[Show abstract][Hide abstract] ABSTRACT: Interleukin 6 (IL-6), promptly and transiently produced in response to infections and tissue injuries, contributes to host defense through the stimulation of acute phase responses, hematopoiesis, and immune reactions. Although its expression is strictly controlled by transcriptional and posttranscriptional mechanisms, dysregulated continual synthesis of IL-6 plays a pathological effect on chronic inflammation and autoimmunity. For this reason, tocilizumab, a humanized anti-IL-6 receptor antibody was developed. Various clinical trials have since shown the exceptional efficacy of tocilizumab, which resulted in its approval for the treatment of rheumatoid arthritis and juvenile idiopathic arthritis. Moreover, tocilizumab is expected to be effective for other intractable immune-mediated diseases. In this context, the mechanism for the continual synthesis of IL-6 needs to be elucidated to facilitate the development of more specific therapeutic approaches and analysis of the pathogenesis of specific diseases.
Cold Spring Harbor perspectives in biology 09/2014; 6(10). DOI:10.1101/cshperspect.a016295 · 8.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Interleukin-6 (IL-6) is a cytokine with redundant and pleiotropic activities, and its synthesis is tightly regulated by transcriptional and posttranscriptional mechanisms. When infections and tissue injuries occur, IL-6 synthesis is promptly induced and provides an emergent signal that contributes to host defense through the stimulation of acute-phase responses, immune reactions, and hematopoiesis. After the environmental stress is removed from the host, the production of IL-6 is terminated. However, dysregulated continual synthesis of IL-6 is involved in the development of chronic inflammatory autoimmune diseases. For this reason, tocilizumab, a humanized anti-IL-6 receptor antibody, was developed. Worldwide clinical trials have demonstrated the outstanding efficacy of tocilizumab in rheumatoid arthritis, systemic juvenile idiopathic arthritis, and Castleman's disease; thus, a new era has come for the treatment of these diseases, which were previously considered intractable. Moreover, favorable results from off-label use of tocilizumab strongly suggest that it will be widely applicable for various refractory inflammatory autoimmune diseases. In this context, the mechanism for the continual synthesis of IL-6 needs to be elucidated in order to investigate the pathogenesis of specific diseases and to facilitate the development of more specific therapeutic strategies.
Seminars in Immunology 02/2014; 26(1). DOI:10.1016/j.smim.2014.01.009 · 6.12 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The signalling pathway that comprises JAK kinases and STAT proteins (for signal transducer and activator of transcription) is important for relaying signals from various cytokines outside the cell to the inside. The feedback mechanism responsible for switching off the cytokine signal has not been elucidated. We now report the cloning and characterization of an inhibitor of STAT activation which we name SSI-1 (for STAT-induced STAT inhibitor-1). We found that SSI-1 messenger RNA was induced by the cytokines interleukins 4 and 6 (IL-4, IL-6), leukaemia-inhibitory factor (LIF), and granulocyte colony-stimulating factor (G-CSF). Stimulation by IL-6 or LIF of murine myeloid leukaemia cells (M1 cells) induced SSI-1 mRNA expression which was blocked by transfection of a dominant-negative mutant of Stat3, indicating that the SSI-1 gene is a target of Stat3 (refs 4, 5, 6, 7). Forced overexpression of SSI-1 complementary DNA interfered with IL-6- and LIF-mediated apoptosis and macrophage differentiation of M1 cells, as well as IL-6 induced tyrosine-phosphorylation of a receptor glycoprotein component, gp130, and of Stat3. When SSI-1 is overexpressed in COS7 cells, it can associate with the kinases Jak2 and Tyk2. These findings indicate that SSI-1 is responsible for negative-feedback regulation of the JAK-STAT pathway induced by cytokine stimulation.
[Show abstract][Hide abstract] ABSTRACT: Objectives: The retention of the anti-rheumatic agent tocilizumab (TCZ) has not been well documented in patients with rheumatoid arthritis (RA). We conducted an observational study to compare the retention of TCZ and anti-tumour necrosis factor (TNF) drugs in the treatment of patients with RA. Method: We reviewed continuation rates and causes of discontinuation of biological agents (biologics) by assessing medical records of patients with RA who were administered biologics at our institute from September 1999 to April 2012, using the Osaka University Biologics for Rheumatic Diseases (BiRD) registry. Results: A total of 401 patients were included. TCZ, infliximab (IFX), etanercept (ETN), and adalimumab (ADA) were administered to 97, 103, 143, and 58 patients, respectively. There were some differences between the baseline characteristics of the groups. The median duration (range) of TCZ, IFX, ETN, and ADA administration was 2.5 (0.1-12.6), 1.9 (0.0-7.7), 2.9 (0.0-11.3), and 1.3 (0.0-3.4) years, respectively. Continuation rates for TCZ and ETN were significantly higher than those for IFX and ADA. Multivariate analyses showed that discontinuation due to lack or loss of efficacy was significantly less common in the TCZ group than in the other groups. Discontinuation due to overall adverse events was not significantly different between treatment groups. Conclusion: TCZ and ETN show better retention than IFX or ADA in the treatment of RA.
Scandinavian journal of rheumatology 03/2013; DOI:10.3109/03009742.2012.762037 · 2.61 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Systemic sclerosis (SSc) presents stiffness of extremities due to sclerosis of the tissue especially at fingers, hands, and forearms. Here we report the case of a patient with diffuse cutaneous SSc who was administered anti-interleukin-6 receptor antibody tocilizumab (TCZ). Skin condition of SSc is evaluated by pinching the skin according to the Rodnan skin score, but sometimes tissue atrophy results in overestimation of the condition. To understand how the extremities softened after initiation of TCZ, we observed mobility of extremities. Range of motion (ROM) of joints was measured every four months after initiation of TCZ. The patient presented not only reduction of Rodnan score but also amelioration of mobility of extremities. The Rodnan skin score reduced from 35 to 7 within sixteen months, and ROM of most joints except ankle was expanded.
Modern Rheumatology 03/2013; 25(1). DOI:10.1007/s10165-013-0855-6 · 2.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
The prevalence of allergic diseases has increased all over the world during the last 2 decades. Dietary change is considered to be one of environmental factors that cause this increase and worsen allergic symptoms. If it is the case, an appropriate intake of foods and beverages with antiallergic activity is anticipated to prevent the onset of allergic diseases and ameliorate allergic symptoms. Flavonoids, ubiquitously present in vegetables, fruits or tea possess antiallergic and antioxidant effects, so that we examined the efficacy of a flavonoid on clinical symptoms of Japanese cedar pollinosis.
We investigated the efficacy of enzymatically modified isoquercitrin (EMIQ), a quercetin glycoside, to relieve symptoms of Japanese Cedar pollinosis by 3 different clinical trials. In either trial patients were randomly assigned to the EMIQ group or the placebo group and took one capsule containing EMIQ plus corn starch or corn starch only twice a day. The efficacy was evaluated with the total symptom, medication or QOL score. Study 1 (reference 1) and 2 (reference 2); EMIQ (100 mg/day) versus placebo, for 8 weeks, started after (study 1) and before (study 2) the onset of pollen release, Study 3; EMIQ (200 mg/day) versus placebo, for 4 weeks, started after the onset of pollen release.
In study 1 and 2, during the entire study period, ocular + medication score for the EMIQ group was significantly lower (P < 0.05) than that of the placebo group. When limited to the period, total symptom + medication score for the EMIQ group was significantly lower than that for the placebo group in all 3 studies.
These results indicate that intake of EMIQ, a quercetin glycoside proved to be effective for the relief of symptoms caused by Japanese cedar pollinosis.
World Allergy Organization Journal 02/2012; 5(Suppl 2):S181. DOI:10.1097/01.WOX.0000411687.36323.8b
[Show abstract][Hide abstract] ABSTRACT: Background
A humanized anti-interleukin-6 receptor, tocilizumab, has been approved as a biological drug for the treatment of rheumatoid arthritis, systemic juvenile idiopathic arthritis and Castleman's disease. Since dysregulation of IL-6 production also plays a pathologic role in other various autoimmune and allergic diseases, we tested whether tocilizumab might have beneficial effect on refractory autoimmune or allergic diseases to conventional treatment regimens.
After informed consent by patients and approval by the Ethics Committee of Osaka University Hospital were obtained, patients were treated with tocilizumab at 8 mg/kg every 4 weeks.
The diseases for which off-label use of tocililizumab was performed included amyloid A amyloidosis, relapsing polychondritis, systemic sclerosis, HLA-B27 positive spondyloarthritis such as reactive arthritis and psoriatic arthritis, polymyalgia rheumatica and polymyositis. After 3 injections of tocilizumab amyloid fibril deposits in the colon disappeared in a patient with gastrointestinal AA amyloidosis, who was resistant to anti-TNF drugs and disease-modifying antirheumatic drugs. In 2 patients with refractory relapsing polychondritis, the continuous tocilizumab treatment for more than 3 years could ameliorate clinical symptoms related to upper and lower airways and stabilize the disease activity. The skin sclerosis of 2 patients with systemic sclerosis became softened with reductions of 52 and 23% in the modified Rodnan total skin score by the tocilizumab treatment. Two administrations of tocilizumab led to the disappearance of joint swelling, pain and complete resolution of symptoms in a patient with refractory reactive arthritis to several therapeutic regimens for 4 years, whereas 2 patients with severe psoriatic arthritis did hardly respond to tocilizumab. In a patient with polymyalgia rheumatica, the tocilizumab treatment caused a reduction of the disease activity score (PMR-AS) from 22.14 to 0.74, indicating remission. Creatine phosphokinase normalized by 2 patients with polymyositis who had been resistant to corticosteroids and immunosuppressive drugs, in association with the disappearance of the high intensity zones in the thigh muscles on MR images.
These clinical effects of tocilizumab suggest that it may be an optional treatment for refractory autoimmune or allergic diseases although further clinical trails will be essential.
World Allergy Organization Journal 02/2012; 5(Suppl 2):S111. DOI:10.1097/01.WOX.0000412109.80532.b7
[Show abstract][Hide abstract] ABSTRACT: A 65-year-old woman who had suffered from chronic graft-versus-host disease (GVHD) presented with extensive purpura and was diagnosed with acquired hemophilia A. Because she was refractory to corticosteroids and her condition was complicated with diabetes mellitus, glaucoma, and hypoglobulinemia, she was treated with tocilizumab. Tocilizumab treatment increased the activity of factor VIII in a rapid and sustained manner, leading to a reduction of the prednisolone dose. Tocilizumab may thus be an optional treatment modality for acquired hemophilia A.
Modern Rheumatology 08/2011; 21(4):420-2. DOI:10.1007/s10165-010-0411-6 · 2.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A 47-year-old female patient with Behçet's disease had been treated with colchicine, prednisolone, cyclosporine A, and infliximab. Because she relapsed, however, treatment with tocilizumab, a humanized anti-interleukin 6 receptor antibody, was started. This treatment suppressed the patient's clinical manifestations, including ocular attacks, for 1 year and improved her visual acuity. This experience indicates that tocilizumab may constitute a therapeutic option for refractory Behçet's disease.
Modern Rheumatology 07/2011; 22(2):298-302. DOI:10.1007/s10165-011-0497-5 · 2.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Interleukin (IL)-6 is a cytokine with multiple biological activities. It contributes to host defense against pathogens, whereas accelerated production of IL-6 plays a significant pathological role in various diseases. Clinical trials have demonstrated the efficacy of tocilizumab, a humanized anti-IL-6 receptor antibody, for patients with rheumatoid arthritis, Castleman's disease or juvenile idiopathic arthritis, leading to approval of this innovative drug for the treatment of these diseases. Since IL-6 has been demonstrated to play a significant role in the development of various other autoimmune and inflammatory diseases, tocilizumab can be expected to become a novel drug for such diseases as well.
[Show abstract][Hide abstract] ABSTRACT: Interleukin (IL)-6 is a typical cytokine featuring redundancy and pleiotropic activity. It contributes to host defense against pathogens, but dysregulation of IL-6 production plays a significant pathological role in various autoimmune and inflammatory diseases. Because IL-6 blockade was expected to constitute a novel strategy for the treatment of such diseases, tocilizumab, a humanized anti-IL-6 receptor antibody (anti-IL-6RAb), was developed. Clinical trials have demonstrated the efficacy of anti-IL-6RAb for patients with rheumatoid arthritis, Castleman's disease, and juvenile idiopathic arthritis, resulting in approval of this innovative biologic for the treatment of these diseases, and it can be expected to become a novel drug for various other autoimmune and inflammatory diseases. In murine models of autoimmune diseases, anti-IL-6RAb induces Treg and inhibits Th17 and/or Th1 differentiation, indicating that anti-IL-6RAb may be able to repair Th17/Treg imbalance in human diseases as well.
[Show abstract][Hide abstract] ABSTRACT: SSc is an autoimmune disease characterized by fibrosis of the skin and internal organs. Although the aetiology remains uncertain, many reports have suggested that IL-6 is involved in SSc pathogenesis. Tocilizumab, an anti-IL-6 receptor antibody, is an anti-arthritis medicine that works through the blockade of IL-6 functions. To examine the effect of tocilizumab on SSc, we administered tocilizumab to two SSc patients.
Two dcSSc patients were administered tocilizumab at 8 mg/kg once a month for 6 months. One patient had pulmonary fibrosis assessed by CT and spirometry, and the other had chronic renal failure caused by scleroderma renal crisis. Their skin condition was monitored with a Vesmeter and the modified Rodnan total skin score (mRTSS). Skin biopsies were obtained before and after the tocilizumab treatment to investigate the histological changes.
After tocilizumab treatment, both patients showed softening of the skin with reductions of 50.7 and 55.7% in the total z-score of Vesmeter hardness and 51.9 and 23.0% in the mRTSS, respectively. Histological examination showed thinning of the collagen fibre bundles in the dermis. The creatinine clearance in the patient with chronic renal failure improved from 38 to 55 ml/min. However, the fibrotic changes in the lung in the other patient remained unchanged.
In the two cases of SSc that we report here, softening of the skin was observed during the treatment with tocilizumab.
[Show abstract][Hide abstract] ABSTRACT: Tocilizumab is a humanized anti-IL-6 receptor monoclonal antibody, which binds to circulating soluble IL-6 receptor and membrane-expressed IL-6 receptor, inhibiting IL-6 binding to both forms of IL-6 receptor. Several Phase III clinical trials demonstrate the clinical efficacy of tocilizumab as monotherapy or with disease-modifying anti-rheumatic drugs for adult patients with moderately to severely active rheumatoid arthritis. Tocilizumab in combination with methotrexate after 24 weeks of treatment could induce disease remission in 30% of patients with rheumatoid arthritis refractory to anti-TNF antagonist therapy. The most common adverse reactions reported in clinical studies are upper respiratory tract infection, nasopharyngitis, headache, hypertension and mild, reversible increases in alanine aminotransferase enzymes. Serious adverse reactions include infections, gastrointestinal perforations and hypersensitivity reactions, including anaphylaxis. The clinical efficacy and safety of tocilizumab has led to the approval of this innovative drug for the treatment of rheumatoid arthritis in more than 70 countries worldwide.