Background/Purpose: Animal and human data suggest that IFNγ plays a pathogenic role in HLH. A phase 2 trial with the anti-IFNγ monoclonal antibody NI-0501 in primary HLH provides encouraging preliminary data. Gain-of-function mutations in NLRC4 are associated with a distinct autoinflammatory syndrome, with recurrent HLH, fever episodes and enterocolitis.

Methods: We reported a patient with severe early onset progressive HLH carrying a de novo missense mutation in NLRC4(T337N), the immune abnormalities leading to abnormal production of IFNγ and the response to treatment with NI-0501. We evaluated cytokine levels by multiplex assay and by specific ELISAs and expression of IFNγ in freshly isolated PBMCs by cytometry.

Results: LR, caucasian male, presented, at 20 days of age, fever and rash and progressively developed clinical and laboratory features of HLH leading rapidly to liver failure and subsequent multiorgan failure. Genes causing primary-HLH and functional tests were negative. High-dose glucocorticoids and cyclosporine-A led to partial improvement. Development of sepsis triggered HLH reactivation. Measurable IFNγ levels (6pg/ml) and high levels of the IFNγ inducible chemokines CXCL9 (5670pg/ml) and CXCL10 (4400pg/ml) were found, the latter demonstrating activation of the IFNγ pathway. NI-0501 was started (compassionate use) on background of dexamethasone (13.6mg/m2) and cyclosporine-A. After 3 months, the child was discharged in excellent conditions (prednisone 0.3 mg/kg). Markedly elevated production of IFNγ was revealed by the administration of NI-0501 through measurement of total IFNγ bound to circulating NI-0501. This IFNγ was fully neutralized, as shown by rapidly undetectable levels of CXCL9 and CXCL10. The percentage of CD4+, CD8+ and CD56+ cells expressing IFNγ was significantly increased in the NLRC4 patient without (0.95%, 0.88%, 0.80%, respectively) and with stimulation with PMA/ionomycin (6.44%, 10.20%, 25,00%). Serum levels of IL-18 were markedly higher (as expected in NLRC4-mediated disease) at >300 ng/ml before treatment and remained elevated throughout treatment (ranging between 25 and 35 ng/ml), with the patient showing no symptoms. Incubation of PBMCs from healthy controls with NLRC4 patient’s sera in the presence of IL-12 (known costimulus for IFNγ synthesis) led to a marked hyperproduction of IFNγ (>20ng/ml), compared to sera from patients with other autoinflammatory diseases (0.59±0.47 ng/ml). This increase in IFNγ production was neutralized by incubation with an anti-IL18 receptor antibody. After 7 months of NI-0501 treatment, all therapies, including NI-0501, were discontinued, without any clinical or laboratory sign of HLH reactivation, even in the presence of occasional increases in IL-18 levels.

Conclusion: Our data suggest that in NLRC4-related disease overproduction of IL-18, induced by an hyperfunctional NLRC4 inflammasome, may be one of the contributors to the up-regulation of IFNγ production that appears to be driving HLH. In this patient, neutralization of IFNγ allowed control of all disease features, enabling withdrawal of all treatments, including glucocorticoid and cyclosporyn-A. No safety concern emerged. C.B. and G.P. contributed equally to this study

« Back to 2016 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/immune-abnormalities-leading-to-exaggerated-production-of-ifn-gamma-ifn%ce%b3-and-the-therapeutic-response-to-an-anti-ifn%ce%b3-antibody-in-a-patient-with-nrlc4-mediated-disease/