Favourable effect of TNF‐α inhibitor (infliximab) on Blau syndrome in monozygotic twins with a de novoCARD15 mutation

Abstract

Blau syndrome is a hereditary granulomatous disease caused by mutations in the CARD15 gene that is diagnosed in children of young age with exanthema/erythema, arthritis/periarthritis and/or uveitis. We report two cases of Blau syndrome in Danish Caucasian monozygotic male twins, exhibiting a heterozygous de novo R334W mutation in codon 334 of CARD15. The patients were initially diagnosed as having sarcoidosis. In both twins, symptoms (exanthema, arthritis/periarthritis) started at 1 year of age, and were followed by uveitis at 7-10 years of age. There was no involvement of the lungs or other organs. An initial course of standard antituberculous treatment had no effect on the symptoms. Hydroxychloroquine and cyclosporine A were also ineffective, and the latter caused impaired renal function. Partial symptomatic relief was obtained with prednisolone and increased benefit was observed in combination with methotrexate. Subsequent introduction of the TNF-alpha inhibitor eternacept did not discernibly benefit the clinical condition, but was associated with recurrent infections. In contrast, a trial of infliximab therapy demonstrated clinical efficacy and eliminated all symptoms, restoring a high quality of life. At follow up at 20 years of age (after 2-5 years of infliximab treatment) the twins had an almost normal physical appearance and a normal psychomotoric development, indicating a favourable short-term prognosis of the disease. Blau syndrome has pathologic, clinical and therapeutic features in common with sarcoidosis, but rarely involves the lungs or other parenchymatous organs. In children, discrimination between early onset sarcoidosis and Blau syndrome should include a CARD15 mutation analysis.

Childhood sarcoidosis: long-term follow-up

“…The present authors' original series [3] comprised a pair of monozygotic twins having early onset disease with arthritis/periarthritis. They were subsequently diagnosed by genetic analysis as having Blau syndrome [7]. It is possible that many children previously classified as ''early onset sarcoidosis'' may in fact have Blau syndrome if properly investigated for NOD2 mutations.…”

“…From the present series of 49 patients, three patients were excluded: a pair of monozygotic twins, who later proved to have Blau syndrome [7] and an ethnic Lebanese young male who had returned to his country and was unavailable for follow-up. The final series thus comprised 24 males and 22 females (male/female ratio 1:1), all ethnic Caucasian Danes.…”

The spectrum of autoinflammatory diseases: recent bench to bedside observations

“…It is notable that there is no increase in NOD2/ CARD15 mutations in patients with adult-onset sarcoidosis compared with controls [46]. TNF inhibition using infliximab but not etanercept was described as beneficial in a recent report of twins with PGA [47].…”

Diagnosis and Treatment of Blau Syndrome/Early-onset Sarcoidosis, an Autoinflammatory Granulomatous Disease, in an Infant

“…High-dose prednisolone can be used during attacks and low dose in more stable periods (10). Also, TNF-α inhibitors, such as infliximab and adalimumab, are used in BS/EOS (10,11). Interleukin (IL)-1β receptor antagonist, such as anakinra and canakinumab, have been used with variable clinical outcome (3,12).…”