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Interleukin-6 inhibitors in COVID-19

- 6 min read
written by Shield Connect

Interleukin (IL-6) is a proinflammatory cytokine produced by lymphocytes, monocytes, and fibroblast cells in the body which is responsible for cytokine release strorm (CRS).

Interleukin (IL-6) is a proinflammatory cytokine produced by lymphocytes, monocytes, and fibroblast cells in the body which is responsible for cytokine release strorm (CRS). SARS-CoV-2 induces a dose-dependent secretion of the IL-6 from the bronchial epithelial cells which leads to increase in inflammation resulting to collapsing of respiratory system. In this regard, there has been increasedinterests in employing IL-6 inhibitors in COVID-19 patients although anti-IL-6 drugs are associated with some adverse reactions1,2.

L-6
Fig: IL-6 receptor complex and IL-6 signalling inhibitors. Classical IL-6 signalling pathway and trans signalling pathway; (B) Binding sites at IL-6 signalling complex for therapeutic IL-6 inhibitors.

There are two classes of Food and Drug Administration (FDA)-approved IL-6 inhibitors including.,3

  1. Anti-IL-6 receptor monoclonal antibodies
    • g., Tocilizumab,Sarilumab
  2. Anti-IL-6 monoclonal antibodies
    • g., Siltuximab
    • Anti-IL-6 receptor monoclonal antibodies

Tocilizumab

Tocilizumab is a recombinant humanized anti-IL-6R receptor FDA approved monoclonal antibody. It is recommended in the patient with rheumatologic disorders and cytokine release syndrome (CRS) induced by chimeric antigen receptor T cell (CAR T-cell) therapy.

Adverse Effects

      • Elevated liver enzyme levels that appear to be dose dependent.
      • Neutropenia or thrombocytopenia are uncommon.
        • Additional adverse effects, such as risk for serious infections
        • e.g., tuberculosis [TB], bacterial or fungal infections

Considerations in Pregnancy

There are insufficient data to determine whether there is a tocilizumab-associated risk for major birth defects or miscarriage. It was evident that monoclonal antibodies are actively transported across the placenta as pregnancy progresses.

Considerations in Children

There are no systematic observational or randomized controlled trial data available on the effectiveness of tocilizumab for the treatment of COVID-19 or multisystem inflammatory syndrome in children (MIS-C) in children.

Important

Recent study reveals that treatment with tocilizumab resulted in poor outcomes in COVID-19 patients and it was not able to prevent secondary hemophagocytic lymphohistiocytosis.

Sarilumab

Sarilumab is a fully human IgG1 monoclonalantibody that targets both IL-6R and mIL-6R, hence inhibiting both classical and trans-IL-6-mediated inflammatory pathways.

Adverse Effects

  • Transient and/or reversible elevations in liver enzymes
  • Rare occurrences of neutropenia and thrombocytopenia. Risk for serious infections (e.g., TB, bacterial or fungal infections)
  • Bowel perforation with long-term use of sarilumab.

Considerations in Pregnancy

There are insufficient data to determine whether there is a sarilumab-associated risk for major birth defects or miscarriage.

Considerations in Children

There are no systematic observational or randomized controlled trial data available on the efficacy of sarilumab for the treatment of COVID-19 or MIS-C in children.

Important

Sarilumab is not approved for the treatment of CRS. The IV formulation is not approved by the FDA, but it is being studied in a clinical trial of hospitalized patients with COVID-19.

  • Anti-Interleukin-6 Monoclonal Antibody

Siltuximab

Siltuximab is a chimeric human-mouse monoclonal antibody against IL-6 for the treatment of patients with multicentric Castleman disease (MCD)approved by the Food and Drug Administration (FDA). It binds directly to soluble IL-6 and prevents it from acting on the IL-6 receptor to activate the IL-6 signaling pathways.

Adverse Effects

The primary adverse effects reported for siltuximab have been related to

  • Rach.
  • Additional adverse effects (e.g., serious bacterial infections) have been reported only with long-term dosing of siltuximab once every 3 weeks.

Considerations in Pregnancy

There are insufficient data to determine whether there is a siltuximab-associated risk for major birth defects or miscarriage.

Considerations in Children

The safety and efficacy of siltuximab have not been established in pediatric patients.

Therefore IL-6 signal inhibitors, along with other treatmentcould provide efficacyto hospitalized COVID-19 patient although there are many questions related to efficacy and safety still unanswered.

References:

  1. Yoshikawa T et al., severe acute respiratory syndrome (SARS) coronavirus-induced lung epithelial cytokines exacerbate SARS pathogenesis by modulating intrinsic functions of monocyte-derived macrophages and dendritic cells. J Virol. 2009;83(7):3039-3048.
  2. Nasonov and M. Samsonov, The role of Interleukin 6 inhibitors in therapy of severe COVID-19, Biomedicine & Pharmacotherapy, 131, 2020, 110698.
  3. Crisafulli S et al., Potential Role of Anti-interleukin (IL)-6 Drugs in the Treatment of COVID-19: Rationale, Clinical Evidence and Risks. BioDrugs 2020; 34(4): 415-422.

Picture Credit:JarunOntakrai(Shutterstock.com)

Dr. Chrishtopher Dr Christopher S. K
MBBS, DNB (Gen.Surgery), MNAMS, FIAGES, FMAS, FACRSI, FACS(USA), FAIS, FBMS(Taiwan), FRSPH(UK), D.MAS(France), FMIS(IRCAD), FICRS(WALS), F.MAS, D.MAS(WALS)
Consultant Advanced Minimally Invasive Bariatric, GI & Laser Surgeon
Specialised in Endoscopy, Laser, Laparoscopic & Robotic Surgery

 

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