Infliximab, steroids may outperform anakinra for IVIG-resistant MIS-C

Infliximab or corticosteroids may be more effective than anakinra as adjunctive therapy for children with multisystem inflammatory syndrome in children (MIS-C) who do not respond to intravenous immunoglobulin (IVIG), according to results of the randomized MISTIC trial published in The Journal of Pediatrics.¹

After adjustment for age and sex, children initially treated with anakinra had significantly greater odds of requiring an additional randomized anti-inflammatory therapy compared with those initially treated with infliximab (odds ratio [OR], 3.42; 95% CI, 1.03-12.29; P = .049).¹

“Thus, based on this study, infliximab or steroids may be more effective than anakinra as adjunctive therapy for MIS-C,” the investigators wrote.¹

Comparing adjunctive therapies for IVIG-resistant MIS-C

MIS-C emerged during the COVID-19 pandemic as a serious inflammatory condition occurring after SARS-CoV-2 exposure. Although some children improve with IVIG alone, patients with persistent fever, inflammation, or cardiovascular dysfunction may require additional anti-inflammatory therapy. Infliximab, anakinra, and corticosteroids have all been used, but comparative randomized evidence has been limited.¹

The MISTIC trial was conducted at Rady Children’s Hospital San Diego and Children’s Hospital of Michigan from December 2020 through October 2022. Children with MIS-C who did not respond to IVIG were randomized to infliximab, intravenous methylprednisolone, or anakinra. Participants who did not respond to their first randomized treatment could undergo a second randomization to 1 of the remaining therapies.¹

Investigators screened 100 patients with MIS-C. Five responded to IVIG alone, and 73 were enrolled and randomized. Two patients assigned to anakinra were withdrawn before receiving the drug because they were found to be ineligible, leaving 71 patients in the analysis: 25 receiving infliximab, 24 receiving steroids, and 22 receiving anakinra. The median patient age was 7.6 years, and 62% were male.¹

Anakinra associated with greater need for additional therapy

The primary outcome was the need for a second randomization. This occurred in 40% of patients initially receiving infliximab, 41.7% receiving steroids, and 68.2% receiving anakinra.¹

After adjustment for age and sex, patients receiving anakinra had 3.42-fold higher odds of requiring second randomization compared with infliximab. The adjusted odds were also higher with anakinra compared with steroids, but the difference was not statistically significant (OR, 2.94; 95% CI, 0.88-10.50; P = .086). Odds were similar for steroids compared with infliximab (OR, 1.17; 95% CI, 0.36-3.78; P = .797).¹

The investigators noted, “This was the case even though the median difference of the CRP prior to administration of the first randomized drug was higher in patients who received infliximab compared with anakinra, suggesting that even in a patient with more inflammation, the need for additional anti-inflammatory therapy was less if the first randomized drug was infliximab rather than anakinra.”¹

No significant differences were observed among treatment groups in fever cessation, time to a 50% reduction in C-reactive protein, duration of inotropic support, recovery of left ventricular ejection fraction, or hospital length of stay.¹

Safety findings and study limitations

Twenty-eight adverse events occurred, with none classified as serious. Investigators considered 17 possibly, probably, or definitely related to study treatment. Of these, 16 were attributed to steroids and 1 to anakinra. Bradycardia accounted for 8 steroid-related adverse events.¹

The study was limited by its smaller-than-planned enrollment. Investigators initially sought 108 evaluable participants, but declining MIS-C incidence led to administrative closure with 71 patients completing the trial, potentially limiting statistical power. Masking also was not possible because administration differed among the 3 therapies.¹

“In conclusion, participants with IVIG-resistant MIS-C who received anakinra as their first treatment regimen in combination with IVIG had significantly higher odds of needing a second randomization compared with those who were treated with infliximab or steroids,” the authors wrote.¹

Reference

1. Jain S, He F, Cheng Y, Ang JY, Burns JC, Tremoulet A. Multisystem inflammatory syndrome therapies in children: a comparative effectiveness trial. J Pediatr. Published online August 2026. doi:10.1016/j.jpeds.2026.115293.