Successful treatment with belimumab for immune thrombocytopenia associated with systemic lupus erythematosus: A report of two cases.

Immune thrombocytopenia (ITP) is a common complication of systemic lupus erythematosus (SLE). Glucocorticoids (GCs) and hydroxychloroquine are first-line therapy for SLE-associated ITP (SLE-ITP). SLE-ITP in most of patients is less severe and well controlled with GCs, but some of the patients are GC resistant and require additional immunosuppressants including calcineurin inhibitors, azathioprine, and rituximab. We present two cases of SLE-ITP patients treated with belimumab who were resistant to GCs and achieved remission. For severe SLE-ITP, belimumab has emerged as a novel induction therapeutic option.

Hereditary angio-oedema with normal C1-INH, developing recurrent acute abdomen after taking low-dose oestrogen-progestin: A case report.

Hereditary angio-oedema (HAE) is a rare genetic disease characterised by repeated episodes of temporary organ swelling. Three types of HAE are known, of which HAE with normal C1 inactivator is difficult to be diagnosed due to its lack of laboratory abnormalities. Here, we describe a case of HAE with normal C1 inactivator and recurrent acute abdomen following low-dose oestrogen-progestin therapy. Notably, genetic analysis by Sanger sequencing led to the identification of a recurrent heterozygous missense mutation c.988A > G (p.K330E) in the plasminogen (PLG) gene of the patient. Prophylactic tranexamic acid and on-demand selective bradykinin B2 receptor blockers are used to treat her symptoms.

Decreased expression of interleukin-21 receptor on peripheral B lymphocytes in systemic lupus erythematosus.

Interleukin-21 (IL-21) is the most recent member of the common gamma-chain-dependent cytokine family. We studied the expression of the IL-21 receptor (IL-21R) on peripheral B lymphocytes in patients with systemic lupus erythematosus (SLE) or primary Sjögren's syndrome (pSjS), and healthy controls. Naive B lymphocytes expressed higher levels of IL-21R than memory B lymphocytes and plasmablasts, both in SLE patients and healthy controls. The proportion of IL-21R+ cells in the total peripheral B lymphocytes, as well as those in the respective B lymphocyte subsets, was significantly lower in SLE compared with those of pSjS or healthy controls (p=0.0002 and p<0.0001, respectively, in total B lymphocytes). The decreased expression of IL-21R in SLE was significantly associated with nephritis and high titer anti-double-strand DNA antibody. In some SLE patients, IL-21-induced proliferation of CD19+ B lymphocytes, in the presence of CD40 stimulation, was impaired. The abnormalities of IL-21R signaling might contribute to the pathological features of SLE, such as B lymphocytopenia.

Novel mutations in TNFRSF1A in patients with typical tumor necrosis factor receptor-associated periodic syndrome and with systemic lupus erythematosus in Japanese.

Molecular defects of TNFRSF1A was investigated in members of a family presenting with typical phenotypes of tumor necrosis factor receptor-associated periodic syndrome (TRAPS) and in patients with the autoimmune disorders, systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Genomic DNA from the members of a family with typical TRAPS, as well as from 100 patients with SLE, 100 patients with RA and 100 healthy individuals, was studied for mutations in exons 2, 3 and 4 of the TNFRSF1A gene. All individuals were Japanese. Three novel missense mutations were identified in the TNFRSF1A. The C70G mutation was identified in family members with typical TRAPS, which was the second case in eastern Asian population. In addition, the T61I and R104Q mutations were each identified in 2 of the 100 SLE patients. The T61I mutation was identified in one of the 100 healthy individuals. No mutations were identified in the 100 RA patients. Functional analysis revealed that PMA-induced shedding of TNFRSF1A from PBMCs was impaired in a patient carrying T61I. A larger scale of study will clarify whether these two mutations, T61I and R104Q, are associated with chronic inflammatory disorders, such as SLE, or not.

Mechanisms for cytotoxic effects of anti-tumor necrosis factor agents on transmembrane tumor necrosis factor alpha-expressing cells: comparison among infliximab, etanercept, and adalimumab.

OBJECTIVE: Three anti-tumor necrosis factor alpha (anti-TNFalpha) agents have been proved to be effective for rheumatoid arthritis (RA) and other inflammatory disorders. Infliximab and adalimumab have been generated as anti-TNFalpha monoclonal antibodies, while etanercept is engineered from human type II TNF receptors. In spite of all 3 agents' equal efficacy for RA, both infliximab and adalimumab are effective for other diseases such as Crohn's disease and Wegener's granulomatosis, while etanercept is not. We undertook this study to understand the different clinical effects of these anti-TNFalpha agents by analyzing their biologic activities on transmembrane TNFalpha. METHODS: Jurkat T cells stably expressing an uncleavable form of transmembrane TNFalpha were used for the following studies: 1) flow cytometric analysis of binding activities of anti-TNF agents to cell surface transmembrane TNFalpha, 2) complement-dependent cytotoxicity (CDC), 3) antibody-dependent cell-mediated cytotoxicity (ADCC) by using peripheral blood mononuclear cells, and 4) outside-to-inside (reverse) signal transduction through transmembrane TNFalpha estimated by apoptosis and cell cycle analysis using flow cytometry. RESULTS: All of the anti-TNFalpha agents bound to transmembrane TNFalpha. Infliximab and adalimumab exerted almost equal CDC activities, while etanercept showed considerably lower activity. ADCC activities were almost equal among these 3 agents. Adalimumab and infliximab induced apoptosis and cell cycle arrest in transmembrane TNFalpha-expressing Jurkat T cells, reflecting an outside-to-inside signal transduction through transmembrane TNFalpha. CONCLUSION: Three different anti-TNF agents showed different biologic effects on transmembrane TNFalpha. This finding suggests that CDC and outside-to-inside signals by anti-TNFalpha antibodies may explain the successful clinical efficacy of adalimumab and infliximab in Crohn's disease and Wegener's granulomatosis.