Background/Purpose: Evidence based treatment options for children and adults with unclassified autoinflammatory diseases (AID) are limited. Frequently, IL-1-inhibition is primarily tried to control the severe autoinflammatory symptoms. Tocilizumab (TMB) is approved for treatment of systemic juvenile idiopathic arthritis¹. The aim of this study was to evaluate efficacy and safety of Tocilizumab (TMB) in patients with unclassified AID, who did not achieve remission by IL-1-blockade therapy.

Methods: A single-center retrospective cohort study included consecutive children with typical clinical AID features of chronic recurrent fevers and increased inflammatory markers. All children did not meet any of the new classification criteria² for either familial Mediterranean fever (FMF); tumor necrosis factor receptor-associated periodic syndrome (TRAPS); mevalonate kinase deficiency (MKD); cryopyrin-associated periodic syndrome (CAPS) or periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA). All patients were non-responders to IL-1-inhibitors (canakinumab or anakinra) and subsequently received TMB (8-12mg/kg i.v. every 2 weeks). Data collection included demographics, clinical phenotype, inflammatory markers, duration and dose of IL-1-inhibition, disease activity (physician and patient global assessment).  Outcome: remission was defined as VAS of the physician global assessment ≤ 2 and inflammatory markers in the normal reference range (CRP ≤ 0.5mg/dl and/or SAA ≤ 10mg/l).

Results:
 

Seven patients met the inclusion criteria, five males (71%) and two females (29%); median age at start of TMB therapy was 9 years (range 2-17). First follow-up was after 3 months (range 3-6) and second follow-up was after 12 months (range 10-14) of TMB therapy. At baseline, median disease activity (VAS physician) was 4 (range 2-6) and decreased to 1 (range 0-5) at first follow-up and again 1 (range 0-3) at second follow-up. Median CRP decreased from 1.23 mg/dl at baseline to 0.01 mg/dl at first follow-up. At baseline, median SAA levels were 20 mg/l (range 1-1010) and decreased to 1 mg/l (range 1-1.9) at first follow-up. At first follow-up, 4/7 patients (57%) achieved remission and at second follow-up, 4/5 patients met remission criteria (80%). One patient, who did not achieve remission at first follow-up, fulfilled the remission criteria at second follow-up. Over the entire observation period, a total of 5 patients (71%) achieved remission. Adverse events (neutropenia) were observed in 2 patients (29%).

Conclusion: TMB appears to be an effective treatment option for patients with unclassified AIDs, who do not respond favorably to IL-1-blockade. No unexpected adverse events occured. Clinical features and inflammatory markers rapidly improved; the response was sustained at the 12 months follow-up. Translational studies are urgently required to define the optimal treatment target in unclassified AIDs early on.

References:

(1) de Benedetti F, et al. N Engl J Med 2012; 367:2385-2395

(2) Gattorno M, Hofer M, Federici S, et al. Ann Rheum Dis 2019; April 24

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/tocilizumab-an-effective-rescue-therapy-for-refractory-unclassified-autoinflammatory-diseases-in-children/