Incidence and Risk Factors for Serious Infection in Patients with Rheumatoid Arthritis Treated with Tumor Necrosis Factor Inhibitors: A Report from the Registry of Japanese Rheumatoid Arthritis Patients for Longterm Safety

Komano, Yukiko; Tanaka, Michi; Nanki, Toshihiro; Koike, Ryuji; Sakai, Ryoko; Kameda, Hideto; Nakajima, Ayako; Saito, Kazuyoshi; Takeno, Mitsuhiro; Atsumi, Tatsuya; Tohma, Shigeto; Ito, Satoshi; Tamura, Naoto; Fujii, Tomoyuki; Sawada, Tetsuji; Ida, Hiroaki; Hashiramoto, Akira; Koike, Takao; Ishigatsubo, Yoshiaki; Eguchi, Katsumi; Tanaka, Yoshiya; Takeuchi, Tsutomu; Miyasaka, Nobuyuki; Harigai, Masayoshi

doi:10.3899/jrheum.101009

Cited by 144 publications

(91 citation statements)

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“…Quantitative realtime PCR was performed as described previously (24). The cDNA was amplified with primers for LPA 1 (sense 5Ј-ACC-CAA-TAC-TCG-GAG-ACT-GAC-TGT-3Ј, antisense 5Ј-CG-T-CAG-GCT-GGT-GTC-AAT-GA-3Ј), LPA 2 (sense 5Ј-TCA-TCA-TGG-GCC-AGT-GCT-ACT-3Ј, antisense 5Ј-GTG-GGA-GCT-GAG-CTC-TTT-GC-3Ј), LPA 3 (sense 5Ј-CTT-GAC-TGC-TTC-CCT-CAC-CAA-3Ј, antisense 5Ј-CGC-ATC-CTC-ATG-ATT-GAC-ATG-3Ј), LPA 4 (sense 5Ј-TCC-TCA-GTG-GCG-GTA-TTT-CAG-3Ј, antisense 5Ј-AAG-CAG-GTG-GTG-GTT-GCA-TT-3Ј), LPA 5 (sense 5Ј-GGT-GGT- 2038 MIYABE ET AL GAG-CGT-GTA-CAT-GTG-T-3Ј, antisense 5Ј-AGT-GGT-GCA-GTG-CGT-AG-TAG-GA-3Ј), LPA 6 (sense 5Ј-AGA-A-CC-AAA-AGA-AAT-GCA-AAG-ATT-G-3Ј, antisense 5Ј-ACG-GCG-GGT-GCA-CTT-C-3Ј), IL-17 (sense 5Ј-TCT-TTA-ACT-CCC-TTG-GCG-CA-3Ј, antisense 5Ј-GGT-AGT-CTG-AGG-GCC-TTC-TGG-3Ј), and 18S ribosomal RNA (rRNA) (sense 5Ј-AAC-CAG-ACA-AAT-CGC-TCC-AC-3Ј, antisense 5Ј-ACT-CAA-CAC-GGG-AAA-CCT-CA-3Ј) (used as an internal control to standardize the amount of sample mRNA), and the relative expression of real-time PCR products was determined. Induction and assessment of CIA.…”

Section: Methodsmentioning

confidence: 99%

“…However, in some patients RA does not respond to the treatment, and biologic agents increase the risk of severe infection (5,6). Therefore, there remains a need for new RA therapies that are effective and safe compared with conventional treatments.…”

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confidence: 99%

“…However, blocking of ATX should diminish LPA levels, which would then cause the reduction of signals from all LPA receptors (LPA [1][2][3][4][5][6] ) rather than selectively blocking one and allowing the activity of the others to remain intact. In addition, it was shown that ATX exerts blood vesselstabilizing actions, and in fact, ATX-deficient mice die in utero due to severe vascular defects (19).…”

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confidence: 99%

“…Lysophosphatidic acid (LPA) is a bioactive lipid that binds to a group of cell surface G protein-coupled receptors (LPA receptors 1-6 [LPA [1][2][3][4][5][6]) and has been implicated as an important mediator of angiogenesis, inflammation, and cancer growth (7)(8)(9). LPA is generated via hydrolysis of lysophosphatidylcholine by a secretory protein, autotaxin (ATX) (10), which exerts lysophospholipase D activity (11)(12)(13).…”

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confidence: 99%

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Necessity of Lysophosphatidic Acid Receptor 1 for Development of Arthritis

Miyabe

Iwai

et al. 2013

Arthritis & Rheumatism

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Objective. Lysophosphatidic acid (LPA) is a bioactive lipid that binds to a group of cell surface G protein-coupled receptors (LPA receptors 1-6 [LPA 1-6 ]) and has been implicated as an important mediator of angiogenesis, inflammation, and cancer growth. This study was undertaken to analyze the effects of LPA 1 on the development of arthritis.Methods. Expression of LPA receptors on synovial tissue was analyzed by immunohistochemistry and quantitative reverse transcription-polymerase chain reaction. The effects of abrogation of LPA 1 on collageninduced arthritis (CIA) were evaluated using LPA 1 -deficient mice or LPA 1 antagonist. Migrating fluorescence-labeled CD11b؉ splenocytes, which were transferred into the synovium of mice with CIA, were counted. CD4؉ naive T cells were incubated under Th1-, Th2-, or Th17-polarizing conditions, and T helper cell differentiation was assessed. Osteoclast formation from bone marrow cells was examined.Results. LPA 1 was highly expressed in the synovium of patients with rheumatoid arthritis (RA) compared with that of patients with osteoarthritis. LPA 1 -deficient mice did not develop arthritis following immunization with type II collagen (CII). LPA 1 antagonist also ameliorated murine CIA. Abrogation of LPA 1 was associated with reductions in cell infiltration, bone destruction in the joints, and interleukin-17 production from CII-stimulated splenocytes. Infiltration of transferred CD11b؉ macrophages from LPA 1 -deficient mice into the synovium was suppressed compared with infiltration of macrophages from wild-type mice. LPA 1 antagonist inhibited the infiltration of macrophages from wild-type mice. Differentiation into Th17, but not Th1 or Th2, and osteoclast formation were also suppressed under conditions of LPA 1 deficiency or LPA 1 inhibition in vitro.Conclusion. Collectively, these results indicate that LPA/LPA 1 signaling contributes to the development of arthritis via cellular infiltration, Th17 differentiation, and osteoclastogenesis. Thus, LPA 1 may be a promising target molecule for RA therapy.Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by inflammatory cell infiltration and bone destruction at multiple joints. The inflammation process in RA leads to synovial hyperplasia with proliferation of fibroblast-like synoviocytes (FLS), angiogenesis, and infiltration of inflammatory cells, including lymphocytes and macrophages (1,2).

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Necessity of Lysophosphatidic Acid Receptor 1 for Development of Arthritis

Miyabe

Iwai

et al. 2013

Arthritis & Rheumatism

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“…However, some populations of RA patients remain refractory to various biological agents. In addition, the risk of severe infections is increased by biological drugs [27,28] . Therefore, the development of novel therapeutic agents is still needed.…”

Section: Introductionmentioning

confidence: 99%

Hyperoside exerts anti-inflammatory and anti-arthritic effects in LPS-stimulated human fibroblast-like synoviocytes in vitro and in mice with collagen-induced arthritis

Jin¹,

Yan

Wang

et al. 2016

Acta Pharmacol Sin

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Aim: Hyperoside is a flavonol glycoside mainly found in plants of the genera Hypericum and Crataegus, which has shown anti-oxidant, anti-cancer and anti-inflammatory activities. In this study, we investigated the effects of hyperoside on human rheumatoid fibroblastlike synoviocytes (FLSs) in vitro and on mouse collagen-induced arthritis (CIA) in vivo. Methods: FLSs were isolated from primary synovial tissues obtained from rheumatoid arthritis (RA) patients and exposed to LPS (1 µg/mL). Cell viability and proliferation were measured with MTT and BrdU assay. Cell migration was assessed using wound-healing assay and Transwell assay. DNA binding of NF-κB was measured using a TransAM-NFkappaB kit. The localization of p65 subunit was detected with immunocytochemistry. CIA was induced in mice by primary immunization with Bovine Type II collagen (CII) emulsified in CFA, followed by a booster injection 3 weeks later. The arthritic mice were treated with hyperoside (25, 50 mg·kg -1 ·d -1, ip) for 3 weeks, and the joint tissues were harvested for histological analysis. Results: Hyperoside (10, 50, 100 µmol/L) dose-dependently inhibited LPS-induced proliferation and migration of human RA FLSs in vitro. Furthermore, hyperoside decreased LPS-stimulated production of TNF-α, IL-6, IL-1 and MMP-9 in the cells. Moreover, hyperoside inhibited LPS-induced phosphorylation of p65 and IκBα, and suppressed LPS-induced nuclear translocation of p65 and DNA biding of NF-κB in the cells. Three-week administration of hyperoside significantly decreased the clinical scores, and alleviated synovial hyperplasia, inflammatory cell infiltration and cartilage damage in mice with CIA. Conclusion: Hyperoside inhibits LPS-induced proliferation, migration and inflammatory responses in human RA FLSs in vitro by suppressing activation of the NF-κB signaling pathway, which contributes to the therapeutic effects observed in mice with CIA.

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