EULAR/ERA-EDTA recommendations for the management of ANCA-associated vasculitis.

In this article, the 2009 European League Against Rheumatism (EULAR) recommendations for the management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) have been updated. The 2009 recommendations were on the management of primary small and medium vessel vasculitis. The 2015 update has been developed by an international task force representing EULAR, the European Renal Association and the European Vasculitis Society (EUVAS). The recommendations are based upon evidence from systematic literature reviews, as well as expert opinion where appropriate. The evidence presented was discussed and summarised by the experts in the course of a consensus-finding and voting process. Levels of evidence and grades of recommendations were derived and levels of agreement (strengths of recommendations) determined. In addition to the voting by the task force members, the relevance of the recommendations was assessed by an online voting survey among members of EUVAS. Fifteen recommendations were developed, covering general aspects, such as attaining remission and the need for shared decision making between clinicians and patients. More specific items relate to starting immunosuppressive therapy in combination with glucocorticoids to induce remission, followed by a period of remission maintenance; for remission induction in life-threatening or organ-threatening AAV, cyclophosphamide and rituximab are considered to have similar efficacy; plasma exchange which is recommended, where licensed, in the setting of rapidly progressive renal failure or severe diffuse pulmonary haemorrhage. These recommendations are intended for use by healthcare professionals, doctors in specialist training, medical students, pharmaceutical industries and drug regulatory organisations.

Imatinib mesylate inhibits in vitro and ex vivo biological responses related to vascular occlusion in giant cell arteritis.

OBJECTIVES: Ischaemic complications occur in 15-20% of patients with giant cell arteritis (GCA). The aim of our study was to explore the effect of mesenchymal growth factors expressed in GCA lesions on myointimal cell responses related to the development of intimal hyperplasia and vessel occlusion. METHODS: We developed a method to obtain primary human temporal artery derived myointimal cells (HTAMCs) based on the culture of temporal artery sections on Matrigel. RESULTS: Among the factors tested (platelet-derived growth factor (PDGF)-AB, fibroblast growth factor (FGF)-2, vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), transforming growth factor (TGF)beta, chemokine (C-C motif) ligand (CCL)2, interleukin (IL)6 and IL1beta), PDGF exhibited the strongest activity in inducing HTAMC proliferation and migration. As assessed by protein array, immunoassay and quantitative real-time reverse transcriptase (RT)-PCR, PDGF stimulated matrix proteins (collagen I, collagen III and fibronectin) as well as CCL2 and angiogenin production by HTAMCs. Imatinib mesylate inhibited PDGF-mediated activation of signalling pathways (Src, extracellular signal-regulated kinase (ERK) and Akt phosphorylation) related to cell motility and survival, efficiently resulting in inhibition of PDGF-induced HTAMC responses. Myointimal cell outgrowth from cultured temporal artery sections from patients with GCA, where multiple interactions take place, was also efficiently reduced by imatinib. CONCLUSION: Among several mediators produced in GCA, PDGF has the highest vaso-occlusive potential. PDGF may also contribute to disease perpetuation by stimulating the production of angiogenic factors (angiogenin) and chemoattractants (CCL2). Imatinib mesylate strongly inhibits PDGF-mediated responses, suggesting a therapeutic potential to limit vascular occlusion and ischaemic complications in large vessel vasculitis.

Interferon-alpha may exacerbate cryoblobulinemia-related ischemic manifestations: an adverse effect potentially related to its anti-angiogenic activity.

The discovery of the strong association between hepatitis C virus (HCV) infection and the development of mixed cryoglobulinemia has motivated active testing of antiviral-directed alternative therapies. Several trials have demonstrated that classic cryoglobulinemia-associated manifestations improve with interferon-alpha (IFNalpha) treatment. Herein we report on 3 HCV-infected patients with severe cryoglobulinemia-related ischemic manifestations who were closely followed up during IFNalpha therapy. Clinical evaluations with special attention to ischemic lesions, liver function tests, and cryocrit determinations were serially performed. In addition to prednisone and immunosuppressive agents, the patients received IFNalpha at 3 x 10(6) units, 3 times per week for 2 months, 3 months, and 4 months, respectively. In all 3 patients, systemic features improved, liver function results returned to normal, and cryocrit values decreased. However, ischemic lesions became less vascularized and ischemia progressed, leading to transmetatarsal and subcondylar amputation, respectively, in 2 of the patients and fingertip necrosis and ulcer enlargement in the third. Skin biopsies performed before IFNalpha therapy and after 2 months of IFNalpha therapy in the third patient showed a significant decrease in subepidermal microvessels. When IFNalpha was discontinued, the lesions finally healed. Cryoglobulinemia-related ischemic lesions may worsen during IFNalpha treatment, presumably through a decrease in inflammation-induced angiogenesis. The anti-angiogenic activity of IFNalpha may delay the appropriate healing of ischemic lesions.

Effect of the mode of calcitriol administration on PTH-ionized calcium relationship in uraemic patients with secondary hyperparathyroidism.

To assess the effect of the different modes of calcitriol administration on PTH-ionized calcium relationship we conducted a prospective clinical trial in 33 patients on chronic haemodialysis with secondary hyperparathyroidism (four times upper normal limit intact PTH) who were randomly assigned, with stratification to PTH levels, to receive daily oral, intermittent oral, or intermittent intravenous calcitriol at the same dose of 0.045 micrograms/kg/weekly. PTH-iCa curves were generated by inducing hypo- or hypercalcaemia in sequential haemodialysis 1 week apart, before and after 10 weeks on treatment. All patients were dialysed against a dialysate calcium concentration of 2.5 mEq/l throughout the study period. After drop-outs, 26 patients completed the study: 11 on intravenous calcitriol (mean basal PTH +/- SD: 666 +/- 280 pg/ml), eight on intermittent oral calcitriol (mean basal PTH: 831 +/- 361), and seven on daily oral calcitriol (mean basal PTH: 719 +/- 280). Serum ionized calcium and phosphorus significantly increased in intravenous and daily oral groups after calcitriol treatment, but not in the intermittent oral group. Basal PTH did not significantly change in the three groups after 10 weeks on treatment. Maximal PTH significantly decreased in intravenous group (1449 +/- 660 versus 1122 +/- 691 pg/ml, P = 0.0085) and at the limit of statistical significance in the intermittent oral group (1701 +/- 774 versus 1445 +/- 634, P = 0.12), but it did not change in the daily oral group. Minimal PTH did not modify in the three groups. In all three groups, a shift to the right in the PTH-iCa relationships were observed, with significant changes in the set point of calcium.(ABSTRACT TRUNCATED AT 250 WORDS)