Physicians may need to consider offering an HZ preventive vaccine to patients receiving combination treatment with biologic medications and methotrexate, particularly if they have additional risk factors for HZ.

Drug survival has recently become an important clinical issue in psoriasis. However, there has been little research into factors associated with drug survival of methotrexate and acitretin. The aim of this study was to investigate factors associated with drug survival of methotrexate and acitretin treatment for psoriasis. Survival analysis was performed in patients who received methotrexate or acitretin for the treatment of psoriasis, drawn from the Clalit Health Services database. Investigated factors included demographic variables, obesity, metabolic syndrome, psoriatic arthritis, administration route and folic acid supplementation. Among 6,256 patients, factors associated with treatment drop-out were: younger age (p <0.001) and psoriatic arthritis (acitretin p < 0.001). For methotrexate, metabolic syndrome (p = 0.033), intramuscular administration route of injection (p <0.001) and lack of folic acid supplementation (p <0.001) were associated with treatment drop-out. In patients with psoriasis, some ancillary factors may modify the drug survival of acitretin and methotrexate.

Antiinflammatory clinical-grade, plasma-derived human α-1 antitrypsin (hAAT) protects islets from allorejection as well as from autoimmune destruction. hAAT also interferes with disease progression in experimental autoimmune encephalomyelitis (EAE) and in collagen-induced arthritis (CIA) mouse models. hAAT increases IL-1 receptor antagonist expression in human mononuclear cells and T-regulatory (Treg) cell population size in animal models. Clinical-grade hAAT contains plasma impurities, multiple hAAT isoforms and various states of inactive hAAT. We thus wished to establish islet-protective activities and effect on Treg cells of plasmidderived circulating hAAT in whole animals. Islet function was assessed in mice that received allogeneic islet transplants after mice were given hydrodynamic tail-vein injection with pEF-hAAT, a previously described Epstein-Barr virus (EBV) plasmid construct containing the EBV nuclear antigen 1 (EBNA1) and the family of repeat EBNA1 binding site components (designated "EF") alongside the hAAT gene. Sera collected from hAAT-expressing mice were added to lipopolysaccharide (LPS)-stimulated macrophages to assess macrophage responsiveness. Also, maturation of peritoneal cells from hAAT-expressing mice was evaluated. hAAT-expressing mice accepted islet allografts (n = 11), whereas phosphate-buffered saline-injected animals (n = 11), as well as mice treated with truncated-hAAT-plasmid (n = 6) and untreated animals (n = 20) rapidly rejected islet allografts. In hAAT-expressing animals, local Treg cells were abundant at graft sites, and the IL-1 receptor antagonist was elevated in grafts and circulation. Sera from hAAT-expressing mice, but not control mice, inhibited macrophage responses. Finally, peritoneal cells from hAAT-expressing mice exhibited a semimature phenotype. We conclude that plasmid-derived circulating hAAT protects islet allografts from acute rejection, and human plasma impurities are unrelated to islet protection. Future studies may use this in vivo approach to examine the structure-function characteristics of the protective activities of AAT by manipulation of the hAAT plasmid.

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Alpha-1-antitrypsin (AAT) exerts anti-inflammatory and tolerogenic activities during islet allograft transplantation in diabetes mouse models. Although a serine protease inhibitor, evidence suggests that AAT possesses activities that are independent of protease inhibition. The previously reported plasmid, pEF-hAAT, contains the genomic sequence of human AAT (hAAT) and sustains circulating levels after single hydrodynamic tail-vein injection (HDI) in mice. To asses whether expression of hAAT by pEF-hAAT protects islets from acute rejection, pEF-hAAT (100 μg, n = 6) or PBS (n = 4, control) were hydrodynamically introduced to mice. Liver expression and circulating hAAT levels were determined. Supernatant of transfected Hepa1c cells exhibited anti-elastase activity. Sixteen days post HDI mice were injected streptozotocin (225 mg/kg) and grafted with 450 allogenic islets. Circulating hAAT levels (1-350 μg/ml) persisted for over 30 days. Normoglycemia was achieved and islets were accepted in 6 out of 6 recipients that expressed hAAT. All 4 control animals exhibited acute islet allograft rejection by day 12. We conclude that plasmid-derived long-term expression of as low as 1 μg/ml hAAT exhibits islet-allograft protection. Using site-directed mutagenesis of pEF-hAAT we will examine whether activities that are independent of protease inhibition partake in the protection of islet allografts.