ObjectiveTo investigate the efficacy and safety of the interleukin-6 receptor antibody tocilizumab in patients with Takayasu arteritis (TAK).MethodsPatients with TAK who had relapsed within the previous 12 weeks were induced into remission with oral glucocorticoid therapy. In this double-blind, placebo-controlled trial, patients were randomly assigned 1:1 to receive weekly tocilizumab 162 mg or placebo subcutaneously, and oral glucocorticoids were tapered 10 %/week from week 4 to a minimum of 0.1 mg/kg/day until 19 patients relapsed. The primary endpoint was time to relapse of TAK, defined as ≥2 of the following: objective systemic symptoms, subjective systemic symptoms, elevated inflammation markers, vascular signs and symptoms or ischaemic symptoms.ResultsThe intent-to-treat and safety populations included 18 tocilizumab-treated and 18 placebo-treated patients. The per-protocol set (PPS) included 16 tocilizumab-treated and 17 placebo-treated patients. HRs for time to relapse of TAK were 0.41 (95.41% CI 0.15 to 1.10; p=0.0596) in the intent-to-treat population (primary endpoint) based on relapse in eight tocilizumab-treated and 11 placebo-treated patients and 0.34 (95.41% CI 0.11 to 1.00; p=0.0345) in the PPS. The secondary endpoints, time to relapse assessed by Kerr’s definition and clinical symptoms only, were consistent with the primary endpoint. Serious adverse events were reported in one tocilizumab-treated and two placebo-treated patients. There were no serious infections and no deaths.ConclusionAlthough the primary endpoint was not met, the results suggest favour for tocilizumab over placebo for time to relapse of TAK without new safety concerns. Further investigation is warranted to confirm the efficacy of tocilizumab in patients with refractory TAK.Trial registration numberJapicCTI-142616.
Human parvovirus B19 (B19) DNA was detected in the synovial tissues in 30 of 39 patients with rheumatoid arthritis (RA), and infrequently in those with osteoarthritis and traumatic joints. On the other hand, the expression of the B19 antigen VP-1 was specific (
Hereditary ATTR (ATTRm) amyloidosis (also called transthyretin-type familial amyloid polyneuropathy [ATTR-FAP]) is an autosomal-dominant, adult-onset, rare systemic disorder predominantly characterized by irreversible, progressive, and persistent peripheral nerve damage. TTR gene mutations (e.g. replacement of valine with methionine at position 30 [Val30Met (p.Val50Met)]) lead to destabilization and dissociation of TTR tetramers into variant TTR monomers, which form amyloid fibrils that deposit in peripheral nerves and various organs, giving rise to peripheral and autonomic neuropathy and several non-disease specific symptoms.Phenotypic and genetic variability and non–disease-specific symptoms often delay diagnosis and lead to misdiagnosis. Red-flag symptom clusters simplify diagnosis globally. However, in Japan, types of TTR variants, age of onset, penetrance, and clinical symptoms of Val30Met are more varied than in other countries. Hence, development of a Japan-specific red-flag symptom cluster is warranted. Presence of progressive peripheral sensory-motor polyneuropathy and ≥1 red-flag sign/symptom (e.g. family history, autonomic dysfunction, cardiac involvement, carpal tunnel syndrome, gastrointestinal disturbances, unexplained weight loss, and immunotherapy resistance) suggests ATTR-FAP. Outside of Japan, pharmacotherapeutic options are first-line therapy. However, because of positive outcomes (better life expectancy and higher survival rates) with living donor transplant in Japan, liver transplantation remains first-line treatment, necessitating a Japan-specific treatment algorithm.Herein, we present a consolidated review of the ATTR-FAP Val30Met landscape in Japan and summarize findings from a medical advisory board meeting held in Tokyo on 18th August 2016, at which a Japan-specific ATTR-FAP red-flag symptom cluster and treatment algorithm was developed. Beside liver transplantation, a TTR-stabilizing agent (e.g. tafamidis) is a treatment option. Early diagnosis and timely treatment using the Japan-specific red-flag symptom cluster and treatment algorithm might help guide clinicians regarding apt and judicious use of available treatment modalities.
CD26 is a T cell activation antigen that contains dipeptidyl peptidase IV activity and is known to bind adenosine deaminase. The mechanism by which CD26 costimulation potentiates T cell receptor-mediated T cell activation, leading to subsequent exertion of T cell effector function, is still not clearly defined. In this article, we demonstrate that CD26 localizes into lipid rafts, and targeting of CD26 to rafts is necessary for signaling events through CD26. Importantly, aggregation of CD26 by anti-CD26 mAb crosslinking also causes coaggregation of CD45 into rafts. Moreover, we show that CD26 directly binds to the cytoplasmic domain of CD45. Our results therefore indicate a mechanism whereby CD26 engagement promotes aggregation of lipid rafts and facilitates colocalization of CD45 to T cell receptor signaling molecules p56 Lck , ZAP-70, and TCR, thereby enhancing protein tyrosine phosphorylation of various signaling molecules and subsequent interleukin-2 production.T he CD26 is a 110-kDa cell-surface glycoprotein that possesses dipeptidyl peptidase IV (EC 3.4.14.5) activity in its extracellular domain (1, 2) and has an important role in T cell activation (3). Although constitutively expressed in the liver, intestine, and kidney, CD26 expression level is tightly regulated on T cells, and its density is markedly enhanced after T cell activation (4). In the resting state of human T lymphocytes, CD26 is expressed on a subset of CD4 ϩ memory T cells, and this CD4 ϩ CD26 high T cell population has been shown to respond maximally to recall antigens (5). In fact, CD26 itself is involved in the processes of T cell signal transduction.Activation of resting T cells requires two independent signals, the first stemming from recognition by the T cell receptor (TCR) complex of processed antigen peptides plus major histocompatibility complex molecules on antigen-presenting cells, with the second signal being provided by other receptor-ligand interactions between T cells and antigen-presenting cells (6, 7). Intensive work over the past several years has characterized the T cell surface molecule CD26 as a receptor capable of generating T cell costimulatory signals (8, 9). Crosslinking of CD26 and CD3 with immobilized mAbs induced T cell activation and IL-2 production (5). Moreover, anti-CD26 antibody treatment of T cells led to decreased surface expression of CD26 via its internalization, and this modulation of CD26 resulted in an enhanced proliferative response to anti-CD3 or anti-CD2 stimulation (9). We also demonstrated previously that ligation of CD26 by the anti-CD26 mAb 1F7 induced increased tyrosine phosphorylation of signaling molecules such as c-Cbl, mitogen-activated protein kinase [MAP kinase, or extracellularregulated kinase (ERK1͞2)], Zap70, p56 Lck , and CD3 (10). However, the exact mechanism responsible for CD26-mediated tyrosine phosphorylation and costimulation is unclear, particularly in view of the fact that CD26 has a short conserved cytoplasmic domain consisting of only six amino acid residues, without intrins...
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