Hisaaki Miyahara

EFFECT OF IL-10 ON COLLAGEN-INDUCED ARTHRITIS IN MICE

In the present study we investigated the effect of a potent anti-inflammatory cytokine, interleukin (IL)-10, on the development of collagen-induced arthritis (CIA) in mice. Each DBA1/J mouse was immunized with 200 μg of native collagen and followed by booster injections at 3 weeks. rmIL-10 was injected i.p. daily at a dose of 100 ng/mouse. Mice were divided into four groups according to the administration period of rmIL-10. As a result, a 48-day course of IL-10 treatment significantly suppressed the severity of arthritis. Among the 4 groups, the most pronounced suppression was observed in the group in which IL-10 was given from day 0 to 21. On the other hand, there were no significant differences in the serum IgG anti-type II collagen (CII) titers between the four groups. Moreover, the production of cytokines (IL-6 and tumor necrosis factor-α (TNF-α)) and other mediators (prostaglandin E2 (PGE2) and nitric oxide (NO)) by peritoneal macrophages seemed to show no clear correlation with the severity of arthritis in mice. These results raise the possibility that IL-10 might be a useful agent for suppressing the progression and the development of CIA in mice.

Limb allografts in rats immunosuppressed with FK506. I: Reversal of rejection and indefinite survival

We have tested the effects of FK506 (FK), a new immunosuppressive agent, on a rat limb allograft model. Histoincompatible BN limb allografts were rejected in untreated F344 hosts within 11±1 days (mean ± SD) after operation. A single injection of 2 mg/kg, 10 mg/ kg, or 50 mg/kg of FK on the day of limb transplantation (day 0) significantly prolonged graft survival in a dose-dependent manner—i.e., mean limb survival times (MST) based on gross signs of skin rejection were 16±3 days, 51 ±6 days, or 104±17 days, respectively (P < 0.01). Delayed treatment with a single injection of 10 mg/kg of FK at when early signs of rejection were visible (day 7 or day 10) reversed the ongoing rejection. The MSTs in these groups were comparable to that of those treated with the same dosage of FK on day 0. The FK-induced unresponsiveness toward limb allografts was donor-specific because limb-allografted, FK-protected rats could not accept the skin grafts from a third-party donor. In the next set of experiments, rats were given a single administration of 10 mg/kg of FK on the day of limb allograft, followed by intermittent injections of 3 mg/kg of FK once a week. This regimen produced complete graft survival for more than 200 days, though Pneumocyatis carinii pneumonia occurred in most of the recipients. These results represent the unique effects of FK in preventing or reversing the graft rejection and in inducing indefinite survival in this animal model of composite tissue allografts.

Longterm Safety and Efficacy of Subcutaneous Tocilizumab Monotherapy: Results from the 2-year Open-label Extension of the MUSASHI Study

Objective. To evaluate the longterm safety and efficacy of subcutaneous tocilizumab (TCZ-SC) as monotherapy in patients with rheumatoid arthritis (RA). Methods. Of 346 patients who received 24 weeks of double-blind treatment with either TCZ-SC monotherapy, 162 mg every 2 weeks (q2w); or intravenous TCZ (TCZ-IV) monotherapy, 8 mg/kg every 4 weeks; 319 patients continued to receive TCZ-SC q2w in the 84-week open-label extension (OLE) of the MUSASHI study (JAPICCTI-101117). Efficacy, safety, and immunogenicity were evaluated for all patients treated with TCZ during 108 weeks. Results. The proportions of patients who achieved American College of Rheumatology 20/50/70 responses, low disease activity [28-joint Disease Activity Score (DAS28) ≤ 3.2], or remission (DAS28 < 2.6) at Week 24 were maintained until Week 108. The incidences of adverse events and serious adverse events were 498.3 and 16.9 per 100 patient-years (PY), respectively. The overall safety of TCZ-SC monotherapy was similar to that of TCZ-IV monotherapy. Rates of injection site reactions (ISR) through 108 weeks remained similar to rates through 24 weeks. ISR were mild and did not cause any patient withdrawals. No serious hypersensitivity events (including anaphylactic reactions) occurred. Anti-TCZ antibodies were present in 2.1% of patients treated with TCZ-SC monotherapy. Conclusion. TCZ-SC monotherapy maintained a favorable safety profile and consistent efficacy throughout the 108-week study. Like TCZ-IV, TCZ-SC could provide an additional treatment option for patients with RA.

Inhibition by FK506 of established lesions of collagen-induced arthritis in rats

We investigated the superior poteney of the immunosuppressive agent FK506 on collagen‐induced arthritis in rats. In our initial studies, we demonstrated that only one shot administration of FK506 at a dose of 10 mg/kg on the same day as type II collagen immunization suppressed the incidence of arthritis completely as well as humoral and delayed‐type hypersensitivity (DTH) skin lest responses to type II collagen. Yet no major side effects were observed in the rats treated with such a high dose of FK506. Additional studies demonstrated that pretreatment with FK506 on day — 7 or day — 3 was effective in suppressing the severity of arthritis and immune responses to type II collagen. The immunosuppressive effect of a single high‐dose administration of FK506 continued for at least 1 week in this animal model of arthritis. A single administration of FK506 at a dose of 10 mg/kg on day 12 or 15, after the clinical onset of arthritis, was also effective in suppressing the severity of arthritis and immune response to type II collagen. We conclude that FK506, in this model, possesses an important, curative action when applied therapeutically. The outlook of FK506 treatment in clinical autoimmunity is promising at present.

Hereditary angioedema in Japan: Genetic analysis of 13 unrelated cases

Introduction:The molecular bases and clinical features of hereditary angioedema (HAE) have not been systematically documented in Japan or in other Asian countries. Thus, the authors researched the genetic and clinical characteristics of Japanese patients with HAE. Methods:The authors analyzed the CIINH gene for mutations in 13 unrelated Japanese patients with HAE by means of the polymerase chain reaction and nucleotide sequencing. In addition, the authors searched the literature from January 1969 to October 2010 on Japanese patients with HAE. Results:Seven of the mutations found were novel, including 4 missense mutations (8728T>G, 8831C>A, 16661T>G and 16885C>A), 2 frameshift mutations (2281_2350del70, 14158delT) and 1 large deletion (at least 1 kb-length deletion including exon 4), whereas 6 mutations had previously been reported in European populations. Conclusions:The genetic and clinical characteristics in Japanese patients with HAE may be similar to those in Western patients although our sample size is small and the authors identified 7 novel mutations.

Drug delivery options to increase patient adherence and satisfaction in the management of rheumatoid arthritis - focus on subcutaneous tocilizumab

Rheumatoid arthritis (RA) is a chronic, progressive, inflammatory disease associated with joint destruction. Tocilizumab (TCZ) is a humanized monoclonal anti-interleukin-6 receptor antibody that was initially developed for use as an intravenous (IV) infusion. Previous studies have shown that TCZ-IV is an important treatment option in patients with moderate-to-severe RA. A subcutaneous (SC) formulation of 162 mg TCZ that was recently developed and approved provides an additional treatment option for RA patients. In the present review, we provide an update on the efficacy and safety of TCZ-SC, compared with TCZ-IV. The TCZ-SC doses of 162 mg every 2 weeks (q2w) or weekly (qw) were selected based on pharmacokinetic and pharmacodynamic studies. Both TCZ-SC q2w and qw regimens showed equivalent effects to TCZ-IV in most patients; however, the TCZ-SC qw regimen consistently showed a more rapid effect in terms of C-reactive protein normalization. Randomized controlled studies showed that TCZ-SC monotherapy or combined with disease-modifying antirheumatic drugs demonstrated comparable efficacy to TCZ-IV in patients who were both biologic-naïve and refractory to tumor necrosis factor inhibitors. TCZ-SC at both qw and q2w were generally well-tolerated for up to 24 weeks. There was a low rate of withdrawal due to adverse events, and their incidence was comparable with that seen with TCZ-IV. An injection site reaction was seen in approximately 10% of patients who received the subcutaneous formulation. In conclusion, although clinical results are still limited, the currently available evidence suggests that TCZ-SC is a promising treatment for moderate-to-severe RA, both as monotherapy and combination therapy. More data is needed to determine the optimal dosing schedule.

Comparative histopathological analysis between tenosynovitis and joint synovitis in rheumatoid arthritis.

Aims:  To clarify the histological and biological features of tenosynovitis accompanying rheumatoid arthritis (RA).

Comparative studies of the effects of FK506 and cyclosporin A on passively transferred collagen-induced arthritis in rats

We investigated the effect of a novel immunosuppressive agent, FK506, in comparison with cyclosporin A (CsA) on the development of passive arthritis induced by anti-type II collagen (CII) antisera in rats. FK506 pretreatment shortly before serum transfer markedly suppressed the incidence and the severity of passive arthritis, while CsA pretreatment had no observable effects on this disease when used in doses sufficient to suppress the development of active arthritis induced by CII immunization. In an additional study, we examined whether these agents affect antibody-mediated tolerance induction. CII-specific immunological tolerance was induced by serum transfer, but was unaffected by either FK506 or CsA pretreatment in our regimen. While its precise mechanism of the immunosuppressive activity remains to be elucidated, FK506 can act on the antibody-mediated effector phase of arthritis and may offer new insights into the possible role of potential therapeutic utility in human autoimmune diseases.

Clinical and Genetic Features of Patients With TNFRSF1A Variants in Japan: Findings of a Nationwide Survey

To elucidate the clinical and genetic features of patients with TNFRSF1A variants in Japan using data obtained from a nationwide survey conducted by the Ministry of Health, Labor, and Welfare of Japan study group for tumor necrosis factor receptor–associated periodic syndrome (TRAPS).

Comparative study of effects of cyclosporins A and G on collagen arthritis in mice

The effects of the immunosuppressive agents cyclosporin G (CsG) and cyclosporin A (CsA) on collagen arthritis were compared in mice. When administered subcutaneously daily on days 0–13 after immunization with type II collagen, CsG and CsA were both capable of suppressing the development of collagen arthritis in mice as well as the immunological response to native type II collagen in a dose-dependent manner. Histopathologically, no marked inflammatory lesions were observed in diarthroidal joints from mice treated with 100 mg/kg per day of CsA or 800 mg/kg per day of CsG. However, an analysis of dose response showed CsG to be 8 times less potent than CsA in inhibiting the development of arthritis.