The European Alliance of Associations for Rheumatology (EULAR) recently updated the points-to-consider on the use of immunomodulatory therapies in patients with moderate to severe COVID-19. The full guidance was published in Annals of the Rheumatic Diseases.1

The treatments for SARS-CoV-2 infection are rapidly evolving, posing a challenge for health care professionals and the scientific community. Evidence on the best practices for the clinical management of patients with COVID-19 have been released weekly, thus requiring a need to update policies in this field.

The EULAR taskforce, along with other scientific societies, developed guidance in 2020 for the treatment of COVID-19.2 The objective of the current report was to update the EULAR points-to-consider on the use of immunomodulatory therapies in COVID-19.


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The multidisciplinary taskforce that developed the first version reconvened to establish a team, which included 2 fellow clinicians and a methodologist, to conduct an updated systematic literature review of studies on the management of SARS-CoV-2 infections using immunomodulatory therapies. Studies published between December 11, 2020, and June 30, 2021, were included in the analysis. Studies on the management of SARS-CoV-2 infections with anti-SARS-CoV-2 monoclonal antibodies were also included. Based on the results of the systematic literature review, the 12 points-to-consider were updated and discussed against existing ones. Statements were accepted if more than 75%, 65%, and 50% of the taskforce fellows approved the updates in the first (informal), second, and third rounds, respectively. The level of evidence was established, followed by an anonymous remote polling using a 0 to 10 level of agreement.

The 2 overarching principles remained unchanged compared with the first version in 2020:

  1. The heterogeneity of SARS-CoV-2 infection ranges from asymptomatic to lethal disease due to multiorgan damage.
  2. Based on the stages of the SARS-CoV-2 infection, treatment approaches may vary, including antiviral therapy, oxygen therapy, anticoagulation, and/or immunomodulatory treatments.

Table 1: Updated points-to-consider on the use of immunomodulatory therapies in COVID-19

                              Current Version (2021)          Updates to 2020 Version 
No evidence supports the use of immunomodulatory medications in nonhospitalized patients with SARS-CoV-2 infection. Unchanged
No evidence supports the use of immunomodulatory medications in hospitalized patients with SARS-CoV-2 infection who do not require oxygen therapy. Unchanged
Hydroxychloroquine should not be administered at any stage of SARS-CoV-2 infection. No evidence supports additional benefit to standard-of-care therapy, and in combination with azithromycin; it may worsen the prognosis in patients with severe infection.Unchanged
Systemic glucocorticoids should be used in patients requiring supplemental oxygen and noninvasive/mechanical ventilation to reduce mortality risks. However, evidence indicates some concerns with the use of dexamethasone.  Unchanged
To reduce disease progression and mortality, a combination of glucocorticoids and tocilizumab should be considered in patients requiring supplemental oxygen and noninvasive/mechanical ventilation. More data supporting the efficacy of other IL-6R inhibitors are required.Modified from: Routine use of tocilizumab in patients requiring oxygen therapy, noninvasive or invasive ventilation, is not yet formally recommended due to the evolving RCT landscape.
No robust evidence supports the use of anakinra at any stage of the infection.Modified from: No robust evidence supports the use of anakinra or canakinumab at any stage of the infection.
No robust evidence supports the use of low-dose colchicine at any stage of the infection.New
A combination of glucocorticoids and baricitinib or tofacitinib could be considered in patients requiring oxygen therapy, noninvasive ventilation, or high-flow oxygen, as it may reduce disease progression and mortality risks.Modified from: Combination of remdesivir and baricitinib could be considered in patients requiring noninvasive ventilation or high-flow oxygen, as it may reduce recovery time and improve clinical outcomes. 
Based on the evolving RCT landscape, the use of GM-CSF inhibitors (mavrilimumab, otilimab, and lenzilumab) in COVID-19 is recommended against.New
There is robust evidence against the use of convalescent plasma in patients without hypogammaglobulinemia and with symptom-onset of >5 days.New
Monoclonal antibodies to antispike protein must be considered in patients with risk for severe COVID-19 and symptom-onset of <5 days or still seronegative.New
There is insufficient evidence supporting the use of other immunomodulatory medications, including interferon alpha, interferon beta, interferon kappa, interferon lambda, leflunomide, non-SARS CoV-2 IVIg, eculizumab, and cyclosporine in patients with COVID-19.Modified from: There is insufficient evidence supporting the use of other immunomodulatory medications, including ruxolitinib, intravenous Ig, convalescent plasma therapy (except patients who are Ig-deficient), interferon kappa, interferon beta, leflunomide, colchicine, sarilumab, lenzilumab, eculizumab, cyclosporine, interferon alpha, and canakinumab in patients with COVID-19.

GM-CSF, Granulocyte-Macrophage Colony-Stimulating Factor; IL-6R, interleukin 6 receptor; RCT, randomized controlled trial; Ig, immunoglobulin.

The authors concluded, “The update of these EULAR [points-to-consider] provide relevant and updated guidance on immunomodulatory therapy utilization from the rheumatology perspective and opens the way to a new paradigm: the treatment of immunopathology associated with severe and critical acute infections may benefit from immunomodulatory treatments usually given for autoimmune and inflammatory diseases.”

Disclosure: Some authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.

References

1. Alunno A, Najm A, Machado PM, et al. 2021 update of the EULAR points to consider on the use of immunomodulatory therapies in COVID-19. Ann Rheum Dis. Published online October 7, 2021. doi:10.1136/annrheumdis-2021-221366

2. Alunno A, Najm A, Machado PM, et al. EULAR points to consider on pathophysiology and use of immunomodulatory therapies in COVID-19. Ann Rheum Dis. 2021;80:698-706.