IL-1 and IL-6 Inhibitors for Cytokine Storm Treatment in COVID-19

Jump To Section

• Cytokine Inhibitors vs Steroids
• Combination Therapy Benefits
• Anakinra Safety Profile
• Timing of Treatment
• Rheumatology Patients and COVID
• Full Transcript

Cytokine Inhibitors vs Steroids

Dr. Randy Cron, MD, discusses the comparison between cytokine inhibitors and corticosteroids for cytokine storm treatment. He explains that IL-1 inhibitors like anakinra and IL-6 inhibitors like tocilizumab represent more targeted approaches. These biologic agents work differently from broad immunosuppressants like steroids.

Dr. Randy Cron, MD, notes that the pathophysiological approach often involves starting steroids after the first five days of infection. This timing allows the immune system to ramp up initially without overreacting. The targeted inhibitors may offer advantages for specific cytokine storm syndromes.

Combination Therapy Benefits

Evidence strongly suggests that cytokine blockade works best in combination with steroids. Dr. Randy Cron, MD, emphasizes that IL-6 blockade shows primary benefit when given alongside corticosteroids. The same pattern appears true for IL-1 blockade, though with less available data.

Dr. Randy Cron, MD, explains that giving IL-6 blockade alone tends not to help as much as combination therapy. This finding comes from meta-analyses conducted during the COVID-19 pandemic. The synergistic effect represents an important treatment consideration for severe cases.

Anakinra Safety Profile

Dr. Randy Cron, MD, highlights the favorable safety characteristics of anakinra. This IL-1 inhibitor is a recombinant human protein that the body already produces naturally. Its safety track record allows for use at much higher doses than approved indications.

Unlike broadly immunosuppressive glucocorticoids, anakinra offers targeted inhibition. This specificity means clinicians can potentially administer it earlier in cytokine storm syndromes. The drug's mechanism provides a valuable treatment option for refractory cases.

Timing of Treatment

Early intervention with cytokine blockade appears crucial for optimal outcomes. Dr. Randy Cron, MD, notes that data suggests better results when treatment begins promptly upon recognizing cytokine storm. The exact timing for COVID-19 cases continues to evolve as more evidence emerges.

Dr. Cron indicates that targeted approaches might be beneficial when given earlier than steroids. However, identifying appropriate candidates remains challenging in clinical practice. Most current usage involves conjunction with steroid timing or slightly later for non-responders.

Rheumatology Patients and COVID

Patients with rheumatologic conditions face slightly increased COVID-19 risks. Dr. Randy Cron, MD, explains that these patients generally don't fare as well as the general public. However, their outcomes aren't as severe as some cancer patient populations.

Many rheumatology patients take TNF blockers like etanercept, adalimumab, or infliximab. Others use newer Janus kinase inhibitors for conditions like rheumatoid arthritis. Dr. Randy Cron, MD, notes these medications don't appear dramatically protective against cytokine storm but don't significantly worsen outcomes either.

Full Transcript

Dr. Anton Titov, MD: IL-1 inhibitor would be an example, Anakinra. IL-6 inhibitor that is perhaps in wider use, tocilizumab. How to compare them with steroids? Are they given on top of the steroids or instead?

Dr. Anton Titov, MD: What is the sequence? It makes pathophysiological sense to start steroids, as you mentioned, after the first five days of infection to give the immune system a chance to sort of ramp up but not overreact.

Dr. Anton Titov, MD: What about the timing of use of those agents and the sequence in combination with steroids? What do we know at this point, two years into the pandemic?

Yeah, that's a great question. And we don't have really good answers for that either, because most the trials are really not designed that way.

Dr. Randy Cron, MD: But I will say that most of the evidence, again, probably from the meta-analyses, at least for IL-6 blockade, have shown that the benefit of adding IL-6 blockade has been primarily in the presence of steroids. So if you just get the IL-6 blockade alone, it tends not to help as much as if you're giving it in conjunction with steroids.

It's not perfect data, but it's strongly suggestive of that. Very similar data is out there for IL-1 blockade, for example, there's just a lot less of it. It's been a lot less studied than for IL-6.

The thing I'll say is, with cytokine storms prior to this pandemic, I probably personally have gone to IL-1 blockade with this drug Anakinra, specifically, because it's a recombinant human protein that your body already makes. It actually has a very good safety track record and can be used at much higher doses than it's even approved for.

Because it's not broadly immunosuppressive like glucocorticoids, you can probably get away with giving it earlier for most cytokine storm syndromes. And we do have data now that suggests that the earlier you give it when you recognize a cytokine storm, the better outcomes are.

And so we don't know yet for this particular pandemic. But it might be that given individual cytokine blockade earlier, and maybe even then steroids.

But again, try to identify who that would be, it's very hard to know. So my guess is, it's still being used in conjunction with the time that steroids are being used.

Or slightly later, if they're not responding as well as they're hoping to, for example, to glucocorticoids. But probably earlier is better for the more targeted approaches.

Dr. Anton Titov, MD: Some people are already on the anti-IL-1 drugs or IL-6 perhaps, and on the Janus kinase inhibitors for rheumatoid conditions. Is there any data that they get less cytokine storm syndrome, in a sense as a preventive measure of use? For those people who don't have impending cytokine syndrome, five days after getting COVID-19, for example?

Yeah, that's a good question too. And in rheumatologists and oncologists, and people who are taking care of patients who have chronic illnesses, we were worried about these things early on.

For the most part, at least I could speak to the rheumatology literature probably better. Patients with rheumatologic conditions are at slightly increased risk. I think, overall, patients are not doing as well with COVID-19 than the general public.

Dr. Randy Cron, MD: But not shockingly not as bad as maybe some of the cancer patients, for example. And many of these rheumatology patients, not all but many of them, are on either TNF blockers, tumor necrosis factor blockers, more common ones being like etanercept or adalimumab or infliximab, or some of the new Janus kinase inhibitors are a relatively new players in our field.

But now that adults are getting more and more of those for rheumatoid arthritis, for example, IL-1 blockade is not as common. It can be used for bad kind of refractory gout, but it's more common for rare pediatric disorders, including Still disease or systemic juvenile arthritis.

So we don't have great data there. But for the most part, rheumatologic patients don't tend to do dramatically worse than the general public. And like I said, many of these patients are on these medicines.

So I'm not sure it's protective. But it doesn't seem to make them a whole lot worse off for trying to battle this virus.