Effectiveness of subcutaneous tocilizumab in refractory adult Still's disease: report of three cases and a review of the literature.

Adult Still's disease (ASD) is a systemic inflammatory disorder characterised by spiking fever, skin rash, arthritis, hepatosplenomegaly, and elevated inflammatory markers. Several proinflammatory cytokines, including interleukin (IL)-6, contribute to its pathogenesis. There have been some recent reports on the efficacy of tocilizumab (TCZ), a humanised anti-IL-6 receptor antibody, in the treatment of ASD refractory to conventional therapy. However, most of the evidence is for intravenous administration of TCZ, whereas subcutaneous injection is often preferred in terms of efficiency in cost and labour. We have experienced three patients whose ASD was refractory to corticosteroid and immunosuppressant therapy but showed a marked response to off-label use of subcutaneous TCZ (TCZ-SC). Patient 1 received TCZ-SC 162 mg on days 0 and 14 and every week thereafter. Patients 2 and 3 received TCZ-SC every 2 weeks. At the time of initiation of TCZ-SC, all three patients had elevated inflammatory markers and two had fever despite previous therapy. After the first TCZ-SC injection, the patients became afebrile within one day and inflammatory parameters (i.e. C-reactive protein and erythrocyte sedimentation rate) returned to normal within 2 weeks. None of the patients developed severe infection or other serious side effects during 104 weeks of follow-up. There have been only a limited number of case reports showing that TCZ-SC significantly improves refractory ASD during its active phase. Our experience with these patients suggests that TCZ-SC could, as well as offering cost efficiency in clinical practice, be a potent treatment option for refractory ASD.

Protein phosphorylation involved in the gene expression of the hydrogen sulphide producing enzyme cystathionine γ-lyase in the pancreatic ß-cell.

Cystathionine γ-lyase (CSE) is one of the major enzymes for the production of hydrogen sulphide (H(2)S), a multifunctional gasotransmitter in the pancreatic ß-cell. We examined the mechanisms by which glucose induces CSE expression in mouse pancreatic islets and the insulin-secreting cell line MIN6. CSE expression was increased by anti-diabetic sulphonylureas, and decreased by the ATP-sensitive K(+)-channel opener diazoxide and the voltage-dependent Ca(2+) channel blocker nitrendipine. Application of the synthetic inhibitors of protein kinases revealed the involvement of Ca(2+)/calmodulin-dependent protein kinase (CaMK) II and extracellular signal-regulated protein kinase (ERK) in glucose- and thapsigargin-induced CSE expression. The CaMK IIδ knockdown also suppressed CSE expression. Knockdown of the transcription factors Sp1 and Elk1, both of which can be phosphorylated by ERK, blunted CSE expression. By a reporter assay, we found Sp1 may directly and Elk1 may indirectly regulate CSE expression. These findings suggest Ca(2+)-dependent CSE expression may be mediated via protein phosphorylation of Sp1 and Elk1 in pancreatic ß-cells.