The REMAP-CAP trial recently detected mortality benefit from tocilizumab in patients with COVID-19.  However, several other RCTs have failed to find substantial benefit from tocilizumab.  This begs the question:  Has REMAP-CAP discovered a uniquely beneficial way to use tocilizumab, or is this simply a statistical outlier?  

evidence roundup:  RCTs on tocilizumab

Let’s review the trials.  Studies are arranged based on the frequency of patients who received steroid (from least to most).  This also arranges them in roughly chronological order, since the use of steroid has increased over time. 

[4% of patients received steroid]  Salvarani C et al. Effect of tocilizumab versus standard care on clinical worsening in patients hospitalized with COVID-19 pneumonia (RCT-TCZ-COVID-19, JAMA)

This is an open-label, multicenter RCT involving patients with radiologic infiltrates, PaO2/FiO2 between 200-300 mm, and an inflammatory phenotype (defined by fever and/or CRP >100 mg/L and/or CRP increased to at least twice the admission level).^​1​  At enrollment, patients were allowed to receive oxygen via Venturi mask or high-flow nasal cannula, but could not receive noninvasive or invasive ventilation.  Tocilizumab was provided in two 8 mg/kg doses (max 800 mg) given 12 hours apart.  Patients in the control arm were allowed to receive open-label tocilizumab if they deteriorated.  During the course of the study 5 patients (4%) were treated with steroid. 

Patients were randomized a median of 8 days after symptom onset.  Baseline patient characteristics were as follows:

There was no signal for any clinical efficacy in any endpoint:

Tocilizumab appeared to be safe.  There was no increase in infection among the tocilizumab group (despite an increase in neutropenia among patients receiving tocilizumab): 

[10% of patients received steroid]  Stone JH Efficacy of Tocilizumab in patients hospitalized with COVID-19 (BACC bay group, NEJM)

This was a double-blind, placebo-controlled, multicenter trial involving hospitalized patients with at least two of the following:  fever (>38 C), pulmonary infiltrates, or requirement for supplemental oxygen to achieve a saturation >92%.^​2​  Patients were also required to have at least one laboratory abnormality among the following:  CRP >50 mg/L, ferritin >500 ng/ml, D-dimer >1,000 ng/mL, or LDH >250 U/L.  Tocilizumab was provided in a single 8 mg/kg dose (max 800 mg).  10% of patients received steroid. 

Patients were treated a median of 9 days after symptom onset.  80% of patients were receiving 1-6 liters/minute oxygen, 4% were receiving 6-10 liters/minute oxygen, and 16% required no supplemental oxygen.  Baseline laboratory values were as follows:  

This was a pretty solidly negative trial.  No primary or secondary endpoints showed significant differences: 

Tocilizumab was associated with an increased rate of neutropenia, but this didn’t translate into an increase in infections (indeed, there were fewer infections among the tocilizumab group).  So overall tocilizumab appeared to be safe:

[42% of patients received steroid]  Rosas IO et al. Tocilizumab in hospitalized patients with COVID-19 pneumonia (COVACTA trial, Preprint)

This was a double-blind, placebo-controlled, multicenter RCT involving hospitalized patients with bilateral pulmonary infiltrates and hypoxemia.^​3​  Tocilizumab was administered in a single 8 mg/kg dose (max dose 800 mg).  36% of patients in the tocilizumab group were treated with steroid, compared to 55% in the control group. 

Patients were treated a median of 12 days after symptom onset.  Baseline patient characteristics were as follows: 

The primary endpoint was clinical status after 28 days on a 7-category ordinal scale.  There was no difference in this endpoint.  However, several outcome measures did suggest possible efficacy.  For example, patients initially located outside the ICU were less likely to be transferred to the ICU if treated with tocilizumab (24% vs. 41%; p = 0.01). 

There was no evidence of adverse events from tocilizumab.  As in other studies, patients in the tocilizumab group trended towards having fewer infections:

[48% of patients received steroid]  Hermine O et al.  Effect of tocilizumab versus usual care in adults hospitalized with COVID-19 and moderate or severe pneumonia  (CORIMUNO-TOCI-1, JAMA)

This was an open-label, multicenter RCT involving hospitalized patients requiring at least 3 liters/minute oxygen but not requiring high-flow nasal cannula, noninvasive ventilation, or intubation.^​4​  Tocilizumab was dosed at 8 mg/kg initially, followed by a second dose of 400 mg IV two days later if oxygenation was not improving.  33% of patients in the tocilizumab group were treated with steroid, compared to 61% in the control group. 

Patients were randomized a median of 10 days after symptom onset.  Baseline features were as follows:

Tocilizumab didn’t cause statistically significant improvement but was associated with some favorable trends (figure below).  Effects of tocilizumab may have been diminished due to higher use of steroid in the control group. 

Tocilizumab appeared to have a very favorable toxicity profile (table below).  Some patients treated with tocilizumab did develop neutropenia, but clinical infection was less common among patients treated with tocilizumab. 

[83% of patients received steroid]  Salma C et al. Tocilizumab for patients hospitalized with COVID-19 pneumonia (EMPACTA, NEJM)

This was a double-blind, placebo-controlled, multicenter trial involving hospitalized patients who were hypoxemic, yet were not receiving either noninvasive or invasive ventilation.^​5​  Study sites were selected to include high-risk, minority patients.  Tocilizumab was dosed at 8 mg/kg (max dose 800 mg), given once or twice.  83% of patients received steroid, with 59% of patients receiving dexamethasone. 

Patients were treated a median of 8 days after symptom onset.  Most patients were located on the hospital ward, receiving supplemental oxygen (64%).  Baseline characteristics were as follows:

The primary endpoint was either intubation or death, which was reduced in the tocilizumab group (figure below). 

This is reported as a statistically significant result (p=0.04), but it is not a statistically robust finding.  Survival analysis evaluates the number of events and also how rapidly they occur, combining both of these findings into the final p-value.  However, from a clinical standpoint, the “hardest” endpoint is simply whether or not the patient dies or is intubated (not exactly when this occurs).  If we look solely at the number of clinical failures irrespective of timing, this is not statistically significant (29/249 vs. 24/128 yields a p-value of 0.084 using a Fisher Exact test). 

There was no difference in mortality rate (10.4% for tocilizumab versus 8.6% for placebo).  No signals of harm were found.  Patients in the tocilizumab group tended to have fewer serious infections (5.2% versus 7.1%):

[88% of patients received steroid]  Gordon AC et al. Interleukin-6 receptor antagonists in critically ill patients with COVID-19 – Preliminary report (REMAP-CAP, Preprint)

This was an international, adaptive platform, open-label trial.^​6​  Within 24 hours of initiating organ support in an intensive care unit, patients were randomized to control or IL-6 antagonist (either one or two doses of tocilizumab at 8 mg/kg up to 800 mg, or sarilumab 400 mg once).  Inclusion required: ICU admission within <24 hours, AST/ALT below 5-times normal, platelet count >50 billion/L, and lack of ongoing immunosuppression (including neutropenia).  

Far more patients were treated with tocilizumab (353) than sarilumab (48), so this trial was largely a study of tocilizumab.  88% of patients received concomitant steroid, since the study occurred mostly after publication of the RECOVERY trial on dexamethasone.

Baseline characteristics are shown below:

The primary endpoint was positive:  patients treated with IL-6 inhibition experienced significantly more days free of organ support within the first three weeks (median of 10 versus zero).  Hospital mortality was 28% for tocilizumab (98/350) versus 36% for control (142/397), which was statistically significant (p = 0.03). 

The study was analyzed using Bayesian statistics, with a pre-study prior probability of 50% that IL-6 inhibition would be effective.  This arbitrary 50% probability is arguably too high, given that prior studies were largely unimpressive.  Consequently, the post-study probabilities are very high (e.g., close to 99%).  However, such high post-study probabilities may be artificially high and are not numerically reliable:

The effect of IL-6 inhibition was evaluated in prespecified subgroups based on CRP level (table below).  Effects were similar across all groups.  However, the effects were strongest and statistically significant among patients with the highest CRP levels. 

No signals of harm are reported (for example, only one secondary bacterial infection was reported in the tocilizumab group). 

discussion & deep thoughts about immunomodulation

#1)  Tocilizumab is generally safe

Tocilizumab has now been found to be safe in several multicenter RCTs.  Tocilizumab did seem to cause some neutropenia in some of these studies, but this didn’t translate into an increase in the rate of clinical infection.  In fact, most studies detected fewer infections among patients treated with tocilizumab. 

#2)  Tocilizumab monotherapy doesn’t work

Studies evaluating tocilizumab alone were fairly definitive, revealing no beneficial effect (e.g., Salvarini et al. and Stone et al.).^​1,2​  This shouldn’t come as a big surprise.  The cytokine storm involves dozens of cytokines.  Simply blocking a single cytokine isn’t enough to have a meaningful clinical impact.  Similar results have been found over decades of research into septic shock, wherein many single-cytokine inhibitors have failed. 

#3)  Dexamethasone 6 mg/day may be inadequate in more severe disease

Dexamethasone monotherapy succeeds where tocilizumab monotherapy fails, because dexamethasone has a broader range of effects on the immune system (inhibiting numerous cell types and numerous inflammatory pathways).  

However, dexamethasone 6 mg/day is sometimes insufficient.  This isn’t a lot of steroid (equivalent to 40 mg/day prednisone). Higher steroid doses were used in most ARDS trials (e.g. DEXA-ARDS, which initiated patients on a dose of 20 mg/day).^​7​ I’ve seen several COVID patients develop cytokine storm despite being on 6 mg/day dexamethasone.  The inadequacy of 6 mg/day dexamethasone for some patients is supported by evidence that adding tocilizumab or baricitinib on top of steroid may improve outcomes, compared to steroid alone.^{​5,6,8,9​}

The concept of using a fixed steroid dose irrespective of disease severity doesn’t make sense, nor is it utilized for most other inflammatory lung diseases.  For interstitial inflammatory lung diseases, a higher dose of steroid is often utilized for active and uncontrolled disease.  Once clinical improvement occurs, the steroid dose can be tapered accordingly. 

#4)  Tocilizumab appears to improve outcomes for critically ill patients on dexamethasone

For the sickest patients, dexamethasone 6 mg/day is probably inadequate.  Options in these patients might include:

• Higher doses of steroid (e.g., 125-250 mg IV methylprednisolone or 20 mg dexamethasone daily for 1-3 days, with a subsequent transition to dexamethasone 6 mg/day following clinical and laboratory improvement).  This is supported by the CoDEX trial, which demonstrated that a course of steroid beginning at 20 mg/day dexamethasone was safe and effective among intubated COVID patients.^​10​  A recent RCT likewise found benefit from a three-day minipulse of 250 mg/day methylprednisolone.^​11​
• Dexamethasone 6 mg/day plus tocilizumab.  This is supported by the REMAP-CAP trial above.
• Dexamethasone 6 mg/day plus baricitinib.  This is supported by retrospective studies suggesting benefit from the combination of baricitinib with steroid.^​8,9​  It’s also indirectly supported by the REMAP-CAP trial (since both baricitinib and tocilizumab inhibit the IL-6 receptor).

Based on the REMAP-CAP trial, the combination of dexamethasone plus tocilizumab currently has the strongest evidentiary support among ICU patients.  However, support for tocilizumab remains uncertain, given its relatively weak performance in other studies (especially the EMPACTA trial).  Further studies comparing various combinations of therapy are needed. 

Below is one potential approach to the use of immunomodulators in COVID-19.  Various options reflect an absence of definitive data (e.g., no study has compared higher-dose steroid versus tocilizumab).  Additionally, many hospitals currently lack tocilizumab and/or baricitinib (or will run out of them soon), so steroid-based regimens are pragmatically more feasible.

#5)  What is the role of monitoring CRP?

REMAP-CAP found a benefit of tocilizumab in patients with all three tertiles of CRP.  The benefit was larger in patients with the highest CRP, but overall CRP seems to be only a weak predictor of benefit from tocilizumab.  How can we make sense of this?

My general conceptualization of CRP in COVID-19 is below.^​12​  Early in the disease course, a rapidly rising CRP indicates uncontrolled inflammation, which predicts more severe clinical deterioration.^​13​  After treatment (e.g., steroid +/- baricitinib), the CRP may fall rapidly.  Clinical disease resolution often lags behind the falling CRP, because tissue repair takes time.

A single value of CRP has limited utility, because it doesn’t reflect whether the inflammation is coming or going.  For example, a CRP of 100 mg/L would be worrisome if the patient’s CRP were 30 mg/dL yesterday.  Alternatively, the same value (100 mg/L) would be reassuring if the patient’s CRP were 150 mg/L yesterday.  Interpretation of the CRP requires an integration of the change in CRP over time, within the context of the patient’s overall clinical course.

Whether CRP has any role in titrating immunomodulator therapy remains speculative.  REMAP-CAP demonstrates that the most important determinant of therapy is clinical trajectory.  I tend to believe that tracking the CRP helps me understand each patient’s trajectory and therapy, but there is no high-quality prospective evidence that CRP-based medication titration improves outcomes. 

• Tocilizumab monotherapy has failed to be beneficial, perhaps because it targets only a single cytokine.  Steroid has a broader range of effects, allowing it to be more effective.
• Dexamethasone 6 mg/day is a relatively low steroid dose, which may be inadequate for patients with more severe disease.
• REMAP-CAP evaluated tocilizumab among a population of patients who were admitted to the ICU for organ support (e.g., high-flow nasal cannula or ventilation) and were generally treated with dexamethasone.  The addition of tocilizumab improved outcomes (including mortality).
• REMAP-CAP is an impressive study, but prior studies have failed to show major benefits from tocilizumab. 
• Further evidence is needed to determine optimal dosing strategies and whether to combine multiple agents for the management of critically ill COVID patients.  Unfortunately, medication shortages of IL 6-receptor antagonists are likely, so a flexible approach may be required.

related

• REMAP-CAP IL-6 antagonists: The Bottom Line by David Slessor

Opening image credits: Photo by Torsten Dederichs on Unsplash

references

1. 1.

   Salvarani C, Dolci G, Massari M, et al. Effect of Tocilizumab vs Standard Care on Clinical Worsening in Patients Hospitalized With COVID-19 Pneumonia: A Randomized Clinical Trial. JAMA Intern Med. 2021;181(1):24-31. doi:10.1001/jamainternmed.2020.6615
2. 2.

   Stone J, Frigault M, Serling-Boyd N, et al. Efficacy of Tocilizumab in Patients Hospitalized with Covid-19. N Engl J Med. 2020;383(24):2333-2344. doi:10.1056/NEJMoa2028836
3. 3.

   Rosas I, Bräu N, Waters M, et al. Tocilizumab in Hospitalized Patients With COVID-19 Pneumonia. Published online September 1, 2020. doi:10.1101/2020.08.27.20183442
4. 4.

   Hermine O, Mariette X, Tharaux P, et al. Effect of Tocilizumab vs Usual Care in Adults Hospitalized With COVID-19 and Moderate or Severe Pneumonia: A Randomized Clinical Trial. JAMA Intern Med. 2021;181(1):32-40. doi:10.1001/jamainternmed.2020.6820
5. 5.

   Salama C, Han J, Yau L, et al. Tocilizumab in Patients Hospitalized with Covid-19 Pneumonia. N Engl J Med. 2021;384(1):20-30. doi:10.1056/NEJMoa2030340
6. 6.

   Gordon AC. Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19 – Preliminary report. Published online January 7, 2021. doi:10.1101/2021.01.07.21249390
7. 7.

   Villar J, Ferrando C, Martínez D, et al. Dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial. Lancet Respir Med. 2020;8(3):267-276. doi:10.1016/S2213-2600(19)30417-5
8. 8.

   Rodriguez-Garcia J, Sanchez-Nievas G, Arevalo-Serrano J, Garcia-Gomez C, Jimenez-Vizuete J, Martinez-Alfaro E. Baricitinib improves respiratory function in patients treated with corticosteroids for SARS-CoV-2 pneumonia: an observational cohort study. Rheumatology (Oxford). 2021;60(1):399-407. doi:10.1093/rheumatology/keaa587
9. 9.

   Stebbing J, Sánchez N, Falcone M, et al. JAK inhibition reduces SARS-CoV-2 liver infectivity and modulates inflammatory responses to reduce morbidity and mortality. Sci Adv. Published online November 13, 2020. doi:10.1126/sciadv.abe4724
10. 10.

    Tomazini B, Maia I, Cavalcanti A, et al. 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. JAMA. 2020;324(13):1307-1316. doi:10.1001/jama.2020.17021
11. 11.

    Edalatifard M, Akhtari M, Salehi M, et al. Intravenous methylprednisolone pulse as a treatment for hospitalised severe COVID-19 patients: results from a randomised controlled clinical trial. Eur Respir J. 2020;56(6). doi:10.1183/13993003.02808-2020
12. 12.

    Manson J, Crooks C, Naja M, et al. COVID-19-associated hyperinflammation and escalation of patient care: a retrospective longitudinal cohort study. Lancet Rheumatol. 2020;2(10):e594-e602. doi:10.1016/S2665-9913(20)30275-7
13. 13.

    Mueller AA, Tamura T, Crowley CP, et al. Inflammatory Biomarker Trends Predict Respiratory Decline in COVID-19 Patients. Cell Reports Medicine. Published online November 2020:100144. doi:10.1016/j.xcrm.2020.100144