The coronavirus disease 2019 (COVID-19) pandemic, caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has had a profound and lasting impact on global health and society. Since its emergence in Wuhan, China, in late 2019, COVID-19 has spread relentlessly across the globe, challenging healthcare systems, economies, and daily life as we know it. As of September 2023, the global rate of SARS-CoV-2 infections remains high, with seroprevalence studies showing that> 80% of the population of countries such as South Africa have already been infected (Hajissa et al., 2022). The treatment strategies for COVID-19 depend on its stage and should be tailored to the specific stage of the disease that a patient is experiencing (Stasi et al., 2020; Wang et al., 2023).

Inflammatory markers play a crucial role in the pathogenesis of COVID-19, contributing to the disease’s severity and complications. One of the hallmark features of severe COVID-19 is a hyperinflammatory response often referred to as a “cytokine storm” (Mehta et al., 2020). This involves the overproduction of pro-inflammatory cytokines, including interleukin-6 (IL-6), interleukin-1 beta (IL-1β), and tumor necrosis factor-alpha (TNF-α). This excessive cytokine release can lead to acute respiratory distress syndrome (ARDS) and multi-organ dysfunction (Dastan et al., 2020; Mehta et al., 2020; Rezaei et al., 2021; Rubin et al., 2021). Until now, many antiviral drugs and monoclonal antibodies (bebtelovimab, sotrovimab and etc.) have been used for the treatment of COVID-19. One of the most promising drugs is remdesivir which is an adenosine analogue and has antiviral activity (Li et al., 2023; Mengato et al., 2023). Tocilizumab is an interleukin-6 (IL-6) receptor blocker currently approved for hospitalized patients with high inflammatory status (Samaee et al., 2020). It promotes B and T cells' proliferation, which may trigger further immune activation (Uciechowski and Dempke, 2020). COVID-19 patients treated with tocilizumab have a lower mortality rate and a lower need for mechanical ventilation (Wei et al., 2021). Other interleukin blockers including anakinra which inhibit interleukin-1 have been used in the management of COVID-19 before. Some studies have suggested potential benefits of this medication, including improved oxygenation and reduced need for mechanical ventilation, in patients with severe COVID-19 and signs of hyperinflammation (Cavalli et al., 2020).

The Janus kinase (JAK) inhibitor, baricitinib, inhibits the passage and intracellular assembly of SARS-CoV-2 into target cells through the ACE2 receptor (Keystone et al., 2015). Moreover, this medication suppresses both JAK1/JAK2, which leads to inhibiting the proinflammatory signal of several cytokines, including IL-6, IL-12, IL-23, and IFN-γ (Keystone et al., 2015).

The indication for tocilizumab or baricitinib is almost similar in COVID-19 patients. Patients with a rapid disease progression, high oxygen needs on admission, or patients with risk factors for poor outcomes, including age or medical history plus elevated C-reactive protein (CRP) plus low-flow oxygen, did receive tocilizumab or baricitinib (Karolyi et al., 2022). Unlike tocilizumab, baricitinib could be prescribed at any CRP level, while tocilizumab required a CRP of 75 mg/L (Karolyi et al., 2022).

The effects and outcomes of co-administering these two medications have yet to be assessed in well-designed trials. The potential benefits include the rapid improvement of patients and regulation of the immune system. The potential risks include the increased chance of infections due to over-suppression of the immune system and further immune issues. However, the short duration of administration may reduce the importance of this concern. This study aimed to investigate the effects of co-administering these two medications on the 28-day mortality rate, the need for mechanical ventilation, along with other efficacy parameters and safety issues.

The screening and randomization process of the patients are provided in the CONSORT diagram in Figure 1.

Table 1 demonstrates the demographics and past medical histories of the subjects.

The results regarding the 28-day mortality rate, the need for invasive or non-invasive mechanical ventilation, and the need for the second tocilizumab dose or admission in the ICU are provided in Table 2. As the Table shows, there were no statistical differences in terms of the mentioned parameters between the two groups (Table 2).

The results of this study showed no beneficial effects of combining tocilizumab and baricitinib on the management of severe COVID-19 cases. The health outcomes, including the need for mechanical or non-invasive mechanical ventilation, and the mortality rate were not different between the groups receiving the combination of these two medications and the group receiving a single dose of tocilizumab. The days of hospital stay or the need for second dose of tocilizumab was not affected either.

It is noteworthy that the risk difference in the need for admission to the ICU is calculated to be 0.15. Based on this calculation, the number need to treat (NNT) to prevent one person from admitting to the ICU is 7, which is considered a medium effect size (Rahlfs and Zimmermann, 2019). Hence, combination therapy may have beneficial effects on the prevention from ICU admission. However, the sample size needed to be larger to detect that beneficial effect.

Baricitinib became the first immunomodulatory treatment for COVID-19 to receive FDA approval. This approval was supported by two phase 3, randomized, double-blind placebo-controlled trials (Rubin, 2022). Based on a review article, baricitinib was effective in decreasing respiratory failure and the use of mechanical ventilation, also preventing symptoms deterioration. Furthermore, baricitinib as a single agent or combined with other drugs, improved the peripheral capillary oxygen saturation (SpO2)/fraction of inspired oxygen (FiO2) ratio (Dupuis et al., 2022).

Both baricitinib and tocilizumab are considered a standard of care in managing severe COVID-19 patients with inflammatory status based on COVID-19 treatment guidelines (Bhimraj et al., 2020). Some other studies have also considered the co-administration of these two medications, which may lead to more rapid recovery of the patients from the inflammatory status as they both suppress the immune system (Rosas et al., 2020). The authors of that study believed that the combination therapy of these medications could be considered in COVID-19 patients with impaired PaO₂/PaFi. No serious adverse events were reported in their study (Rosas et al., 2020). In one study, authors concluded that using baricitinib along with standard of care treatments was associated with mortality reduction in hospitalized COVID-19 patients (Banga et al., 2023).

Both tocilizumab and baricitinib have anti-inflammatory properties. Combining these medications may result in a more comprehensive suppression of the hyperinflammatory response often seen in severe COVID-19 cases (Bryus et al., 2022).

In our study, one patient developed thrombosis. The relation of this event to the study intervention may not be conclusive as COVID-19 is a risk factor for developing thrombotic events itself. However, it should be noted that the use of baricitinib also may increase this risk. No infectious-related complications or any issues related to over-suppression of the immune system were noted.

In another observational cohort study performed on microbiologically-confirmed COVID-19 hospitalizations, the addition of baricitinib to the standard of care, including tocilizumab did not reduce the mortality rate in hospitalized COVID-19 patients, which is in line with our results (Masiá et al., 2021). Moreover, no difference in the thromboembolic events or infection rates was detected in that study (Masiá et al., 2021). While some studies have shown promise, the evidence regarding the combined use of tocilizumab and baricitinib for COVID-19 is still evolving. More research is needed to establish the safety and efficacy of this combination definitively. It is noteworthy that both tocilizumab and baricitinib are expensive medications, and using them together may significantly increase the overall treatment cost. The decision to combine these medications should be made on a case-by-case basis, taking into account the patient’s overall health, comorbidities, and individual response to treatment.

The results of the lab tests, demonstrates no significant and meaningful differences regarding the safety issues or the inflammation reduction between the two groups.

While some studies have shown promise, the evidence regarding the combined use of tocilizumab and baricitinib for COVID-19 is still evolving. More research is needed to establish the safety and efficacy of this combination definitively.

This study had some limitations. The main limitation of our study was the absence of a power calculation for sample size determination. Nevertheless, given the calculated risk difference of 0.05 in the primary outcomes, which represents a trivial effect size, it appears that increasing the sample size would not alter the results. In addition, the open-label design of the study could have affected the results which must be taken into account.

Moreover, according to the participants’ baseline characteristics, the patients’ smoking status might be considered a covariate in this study. However, the low number of the events related to the primary outcomes was a limitation for performing adjustment analysis based on regression models.

The combination therapy of tocilizumab plus baricitinib did not have any beneficial effects on managing severe COVID-19 cases. However, the need for ICU admission was meaningfully lower in the combination group.