To the best of our knowledge, this is the first study that investigates the safety and efficacy of IL-6R inhibition in comparison to conventional treatments in patients with sHLH. A higher proportion of patients in the TCZ group experienced disease progression and showed a poor survival rate as compared to those in the control group. Furthermore, infectious adverse events occurred more frequently in the TCZ group. These results suggest that the safety and efficacy of TCZ is not favorable in patients with sHLH as compared to conventional treatment options.
As hypercytokinemia is a pathological hallmark of HLH, and consequently cytokine-targeted therapies are of particular interest in this era of biologic therapies, the results of this study are significant. However, selective neutralization of a single cytokine within the panoply of cytokines engaged in HLH may not always be effective in terminating disease progression. Tumor necrosis factor-α, interferon-γ, and various interleukins, including IL-1, IL-2, IL-6, and IL-18, have been linked to the cytokine cascade implicated in sHLH, and each of these cytokines has a complex interconnection with each other, that is not fully understood [22, 23]. Among the cytokine milieu, IL-6 is a part of the downstream cascade induced by IL-1β and IL-18, rather than a driver cytokine. Therefore, it is uncertain if treatment with TCZ alone has a significant effect on the various inflammatory cytokines involved in sHLH. Moreover, despite the typical IL-6 elevation in the preclinical models of sHLH and other cytokine release syndromes, the role of IL-6 in the pathogenesis of HLH remains unclear. A previous study on the cytokine pattern in HLH showed that IL-6 is only modestly elevated in HLH, contrary to what was observed for other key cytokines [24].
As all the patients in the TCZ group were treated with TCZ as the frontline therapy, the poor prognosis in this group is attributable to the limited efficacy of TCZ, rather than to the selection of refractory cases in the TCZ group. Our result is contrary to that reported in a recent case series, which showed clinical remission in eight of nine sHLH patients treated with TCZ [10]. However, the time to reach remission, response duration, and time interval to death were not clearly described in the same study. Furthermore, four (50.0%) of the patients who achieved remission eventually died during hospitalization, and another three patients developed septic shock. This finding is in line with our result that 62.5% of the patients in the TCZ group experienced at least one infectious complication. Similar trends have been reported in other studies [25, 26]. Lang et al. reported that patients treated with TCZ showed higher rates of infectious complication [25]. Furthermore, a recent study on patients with COVID-19 related cytokine release syndrome demonstrated that late-onset infections (> 48 h following admission) were more common among those who received TCZ [26]. Although the cause of this phenomenon is undeciphered, discrepancies in the levels of acute phase reactants such as C-Reactive Protein following the administration of TCZ, which might mask the typical signs of infection and therefore delay diagnosis have been previously reported [26, 27].
This present study has several limitations. First, on account of the study not being a randomized study, its results could be biased by “confounding by indication.” Although we have demonstrated that the baseline characteristics such as duration of symptoms, clinical manifestations, and H-score were comparable between the two groups, imbalances of unmeasured factors such as preferences of the treating physicians could have influenced the outcome. Second, the number of patients in the TCZ group was relatively small. Therefore, prior to practical application, the results should be consistently replicated and verified in future studies. Finally, the sample size of this study was too small to perform a meaningful subgroup analysis that can be stratified based on etiology.