gms | German Medical Science

Background: Blau syndrome is a monogenic disease resulting from mutations in the pattern recognition receptor NOD2, and is phenotypically characterized by the classical triad of granulomatous polyarthritis, dermatitis and uveitis. However, extra-triad symptoms have increasingly been reported including, but not limited to, vasculitis, granulomatous glomerular and interstitial nephritis, interstitial lung disease, arterial hypertension, pericarditis, and hepatic granulomata [1].

Therapy of Blau syndrome is challenging with following medications being reported with varying responses: steroids, methotrexate, TNF-blocker, anti-Il-1 and anti-IL-6 targeted therapies.

Methods: The objective of this study is to describe the case of a Blau syndrome patient refractory to conventional therapies benefiting from anti-IL-17 therapy.

Results: The female patient of African origin presented at the age of six months with recurrent high fever episodes for days to weeks, polyarthritis, erythematous and ichthyosiform skin manifestations, severe panuveitis, granulomatous liver disease, kidney disease with tubulopathy and severe arterial hypertension. Laboratory evaluation revealed highly elevated inflammation parameters (C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), Serum Amyloid A (SAA)). Liver biopsy showed granulomatous liver disease. Broad infectious disease work-up including tuberculosis was negative. The family history was unremarkable regarding inflammatory or immunological diseases. The suspicion of Blau syndrome was made and genetic analyses revealed a novel de novo mutation in the NOD2 Gene (c.[1807C>A]; Histidin603> Asparagin) confirming the diagnosis Blau syndrome.

The patient was consecutively treated with each high doses of steroids, IL-1 receptor antagonist (anakinra up to 10mg/kg/d) and anti-TNF antibodies (allergic reaction to 3rd dose of infliximab, adalimumab up to 40mg (5mg/kg weekly)) in addition to maintenance doses of steroids, none of which with sustained success. Therefore a hitherto novel therapeutic approach was initiated with an anti-IL-6 therapy (tocilizumab; up to 20mg/kg every 2 weeks) which yielded a good, yet only contemporary response for up to 6 months.

As significant amounts of IL-17 have been identified in granuloma biopsies of Blau syndrome patients² we decided to start a novel therapy targeting the Il-23 / IL-17 pathway. We first used the anti-IL-12 / IL-23 antibody ustekinumab (up to 6mg/kg every 3 weeks) which led to striking clinical and laboratory response for up to 6 months but then lost effectiveness. Therefore we switched to the anti-IL-17A antibody secukinumab (up to 17mg/kg every 4 weeks) leading to substantial therapeutic response again. The patient has now been successfully treated with this therapy for 10 months together with a maintenance dose of prednisolone (0,2 mg/kg/d), electrolyte substitutions due to her tubulopathy and anti-hypertensive therapy. No substantial side effects have been observed so far. Further observation is needed for long term evaluation of the anti-IL-17 therapy response in this single patient.

Conclusion: This case report might encourage the use and report of high-dose anti-IL-17 therapies in further refractory Blau syndrome patients. The repeated secondary loss of effectiveness towards anti-IL-6 antibody tocilizumab and anti-IL-12 / IL-23 antibody ustekinumab after several months of successful treatment might be related to anti-drug antibody formation or the specific pathophysiology of Blau syndrome.