Biologic Disease-Modifying Antirheumatic Drugs to Treat Multisystem Inflammatory Syndrome in Children

Randy Q. Cron


Curr Opin Rheumatol. 2022;34(5):274-279. 

In This Article

Biological Disease-modifying Antirheumatic Drug use in Multisystem Inflammatory Syndrome in Children

Decades ago, IVIg was shown to dramatically reduce the incidence of coronary artery abnormalities in children with KD, and is considered a mainstay of therapy for MIS-C.[38] The mechanism of action of IVIg in treating hyper-inflammation is multifactorial, including blockade of Fc receptors on phagocytic cells, neutralization of cytokines by specific antibodies, complement inhibition, alterations of regulatory T cells, and many others.[39] There are likely multiple mechanisms involved, and IVIg is often used to treat secondary HLH, particularly when triggered by infection.[40] Since MIS-C shares many features with KD, including coronary artery derangements, IVIg has been standard first-line therapy for children hospitalized with MIS-C.[38] IVIg has largely been effective at treating MIS-C,[41] but the addition of GCs to IVIg has been reported to lower the risk of new or persistent cardiovascular dysfunction compared to IVIg alone.[16] Nonetheless, a small subset of children with MIS-C may require additional anti-inflammatory approaches, including targeting of pro-inflammatory cytokines with bDMARDs.

Not knowing which bDMARDs will be effective in treating IVIg and GC refractory MIS-C, initial approaches used anticytokine therapies employed in refractory KD and other secondary HLH.[42] The use of IL-1 inhibition with anakinra (recombinant IL-1 receptor antagonist) was explored early during the pandemic to treat refractory MIS-C.[3,9,11,12] Anakinra was also selected for its rapid and high benefit to side-effect ratio.[43] Additionally, anakinra has a short half-life and a wide therapeutic dosing range making it an attractive therapeutic for CSS.[44] Anakinra has been reported to be highly efficacious in treating many secondary HLH patients,[45,46] and even a case of familial HLH.[33] Moreover, anakinra has anecdotally been reported to treat severe refractory KD,[47] and anakinra is undergoing clinical trials for children with KD coronary artery aneurysms.[48] The shared features between KD and MIS-C, along with anakinra's reported benefits in treating MIS-C, have resulted in anakinra being recommended as an option for MIS-C refractory to IVIg and CS in the latest version of the American College of Rheumatology (ACR) MIS-C clinical guidance treatment algorithm.[38]

The other therapeutic bDMARD option listed in the most recent ACR MIS-C clinical guidance for refractory MIS-C algorithm is infliximab.[38] Infliximab is a monoclonal antibody (mAb) directed against TNF, another pro-inflammatory cytokine implicated in CSS.[49] Perhaps, more relevant, infliximab has proven beneficial in treating refractory KD, even more so than a second dose of IVIg.[50] Thus, early during the pandemic, infliximab was explored for treatment of refractory MIS-C.[3,11] Anecdotally, a clinical case series has reported benefit with infliximab used to treat a dozen children with MIS-C.[51] Fortunately, many children with MIS-C and coronary artery dilation and aneurysms resolve coronary abnormalities as detected by cardiac echocardiogram during outpatient hospital follow-up visits.[52] These studies have included children with MIS-C treated with anakinra, inflixamb, and the anti-IL-6 receptor mAb tocilizumab.[52]

IL-6 is yet another pro-inflammatory cytokine implicated in the pathogenesis of various CSSs.[49] The bDMARD tocilizumab, which blocks IL-6 signaling, garnered a lot of attention early during the COVID-19 pandemic, as IL-6 was noted to be elevated in the serum of severe COVID-19 patients.[53] Early reports suggested tociliuzumab treatment helped severe COVID-19 patients, and meta-analyses have demonstrated some benefit to those with severe COVID-19 pneumonia.[54,55] As soon as MIS-C was recognized as a SARS-CoV-2-associated illness, tocilizumab was also explored as a therapeutic option for children with refractory MIS-C.[11,12] Tocilizumab has been reported in case series to benefit children with MIS-C experiencing cardiogenic shock.[56,57] Tocilizumab has a track record in treating various CSS, and it has the United States Food and Drug Administration (FDA) approval to treat cytokine release syndrome associated with chimeric antigen receptor T cell therapy for refractory leukemia and lymphoma.[58]

Another recent FDA approval for CSS is the anti-IFNγ mAb emapalumab demonstrated to benefit infants with fHLH.[59] Like IL-1, IL-6, and TNF, IFNγ is also elevated in the serum of children with MIS-C.[9,15] In part, as this therapeutic is not readily available, there has been little exploration of its role in MIS-C. Nonetheless, IFNγ is a central cytokine in many CSS scenarios, and blockade with emapalumab may theoretically benefit children with refractory MIS-C. Another CSS-associated pro-inflammatory cytokine found to be elevated in MIS-C is the IL-1 family member IL-18.[9,60] Like IL-1, IL-18 has a natural inhibitor, IL-18 binding protein that, like anakinra, is a therapeutic agent, takedinig alfa. Takedinig alfa has been used to successfully treat a CSS in a child with an autoinflammatory condition resulting from a dominant mutation in NLRC4.[61] Hypothetically, IL-18 blockade may also be of benefit to children suffering refractory MIS-C. Whether targeting IFNγ, IL-18, or other pro-inflammatory cytokines elevated in MIS-C (e.g. IL-17) will benefit children with refractory MIS-C remains unclear. Fortunately, despite a reported ~1.5% mortality rate, outcomes have been very favorable for treating refractory MIS-C using the currently tested bDMARDs that block IL-1, IL-6, and TNF.[56,62–64]