable immune response to SARS-CoV-2 and ultimately impact on the disease prognosis (LoE 3/4).	9.25 (1.2); 100
2. Cellular (LoE 3/4) and humoral (LoE 3) immune responses against SARS-CoV-2 vary across individuals, infection course and disease spectrum, but there is insufficient evidence to associate these directly with outcomes.	8.71 (1.1); 83
3. Levels of many proinflammatory cytokines, especially serum IL-6, are elevated in COVID-19 and could be associated with outcome (LoE 3/4).	8.79 (1.0): 96
4. Hyperactivation of platelets, the complement system, endothelial damage and loss of endothelial homeostasis are pathophysiological mechanisms facilitating hypercoagulability and thrombosis during SARS-CoV-2 infection (LoE 4).	9.0 (1.1); 92
5. Multiparameter algorithms including neutrophil-to-lymphocyte ratio and acute phase reactants (eg, C reactive protein, ferritin) may be helpful to predict survival, mortality or disease progression and severity (LoE 4).	8.88 (1.3); 88
6. Primary infection with SARS-CoV-2 in children is largely a benign event. However, a small number of children develop a multisystem inflammatory syndrome which may reflect distinct pathophysiological mechanisms compared with adults (LoE 4/5).	9.38 (0.9); 96
Immunomodulatory therapy
7. In non-hospitalised patients with SARS-CoV-2 infection there is currently no evidence to support the initiation of immunomodulatory therapy (LoE 2/3/4).	9.58 (1.0); 96
8. In hospitalised patients with SARS-CoV-2 infection that do not need oxygen therapy there is currently no evidence to support the initiation of immunomodulatory therapy to treat their COVID-19 (LoE 2/3/4).	9.04 (1.6); 88
9. Hydroxychloroquine should be avoided for treating any stage of SARS-CoV-2 infection since it does not provide any additional benefit to the standard of care, and could worsen the prognosis in more severe patients particularly if co-prescribed with azithromycin (LoE 2).	9.75 (0.5); 100
10. In patients with COVID-19 requiring supplemental oxygen, non-invasive or mechanical ventilation, systemic glucocorticoids should be used since they can decrease mortality; most evidence concerns the use of dexamethasone (LoE 2/3).	9.67 (0.7); 100
11. An evolving RCT landscape cannot yet allow formal recommendation of the routine use of tocilizumab in patients with COVID-19 requiring oxygen therapy, non-invasive or invasive ventilation (LoE 2).	8.79 (1.2): 83
12. In COVID-19 there is no robust evidence to support the use of anakinra at any disease stage (LoE 2/4).	9.38 (1.0); 96
13. In patients with COVID-19 requiring non-invasive ventilation or high-flow oxygen, the combination of remdesivir plus baricitinib could be considered since it can decrease time to recovery and accelerate improvement in clinical status (LoE 2).	8.19 (2.2); 88
14. In COVID-19 there is currently insufficient evidence to recommend the use of other immunomodulators, including ruxolitinib, IVIg, convalescent plasma therapy except in Ig-deficient patients, interferon kappa, interferon beta, leflunomide, colchicine (LoE 2), sarilumab, lenzilumab, eculizumab, cyclosporine, interferon alpha (LoE 3), canakinumab (LoE 4).	9.42 (0.9); 96

IL-6, interleukin 6; IVIg, intravenous Ig; RCT, randomised controlled trial.