Objective Blocking interleukin-1 with anakinra in patients with the autoinflammatory syndrome neonatal-onset multisystem inflammatory disease (NOMID) reduces systemic and organ-specific inflammation. However, the impact of long-term treatment has not been established. This study was undertaken to evaluate the long-term effect of anakinra on clinical and laboratory outcomes and safety in patients with NOMID. Methods We conducted a cohort study of 26 NOMID patients ages 0.80–42.17 years who were followed up at the NIH and treated with anakinra 1–5 mg/kg/day for at least 36 months. Disease activity was assessed using daily diaries, questionnaires, and C-reactive protein level. Central nervous system (CNS) inflammation, hearing, vision, and safety were evaluated. Results Sustained improvements in diary scores, parent’s/patient’s and physician’s global scores of disease activity, parent’s/patient’s pain scores, and inflammatory markers were observed (all P < 0.001 at 36 and 60 months). At 36 and 60 months, CNS inflammation was suppressed, with decreased cerebrospinal fluid white blood cell counts (P = 0.0026 and P = 0.0076, respectively), albumin levels, and opening pressures (P = 0.0012 and P < 0.001, respectively). Most patients showed stable or improved hearing. Cochlear enhancement on magnetic resonance imaging correlated with continued hearing loss. Visual acuity and peripheral vision were stable. Low optic nerve size correlated with poor visual field. Bony lesions progressed. Adverse events other than viral infections were rare, and all patients continued to receive the medication. Conclusion These findings indicate that anakinra provides sustained efficacy in the treatment of NOMID for up to 5 years, with the requirement of dose escalation. Damage progression in the CNS, ear, and eye, but not bone, is preventable. Anakinra is well tolerated overall.

A B S T R A C T PurposeTo assess the role of the recombinant bacterial enzyme, glucarpidase (carboxypeptidase-G 2 ), leucovorin, and thymidine in the management and outcome of patients with high-dose methotrexate (HDMTX) -induced nephrotoxicity. MethodsPatients with HDMTX-induced nephrotoxicity received one to three doses of intravenous (IV) glucarpidase and leucovorin rescue. The initial cohort (n ϭ 35) also received thymidine by continuous IV infusion. Subsequently, thymidine was restricted to patients with prolonged exposure (Ͼ 96 hours) to methotrexate (MTX) or with substantial MTX toxicity at study entry. Plasma MTX, leucovorin, and 5-methyltetrahydrofolate (5-mTHF) concentrations were measured pre-and postglucarpidase. Toxicities were monitored, and logistic regression analysis was used to assess the relationship of baseline characteristics to the development of severe toxicity and death. ResultsGlucarpidase was administered at a median of 96 hours (receiving thymidine, n ϭ 44) and 66 hours (not receiving thymidine, n ϭ 56) after the start of the MTX infusion. Plasma MTX concentrations decreased within 15 minutes of glucarpidase by 98.7%. Plasma 5-mTHF concentrations also decreased more than 98% after administration of glucarpidase. Of 12 deaths, six were directly attributed to irreversible MTX toxicity. Presence of grade 4 toxicity before administration of glucarpidase, inadequate initial increase in leucovorin dosing, and administration of glucarpidase more than 96 hours after the start of the MTX infusion were associated with development of grade 4 and 5 toxicity. ConclusionEarly intervention with the combination of leucovorin and glucarpidase is highly effective in patients who develop HDMTX-induced renal dysfunction. Severe toxicity and mortality occurred in patients in whom glucarpidase rescue was delayed and occurred despite thymidine administration.

Oral tipifarnib is well tolerated in children receiving the drug twice daily for 21 days and a continuous dosing schedule at 200 mg/m2/dose, which is equivalent to the MTD in adults. The pharmacokinetic profile of tipifarnib in children is similar to that in adults, and at the MTD, FTase is inhibited in PBMC in vivo.