EFFICACY OF TOCILIZUMAB IN MITIGATING INFLAMMATORY CASCADE IN PATIENTS WITH PREDICTED SEVERE ACUTE PANCREATITIS: A MULTICENTER RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED PILOT TRIAL

Introduction:
Progression of acute pancreatitis to moderate to severe disease is associated with as high as 42% mortality rate. Despite this debilitating outcome, there is currently no specific pharmacotherapy for the disease. With better understanding of its pathogenesis, promising pharmacological agents targeting the key detrimental pro-inflammatory cytokines, such as interleukine(IL)-6, have been developed. Tocilizumab, a humanized anti-human IL-6R antibody has been proven to be effective in preventing catastrophic complications of acute pancreatitis in murine studies by inhibiting IL-6 receptor (IL-6R) as evidenced by an increase in free IL-6 level. This study aimed to evaluate the efficacy of Tocilizumab in mitigating initial inflammatory cascade in patients with predicted severe acute pancreatitis using pro-inflammatory cytokine as surrogate markers.

Method:
Adult patients who were diagnosed with acute pancreatitis and were predicted to develop severe pancreatitis, defined as BISAP score ≥ 3 or Modified Marshall score ≥ 2, between January 2021 and October 2023 were randomly assigned to Tocilizumab 4 mg/kg group and placebo (normal saline) group within 12 hours of presentation. IL-6, CRP, and procalcitonin were collected on the date of admission, at 24, and 48-hour.
Results:
20 patients with a mean age of 59.5±18.5 years were enrolled. 10 patients were randomized to the Tocilizumab group and 10 patients were to the placebo group. Baseline characteristics of the patients were not different between the two groups. Alcohol and gallstone were the majority of the etiology of pancreatitis in both groups (45% and 40%, respectively). There were no statistical differences in the duration of the onset of the symptom onset (16.6±14.3 vs 16.4±14.1 hours; p=0.98), the BISAP score (2.6±0.7 vs 2.3 ±0.8; p=0.39) or the modified Marshall score (2.7±1.8 vs 2.7±1.9; p=1.00) between the Tocilizumab and placebo groups, respectively. At 48 hours, there was a significantly higher reduction in CRP (-41.9% vs +31.7%; p<0.01) and increase in IL-6 level (+74.2% vs -44.75; p<0.01) in Tocilizumab group compared to placebo, respectively. There was no difference of Procalcitonin level between both groups at 48 hours. There were no statistical differences in the total hospitalization duration (11.5±7.0 vs 14.4±8.0 days; p=0.40), local complications (0 vs 0%), or mortality rate (30% vs 10%; p=0.58). No Tocilizumab-related adverse event occurred.
Conclusion:
Like murine model and in contrast to CRP level, after giving Tocilizumab in patients with predicted severe pancreatitis, at 48 hr, IL-6 level increased significantly despite no difference in clinical outcomes when compared with controls. We speculate that free serum IL-6 increased because the elimination half-life was prolonged by the formation of tocilizumab/sIL-6R immune complex that inhibiting IL-6R mediated consumption.