Background/Purpose:

Deficiency of interleukin-1 receptor antagonist (DIRA) is a neonatal-onset autoinflammatory syndrome caused by mutations in IL1RN gene and clinically characterized by a perinatal onset of pustular dermatosis, aseptic multifocal osteomyelitis and marked elevation of acute phase reactants. Individual reports have been shown that these patients present a prompt response to the recombinant human IL-1 receptor antagonist (IL1Ra) anakinra. However, long-term efficacy and safety of anakinra treatment in DIRA patients have not been assessed. Thus, the objectives of this study were to assess the clinical and laboratory findings of patients with DIRA followed at the NIH and enrolled in a natural history study to assess long-term outcomes in autoinflammatory syndromes patients.

Methods:

Eight patients with a genetically confirmed diagnosis of DIRA were followed longitudinally. Demographic, clinical and laboratory findings and response to treatment variables were collected for each patient at the enrollment and subsequent clinical visits.  Statistical analyses were performed using unpaired t- test with Welch’s correction.

Results:

Four (50%) patients were female. Age at disease onset ranged from 1 to 15 days of life and age at anakinra starting was 11 (2 – 114) months. Five patients had been receiving anakinra 4 to 54 months prior to the study enrollment. Before IL1Ra was started, 5 patients presented with intermittent fever; all 8 patients had mild to severe pustular rashes and 5 had nail abnormalities. Various degrees of multifocal osteomyelitis were observed in all patients and 3 had odontoid non-fusion. Unspecific lung disease was observed in 3 patients, 2 patients presented thrombotic events and 2 had vasculitis. Laboratory findings prior to anakinra showed mild to severe anemia and increased white blood cell (WBC) count in all 8 patients and thrombocytosis in 5. C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) were elevated in all 8 patients. At the last follow-up visit (6 to 48 month), time on anakinra was 35 (20 – 102) months and anakinra doses ranged from 2.1 to 5.1 (median: 3.5) mg/kg/day. At that time, none of the patients had developed new osteomyelitis lesions, nor pustular skin manifestations and CRP and ESR were 0.21 (0.016 – 0.579) mg/dL and 7 (3 – 13) mm/h, respectively. All patients fulfilled criteria for inflammatory and clinical remission, except for one patient that had CRP of 0.579mg/dL. While acute phase reactants had almost normalized at the time of the first NIH visit, a decrease in the platelets (502 ± 180.0 vs. 273 ± 32.3 x 10³cells/mm³, p=0.016) and in the WBC (15.96 ± 6.56 vs. 8.44 ± 1.98 x 10³cells/mm³, p=0.023) was seen and took longer to normalize. Three serious adverse events were observed: rash and pneumonia in one patient and subarachnoid bleed in one patient. Anakinra was considered well tolerated and an increase of opportunistic or recurrent infections was not observed within the enrolled patients. 

Conclusion: DIRA patients on treatment with anakinra for 20-102 months presented with a sustained clinical and laboratory response and no patient developed novel inflammatory lesions while on treatment. Anakinra is well tolerated and none of the patients has discontinued therapy.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/safety-and-efficacy-of-anakinra-in-patients-with-deficiency-of-interleukin-1-receptor-antagonist/