Efficacy and safety of emapalumab in macrophage activation syndrome.

OBJECTIVES: Macrophage activation syndrome (MAS) is a severe, life-threatening complication of systemic juvenile idiopathic arthritis (sJIA) and adult-onset Still's disease (AOSD). The objective of this study was to confirm the adequacy of an emapalumab dosing regimen in relation to interferon-γ (IFNγ) activity by assessing efficacy and safety. The efficacy outcome was MAS remission by week 8, based on clinical and laboratory criteria. METHODS: We studied emapalumab, a human anti-IFNγ antibody, administered with background glucocorticoids, in a prospective single-arm trial involving patients who had MAS secondary to sJIA or AOSD and had previously failed high-dose glucocorticoids, with or without anakinra and/or ciclosporin. The study foresaw 4-week treatment that could be shortened or prolonged based on investigator's assessment of response. Patients entered a long-term (12 months) follow-up study. RESULTS: Fourteen patients received emapalumab. All patients completed the trial, entered the long-term follow-up and were alive at the end of follow-up. The investigated dosing regimen, based on an initial loading dose followed by maintenance doses, was appropriate, as shown by rapid neutralisation of IFNγ activity, demonstrated by a prompt decrease in serum C-X-C motif chemokine ligand 9 (CXCL9) levels. By week 8, MAS remission was achieved in 13 of the 14 patients at a median time of 25 days. Viral infections and positive viral tests were observed. CONCLUSIONS: Neutralisation of IFNγ with emapalumab was efficacious in inducing remission of MAS secondary to sJIA or AOSD in patients who had failed high-dose glucocorticoids. Screening for viral infections should be performed, particularly for cytomegalovirus. TRIAL REGISTRATION NUMBER: NCT02069899 and NCT03311854.

Emapalumab treatment in an ADA-SCID patient with refractory hemophagocytic lymphohistiocytosis-related graft failure and disseminated bacillus Calmette-Guérin infection.

Emapalumab, a fully human anti-IFNγ monoclonal antibody, has been approved in the US as second-line treatment of primary hemophagocytic lymphohistiocytosis (HLH) patients and has shown promise in patients with graft failure (GF) requiring a second allogeneic hematopoietic stem cell transplantation (HSCT). The blockade of IFNγ activity may increase the risk of severe infections, including fatal mycobacteriosis. We report a case of secondary HLH-related GF in the context of HLA-haploidentical HSCT successfully treated with emapalumab in the presence of concomitant life-threatening infections, including disseminated tuberculosis (TB). A 4 years old girl with Adenosine Deaminase-Severe Combined Immunodeficiency complicated by disseminated TB came to our attention for ex-vivo hematopoietic stem cell-gene therapy. After engraftment failure of gene corrected cells, she received two HLA-haploidentical T-cell depleted HSCT from the father, both failed due to GF related to concomitant multiple infections and secondary HLH. Emapalumab administration allowed to control HLH, as well as to prevent GF after a third haplo-HSCT from the mother. Remarkably, all infections improved with antimicrobial medications and disseminated TB did not show any reactivation. This seminal case supports emapalumab use for treatment of secondary HLH and prevention of GF in patients undergoing haplo-HSCT even in the presence of multiple infections, including TB.

A role for the polyol pathway in the early neuroretinal apoptosis and glial changes induced by diabetes in the rat.

We tested the hypothesis that the apoptosis of inner retina neurons and increased expression of glial fibrillary acidic protein (GFAP) observed in the rat after a short duration of diabetes are mediated by polyol pathway activity. Rats with 10 weeks of streptozotocin-induced diabetes and GHb levels of 16 +/- 2% (mean +/- SD) showed increased retinal levels of sorbitol and fructose, attenuation of GFAP immunostaining in astrocytes, appearance of prominent GFAP expression in Müller glial cells, and a fourfold increase in the number of apoptotic neurons when compared with nondiabetic rats. The cells undergoing apoptosis were immunoreactive for aldose reductase. Sorbinil, an inhibitor of aldose reductase, prevented all abnormalities. Intensive insulin treatment also prevented most abnormalities, despite reducing GHb only to 12 +/- 1%. Diabetic mice, known to have much lower aldose reductase activity in other tissues when compared with rats, did not accumulate sorbitol and fructose in the retina and were protected from neuronal apoptosis and GFAP changes in the presence of GHb levels of 14 +/- 2%. This work documents discrete cellular consequences of polyol pathway activity in the retina, and it suggests that activation of the pathway and "retinal neuropathy" require severe hyperglycemia and/or high activity of aldose reductase. These findings have implications for how to evaluate the role of the polyol pathway in diabetic retinopathy.

Activation of nuclear factor-kappaB induced by diabetes and high glucose regulates a proapoptotic program in retinal pericytes.

To reconstruct the events that may contribute to the accelerated death of retinal vascular cells in diabetes, we investigated in situ and in vitro the activation of nuclear factor-kappaB (NF-kappaB), which is triggered by cellular stress and controls several programs of gene expression. The retinal capillaries of diabetic eye donors showed an increased number of pericyte nuclei positive for NF-kappaB, when compared with nondiabetic donors, whereas endothelial cells were negative. Microvascular cell apoptosis and acellular capillaries were increased only in the diabetic donors with numerous NF-kappaB-positive pericytes. Likewise, high glucose in vitro activated NF-kappaB in retinal pericytes but not in endothelial cells, and increased apoptosis only in pericytes. Studies with NF-kappaB inhibitors suggested that in pericytes, basal NF-kappaB has prosurvival functions, whereas NF-kappaB activation induced by high glucose is proapoptotic. Pericytes exposed to high glucose showed increased expression of Bax and of tumor necrosis factor-alpha, which were prevented by the NF-kappaB inhibitors and mimicked by transfection with the p65 subunit of NF-kappaB, and failed to increase the levels of the NF-kappaB-dependent inhibitors of apoptosis. Colocalization of activated NF-kappaB and Bax overexpression was observed in the retinal pericytes of diabetic donors. A proapoptotic program triggered by NF-kappaB selectively in retinal pericytes in response to hyperglycemia is a possible mechanism for the early demise of pericytes in diabetic retinopathy.

Studies of rat and human retinas predict a role for the polyol pathway in human diabetic retinopathy.

The polyol (sorbitol) pathway of glucose metabolism is activated in many cell types when intracellular glucose concentrations are high, and it can generate cellular stress through several mechanisms. The role of the polyol pathway in the pathogenesis of diabetic retinopathy has remained uncertain, in part because it has been examined preferentially in galactose-induced retinopathy and in part because inhibition studies may not have achieved full blockade of the pathway. Having observed that the streptozotocin-induced diabetic rat accurately models many cellular processes characteristic of human diabetic retinopathy, we tested in the diabetic rat if documented inhibition of the polyol pathway prevents a sequence of retinal vascular abnormalities also present in human diabetes. An inhibitor of aldose reductase, the rate-limiting enzyme in the pathway, prevented the early activation of complement in the wall of retinal vessels and the decreased levels of complement inhibitors in diabetic rats, as well as the later apoptosis of vascular pericytes and endothelial cells and the development of acellular capillaries. Both rat and human retinal endothelial cells showed aldose reductase immunoreactivity, and human retinas exposed to high glucose in organ culture increased the production of sorbitol by a degree similar to that observed in the rat. Excess aldose reductase activity can be a mechanism for human diabetic retinopathy.

Inhibition of MAP-kinase cascade normalizes the proliferation rate of fibroblasts from patients with Type 1 diabetes and nephropathy.

Faster proliferation rate characterizes human skin fibroblasts from patients with Type 1 diabetes and nephropathy (DN), but the reason of this phenomenon is still unknown. Growth factors control cell proliferation through an intracellular mitogen-activated protein (MAP) kinase cascade. We have examined the effect of the inhibition of MAP kinase/ERK kinase (MEK), a key point of the MAP kinase cascade, on the proliferation rate of fibroblasts from 40 patients with Type 1 diabetes (20 with and 20 without DN) and from 10 nondiabetic participants. Proliferation rate was measured by cell count in the presence or absence of 30 mumol/l of the MEK inhibitor PD 098059. In normal cultural conditions, proliferation rate was faster in fibroblasts from patients with (0.175+/-0.009x10(5) cells day-1, mean+/-S.E.M.) than without DN (0.110+/-0.009) and in nondiabetic participants (0.094+/-0.008; ANOVA P<.0001). The inhibition of MEK induced a stronger reduction of proliferation rate in fibroblasts from patients with (0.079+/-0.006x10(5) cells day(-1); 55% of reduction) than without DN (0.068+/-0.006; 38% of reduction) and in nondiabetic participants (0.064+/-0.006; 32% of reduction), and differences among groups were lost. In parallel, PD 098059 induced a greater reduction of MEK-dependent phosphorylation in lysates of fibroblasts from patients with (73%) than without (40%) DN. In conclusion, the inhibition of MEK normalizes the proliferation rate of fibroblasts from patients with DN, suggesting that the MAP kinase cascade could be involved in this cellular dysfunction.