Tocilizumab for the Treatment of SLC29A3 Mutation Positive PHID Syndrome

Abstract

Pigmentary hypertrichosis and non-autoimmune insulin-dependent diabetes mellitus (PHID) is associated with recessive mutations in , encoding the equilibrative nucleoside transporter hENT3 expressed in mitochondria, causing PHID and H syndromes, familial Rosai-Dorfman disease, and histiocytosis-lymphadenopathy-plus syndrome. Autoinflammation is increasingly recognized in these syndromes. We previously reported a 16-year-old girl with PHID syndrome associated with severe autoinflammation that was recalcitrant to interleukin-1 and tumor necrosis factor-α blockade. Tocilizumab is a humanized, monoclonal, anti-human interleukin-6 receptor antibody routinely used to treat arthritis in children and adults. Herein we report the first case of successful treatment of PHID syndrome using tocilizumab. Before commencing tocilizumab, there was evidence of significant systemic inflammation, and progressive sclerodermatous changes (physician global assessment [PGA] 7/10). Twelve weeks after starting tocilizumab (8 mg/kg every 2 weeks, intravenously) systemic inflammatory symptoms improved, and acute phase response markers normalized; serum amyloid A reduced from 178 to 8.4 mg/L. After a dose increase to 12 mg/kg every 2 weeks her energy levels, appetite, fevers, and night sweats further improved. Less skin tightness (PGA 5/10) was documented 12 months later. This excellent clinical and serological response was sustained over 48 months, and cutaneous sclerosis had improved further (PGA 3/10). Her height remained well below the 0.4th centile, and tocilizumab also had no impact on her diabetes or exocrine pancreatic insufficiency. Although the mechanism of autoinflammation of PHID remains uncertain, we suggest that tocilizumab should be the first choice when considering treatment of the autoinflammatory or cutaneous manifestations of this genetic disease.

Efficacy of tocilizumab in adult H syndrome: a promising therapeutic option

“…Three cases of HS and one case of pigmentary hypertrichosis and non‐autoimmune insulin‐dependent diabetes mellitus syndrome have been successfully treated with tocilizumab after a failure of azathioprine, ciclosporin, methotrexate, anakinra, and/or TNF‐alpha inhibitors 2,3 . Increased levels of IL‐6 were found in our patient, supporting the use of tocilizumab.…”

“…Treatment options are limited. Four pediatric patients with SLC29A3 mutations treated with tocilizumab (anti‐IL‐6 receptor) have been reported 2,3 . We report the first case of adult HS successfully treated with tocilizumab.…”

Identification of the Novel Methylated Genes’ Signature to Predict Prognosis in INRG High-Risk Neuroblastomas

“…SLC29A3 encodes a nucleoside transporter which plays a significant role in the cellular uptake of nucleosides and nucleobases. It was previously reported that many diseases were related to RAD51AP1 expression, including autoinflammatory diseases [ 46 ], H syndrome [ 47 ], insulin-dependent diabetes [ 48 ], pigmentary hypertrichosis, autoimmune insulin-dependent diabetes mellitus [ 49 ], and sclerosing bone dysplasias [ 50 ]. Meanwhile, MIMT1 is an MER1 repeat-containing imprinted transcript, which can undergo hypermethylation in the placenta of intrauterine growth-restricted fetuses in cattle [ 51 ], and truncation of exons 3 and 4 of the MIMT1 gene caused intrauterine growth restriction [ 52 ].…”

Homozygosity for a novel large deletion in SLC29A3 in a patient with H syndrome

“…Treatment options reported in the literature include systemic corticosteroids, methotrexate, cyclosporine, cyclophosphamide, interferon alfa, colchicine, interleukin‐1 receptor antagonists, canakinumab, adalimumab, nonsteroidal anti‐inflammatory drugs, tocilizumab, and radiotherapy, primarily for the inflammatory features of the disorder . Treatment with tocilizumab may show the most promise as partial to complete response has been reported with the use of this drug …”

“…[9][10][11] Treatment with tocilizumab may show the most promise as partial to complete response has been reported with the use of this drug. 10,12 Our patient had been evaluated and followed for many years by many specialists without consideration of H syndrome. However, given the characteristic cutaneous features, he was readily diagnosed when seen in our dermatology clinic.…”