JAK1/2 inhibition with baricitinib in the treatment of autoinflammatory interferonopathies.

BACKGROUND: Monogenic IFN-mediated autoinflammatory diseases present in infancy with systemic inflammation, an IFN response gene signature, inflammatory organ damage, and high mortality. We used the JAK inhibitor baricitinib, with IFN-blocking activity in vitro, to ameliorate disease. METHODS: Between October 2011 and February 2017, 10 patients with CANDLE (chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures), 4 patients with SAVI (stimulator of IFN genes-associated [STING-associated] vasculopathy with onset in infancy), and 4 patients with other interferonopathies were enrolled in an expanded access program. The patients underwent dose escalation, and the benefit was assessed by reductions in daily disease symptoms and corticosteroid requirement. Quality of life, organ inflammation, changes in IFN-induced biomarkers, and safety were longitudinally assessed. RESULTS: Eighteen patients were treated for a mean duration of 3.0 years (1.5-4.9 years). The median daily symptom score decreased from 1.3 (interquartile range [IQR], 0.93-1.78) to 0.25 (IQR, 0.1-0.63) (P < 0.0001). In 14 patients receiving corticosteroids at baseline, daily prednisone doses decreased from 0.44 mg/kg/day (IQR, 0.31-1.09) to 0.11 mg/kg/day (IQR, 0.02-0.24) (P < 0.01), and 5 of 10 patients with CANDLE achieved lasting clinical remission. The patients' quality of life and height and bone mineral density Z-scores significantly improved, and their IFN biomarkers decreased. Three patients, two of whom had genetically undefined conditions, discontinued treatment because of lack of efficacy, and one CANDLE patient discontinued treatment because of BK viremia and azotemia. The most common adverse events were upper respiratory infections, gastroenteritis, and BK viruria and viremia. CONCLUSION: Upon baricitinib treatment, clinical manifestations and inflammatory and IFN biomarkers improved in patients with the monogenic interferonopathies CANDLE, SAVI, and other interferonopathies. Monitoring safety and efficacy is important in benefit-risk assessment. TRIAL REGISTRATION: ClinicalTrials.gov NCT01724580 and NCT02974595. FUNDING: This research was supported by the Intramural Research Program of the NIH, NIAID, and NIAMS. Baricitinib was provided by Eli Lilly and Company, which is the sponsor of the expanded access program for this drug.

Effect of long-term intermittent and sustained hypoxia on hypoxic ventilatory and metabolic responses in the adult rat.

The effects of chronic sustained hypoxia (SH) on ventilation have been thoroughly studied. However, the effects of intermittent hypoxia (IH), a more prevalent condition in health and disease are currently unknown. We hypothesized that the ventilatory consequences of SH and IH may differ and be related to changes in N-methyl-D-aspartate (NMDA) glutamate receptor subunit expression. To examine these issues, Sprague-Dawley adult male rats were exposed to 30 days of either SH (10% O2) or IH (21% and 10% O2 alternations every 90 s) or to normoxia (RA), at the end of which ventilatory and O2 consumption responses to a 20-min acute hypoxic challenge (10% O2) were conducted. In addition, dorsocaudal brain stem tissue lysates were harvested at 1 h, 6 h, 1 day, 3 days, 7 days, 14 days, and 30 days of SH and IH and analyzed for NR1, NR2A, and NR2B NMDA glutamate receptor expression by immunoblotting. Normoxic ventilation was higher after both SH and IH (P < 0.001). Peak hypoxic ventilatory response was higher after SH but not after IH compared with RA. However, hypoxic ventilatory decline was more prominent after SH than IH (P < 0.001). NR1 expression showed a biphasic pattern of expression over time that was essentially identical after IH and SH (P value not significant). However, NR2A and NR2B expression was higher in IH compared with SH and RA (P < 0.01). We conclude that long-lasting exposures to SH and IH enhance normoxic ventilation but are associated with different time domains of ventilation during acute hypoxia that may be accounted in part by changes in NMDA glutamate receptor subunit expression.

Respiratory effects of gestational intermittent hypoxia in the developing rat.

Intermittent hypoxia (IH), one of the hallmarks of obstructive sleep apnea, occurs more frequently during pregnancy. We hypothesized that IH may lead to persistent postnatal changes in respiratory responses to acute hypoxia and may also lead to adverse effects on spatial function learning as revealed by the Morris water maze. To examine this issue, time-pregnant Sprague-Dawley rats were exposed to IH and room air (IHRA; 21 and 10% O2 alternations every 90 seconds) or to normoxia (RARA) until delivery. Ventilatory and metabolic responses to a 20-minute acute hypoxic challenge (10% O2) were conducted at postnatal ages 5, 10, 15, and 30 days. In addition, spatial task learning was assessed in the water maze at 1 and 4 months of age. Normoxic ventilation was higher at all time points in IHRA rats than in RARA rats (p < 0.01). Peak hypoxic ventilatory responses were attenuated in IHRA rats at 5 days of age and hypoxic ventilatory depression was accentuated at this age as well. However, ventilatory equivalents (minute ventilation/oxygen consumption) revealed significant reductions in peak hypoxic ventilatory responses of IHRA rats and hypoxic ventilatory depression at all postnatal ages (p < 0.01). Acquisition and retention of a spatial task were similar in the IHRA and RARA groups at both 1 and 4 months of age. We conclude that gestational intermittent hypoxia elicits long-lasting alterations in the control of breathing. We postulate that such IH-induced respiratory plasticity may create selective vulnerability to hypoxia during development.

Treatment of obstructive sleep apnea in children: do we really know how?

Obstructive sleep apnea syndrome (OSAS) is a frequent, albeit underdiagnosed problem in children. If left untreated, OSAS may lead to substantial morbidities affecting multiple target organs and systems. The immediate consequences of OSAS in children include behavioral disturbance and learning deficits, pulmonary hypertension, as well as compromised somatic growth. However, if not treated promptly and early in the course of the disease, OSAS may also impose long-term adverse effects on neurocognitive and cardiovascular function, thereby providing a strong rationale for effective treatment of this condition. This review provides a detailed description of the current treatment modalities for pediatric OSAS, and uncovers the potential limitations of the available data on these issues. Furthermore, we postulate that OSAS will persist relatively often after tonsillectomy and adenoidectomy, and that critical studies need to be conducted to identify such patients and refine the clinical management algorithm for pediatric OSAS.

Domoic acid lesions in nucleus of the solitary tract: time-dependent recovery of hypoxic ventilatory response and peripheral afferent axonal plasticity.

The nucleus of the solitary tract (NTS) plays a pivotal role in the ventilatory response to hypoxia (HVR). However, the effects of excitotoxic lesions and the potential for functional recovery and plasticity remain unknown. Domoic acid (DA) or vehicle were bilaterally injected within the NTS of adult male Sprague Dawley rats. HVR (10% O(2)) and anatomical changes were assessed at 5-90 d after surgery. DA induced dose-dependent HVR attenuations ( approximately 70% at peak effect) that exhibited saturation at concentrations of 0.75-1.0 mm. However, although sodium cyanide-induced ventilatory responses were virtually abolished, DA did not modify baroreceptor gain. Consistent with ventilatory reductions, NTS neurons showed a significant degeneration 3 d after DA injection. In addition, the projection fields and the density of vagal afferent terminals to the NTS, and the motor neurons in the dorsal motor nucleus of the vagus were substantially reduced at 15 d. At 30 d, no functional or neural recovery were apparent. However, at day 60, the reduction in HVR was only approximately 40% of control, and at 90 d, HVR returned to control levels, paralleling regeneration of vagal afferent terminals within the NTS. The regeneration was particularly prominent in the commissural and dorsomedial subnuclei in the absence of cellular recovery. Thus, the integrity of the NTS is critical for HVR, spontaneous HVR recovery occurs after excitotoxic lesions in the NTS, and vagal-glossopharyngeal terminal sprouting in the NTS may underlie the anatomical substrate for such spontaneous functional recovery. The adult brainstem/NTS has self-repairing capabilities and will compensate for functional losses after structural damage by rewiring of its neural circuitry.

Circulating vascular endothelial growth factor levels in patients with obstructive sleep apnea.

STUDY OBJECTIVES: Obstructive sleep apnea (OSA) is associated with intermittent hypoxia during sleep. Vascular endothelial growth factor (VEGF) has detectable levels in the circulation and its expression is highly regulated by oxygen tension. We therefore hypothesized that serum VEGF levels will be elevated in patients with OSA. DESIGN: Blood samples were collected at random times during the day from 68 adults and 41 children who were clinically suspected for the presence of OSA, and who underwent overnight polysomnography. SETTING: University hospital sleep laboratory. PARTICIPANTS: N/A. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: For both children and adults, serum VEGF levels were significantly higher in polysomnographically confirmed OSA (AHI>15 and AI>5 in adults and children respectively) when compared to those with mild or no disease (p<0.0001). Furthermore, significant correlations were found between VEGF concentrations and respiratory disturbance index and sleep time spent at SpO2 <90%. In addition, VEGF levels in children were higher for any given duration of hypoxia during sleep (p<0.0001). No differences in VEGF emerged between evening and morning samples. However, temporal delays in blood sample processing were associated with spuriously increased VEGF concentrations. Exploratory analysis of the data revealed that serum VEGF concentrations of >150 pg/ml in adults and >100 pg/ml in children were predictive of OSA, when an apnea-hypopnea index >30 and an apnea index >5 were used as disease criteria in adults and children, respectively. CONCLUSIONS: We conclude that circulating VEGF levels are frequently elevated in OSA patients, and may play a role in the regulation of tissue oxygen delivery.

Gasping and autoresuscitation in the developing rat: effect of antecedent intermittent hypoxia.

Gasping is a critically important mechanism for autoresuscitation and survival during extreme tissue hypoxia. Evidence of antecedent hypoxia in sudden infant death syndrome suggests that intermittently occurring hypoxic episodes may modify gasping and autoresuscitation. To examine this issue, an intermittent hypoxia (IH) profile consisting of alternating room air and 10% O(2)-balance N(2) every 90 s was applied to pregnant Sprague-Dawley rats (IHRA; n = 50) and to pups after a normal pregnancy (RAIH; n = 50) as well as to control pups (RARA; n = 50). At postnatal day 5, pups were exposed to 95% N(2)-5% CO(2), and gasping and the ability to autoresuscitate were assessed. Compared with RARA, IHRA- and RAIH-exposed pups had a reduced number of gasps, decreased overall gasp duration, and were less likely to autoresuscitate on introduction of room air to the breathing mixture during the last phase of gasping (P < 0.001 vs. RARA). We conclude that both prenatal and early postnatal IH adversely affect gasping and related survival mechanisms.