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As of February 2018, 5 originator TNF inhibitors(infliximab, etanercept, adalimumab, golimumab and certolizumab pegol)and biosimilar agents of infliximab and etanercept are available for rheumatoid arthritis(RA)in Japan. The effectiveness of TNF inhibitors considerably improves with concomitant methotrexate regardless of their immunogenicity. The Japan College of Rheumatology guideline for TNF inhibitor use in RA has been updated in March 2017 according to recent evidences. During the remission induction phase, maintenance of drug trough level above effective blood concentration is paramount, while the tapering and withdrawal of TNF inhibitors may be considered after achieving sustained remission.

Objective: To evaluate the safety and effectiveness of certolizumab pegol (CZP) in a real-world setting among Japanese patients with rheumatoid arthritis., Methods: Post-marketing surveillance data from 2,579 patients treated with CZP were analyzed. Adverse events (AEs) observed during the 24-week CZP treatment period were recorded. Disease activity was evaluated using DAS28-ESR and DAS28-CRP at baseline, Week 12, Week 24, or at withdrawal., Results: The total period of exposure to CZP was 1313.8 patient-years (PY). AEs were reported in 658 (25.5%) patients, at an event rate (ER) of 73.68/100 PY. The most frequent serious AEs were pneumonia, herpes zoster, and interstitial lung disease, at ER per 100 PY of 2.06, 1.29, and 1.22, respectively. Mean disease activity scores at baseline, as measured by DAS28-ESR and DAS28-CRP, were 4.77 ± 1.34 and 4.21 ± 1.27, respectively. Mean changes from baseline at the last observation were -1.29 ± 1.46 and -1.30 ± 1.42, respectively. EULAR good or moderate responses were achieved in 65% of patients. Longer disease duration, prior biologics use, and treatment without MTX co-therapy were associated with EULAR no response., Conclusion: In this interim analysis, no new safety signals were observed. Clinical response to CZP was observed in approximately two thirds of patients.

As of January 2016, 5 originator TNF inhibitors (infliximab, etanercept, adalimumab, golimumab and certolizumab pegol) and an infliximab biosimilar are available for rheumatoid arthritis (RA) in Japan. The efficacy and effectiveness of TNF inhibitors improve with concomitant methotrexate even for the least immunogenic agent. The Japan College of Rheumatology guideline for TNF inhibitor use in RA has been updated in March 2015, including recent evidences of effectiveness and safety partly from the postmarketing surveillance data in Japan. During the remission induction phase, maintenance of drug trough level above effective blood concentration is paramount, while the tapering and withdrawal of TNF inhibitors may be considered after achieving sustained remission.

It has been reported that the exacerbation or development of autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis may have seasonality, although the seasonal characteristic depends on each disease. For example, the sunlight (ultraviolet) and infectious pathogens are involved in important environmental factors contributing the seasonality of the diseases. Furthermore, recent advances include the association between vitamin D and autoimmune diseases, and the different pathogenesis among the same clinical category according to the autoantibodies.

Pharmacological management of rheumatoid arthritis (RA) has been rapidly progressed in recent years, which is appeared in the "treat to target" movement and the recommendations developed by some established international/domestic rheumatology associations. The baseline evaluation of poor prognostic factors as well as disease activity with composite measures is necessary for a personalized management. Methotrexate is currently the anchor drug, and other conventional or biological antirheumatic drugs should be added to it for refractory patients. The development of various novel agents including signal transduction inhibitors should promote further advances in the management of RA and other systemic autoimmune and/or inflammatory diseases.

Etanercept (ETN) is a fusion protein of the receptor (CD120b) for tumor necrosis factor (TNF) and the Fc portion of IgG1. A phase III trail and the JESMR study, both performed in Japan, implicated the importance of concomitant methotrexate (MTX) use in the treatment of rheumatoid arthritis (RA). Further evidences, including the TEAR study and the PRESERVE study, supported the recent treatment strategy for RA, being divided into at least two phases: remission induction phase(step-up or initial combination) and its maintenance phase (step-down). Thus, optimization of RA treatment chiefly based on MTX and anti-TNF biological agents is in progress.

The combination therapy of biological agents such as anti-tumor necrosis factor monoclonal antibody and methotrexate resulted in the arrest of joint destruction in most of the patients with rheumatoid arthritis, and even repair of damaged joints in some patients. The fact that the combination therapy leads to less joint destruction than methotrexate monotherapy in patients with comparable disease activity indicates the beneficial effects of biological agents for patients without remission state. Furthermore, the RISING study revealed the importance of sufficient dosing of biological agents such as infliximab because of the different requirement for the dosage of biological agents among patients with rheumatoid arthritis.

The progress in molecular targeting therapy includes two tides, namely, small molecule compounds and large molecule biological agents. Although the latter prevails in the field of clinical immunology, the former attracts more and more attention in these few years. Most of molecular targeting small compounds are the inhibitors of tyrosine kinases, including pioneering imatinib which inhibits the receptor for platelet-derived growth factor (PDGF), c-Abl, etc. The therapeutic concentrations of imatinib almost completely abrogated the morphological alteration and proliferation of fibroblastic cells induced by PDGF stimulation in 3-dimensional culture system in vitro. Indeed, imatinib has been shown to be effective in various animal disease models for arthritis, interstitial pneumonia, glomerulonephritis, and pulmonary hypertension. Furthermore, its efficacy in patients with systemic sclerosis has been recently reported from several institutes. Since established treatments had not been found for fibrotic lesion before, imatinib, a dual inhibitor of both transforming growth factor beta-, and PDGF-signaling, is likely to be a potent drug against fibrosis. Its efficacy and safety in fibrotic and immune-mediated diseases, such as systemic sclerosis, are currently under investigation throughout the world.

Pathogenesis of rheumatoid arthritis is likely to implicate anti-citrullinated protein/ peptide antibody(ACPA) and an immunodistortion including abnormal T cell subpopulation. Based on above and other recent findings, new biological agents targeted to inflammatory cytokines such as tocilizumab, activated T cells (abatacept) or B cells (ocrelizumab), as well as new small molecule drugs such as JAK3 inhibitor, are sure to further facilitate remission without impaired activity of daily life in patients with RA. The contribution of Japanese physician-scientists to the progress in rheumatology has been significant as described in this review, and it must be increasingly greater in the near future.

Platelet-derived growth factor (PDGF) is a topic in the pathophysiology of various systemic rheumatic diseases. For example, autoantibody against PDGF receptor was identified in patients with systemic sclerosis. Imatinib mesylate has been well tolerable and widely used for chronic myeloid leukemia and gastrointestinal stromal tomor. Imatinib also inhibits the activation of c-Abl, which is a key downstream molecule of transforming growth factor-beta signaling, and PDGF receptors. Thus, imatinib effectively suppresses the activation and proliferation of fibroblasts, mesangial cells and smooth muscle cells. Therefore, imatinib may overcome the limitation of current therapeutic strategy with corticosteroids and immunosuppressive agents for refractory diseases.

Tumor necrosis factor (TNF) -inhibitory biological response modifiers include neutralizing antibodies and receptor-immunoglobulin G (IgG) fusion proteins. These agents induce an amelioration of clinical signs and symptoms in most of the patients within a few weeks. Moreover, their inhibitory, or often repairing, effects on joint destruction are further excellent even in Japanese patients receiving a relatively lower dose of methotrexate (MTX) probably due to the direct inhibition of osteoclast activation through TNF.

Microscopic polyangiitis (MPA) is a systemic disorder characterized by inflammation of small vessels mainly affecting the kidneys and lungs. We describe a 72-year-old woman who developed multiple cartilage involvements as well as major manifestations of MPA. The left ear biopsy demonstrated cartilaginous inflammation and small vessel vasculitis. She also had conjunctivitis, hearing impairment, interstitial lung disease, glomerulonephritis with vasculitis and mononeuritis multiplex. Serological examinations revealed a positive antineutrophil cytoplasmic antibody (PR-3 ANCA). Cyclophosphamide and oral corticosteroid therapy was instituted and remission achieved. Due to lacks of nasal and bronchial involvements, as well as the evidence of auricular vasculitis, we concluded that her findings mimicking relapsing polychondritis developed as systemic manifestations of MPA.

We clarified the clinical significance of IgG anti-phosphatidylserine-prothrombin complex (PS-PT) antibodies in the antiphospholipid syndrome (APS). The study population consisted of 122 patients with SLE and lupus-like disease. IgG anti-PS-PT antibodies were detected in 44% of 59 patients according to the diagnostic criteria by Harris and Hughes. This frequency was significantly (p < 0.005) higher than the 14% seen in patients without APS. IgG anti-PS-PT antibodies were strongly (p < 0.005) associated with thrombosis. In addition, IgG anti-PS-PT antibodies were positive in 64% of IgG beta2-GPI dependent anti-cardiolipin antibody negative APS patients under the Sapporo criteria. The above findings indicate that IgG anti-PS-PT antibodies as well as beta2,-GPI dependent anti-cardiolipin antibodies should be examined in the diagnosis of APS.

Increased elucidation of the mechanisms of joint destruction has profoundly shaped the development of anti-cytokine therapies for rheumatoid arthritis (RA). Prevention of joint damage by biologics may successfully avoid functional decline and disability. However, treating physicians must carefully weigh the benefits of biologics against cost and their risks, particularly in patients at risk of the reactivation of tuberculosis.

Patients with rheumatoid arthritis(RA) develop both generalized and periarticular osteoporosis. Both of them are believed to be associated with increased production of inflammatory cytokines(TNF alpha, IL-1 beta, IL-6) and increased formation and activation of osteoclasts. Whether glucocorticoids work positively or negatively on generalized/periarticular osteoporosis is still controversial. RANKL has been shown to be expressed on T cells and fibroblast-like cells in the synovium, thus 'RANKL-RANK' pathway is likely to play an important role in periarticular osteoporosis and bone erosion as well as generalized osteoporosis. Among various therapies for generalized/periarticular osteoporosis in RA, anti-cytokine antibodies/antagonists and osteoclast inhibitors including bisphosphonates are promising.