[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.
Full-text · Article · Feb 2012 · World Allergy Organization Journal
[Show abstract][Hide abstract] ABSTRACT: IL-6 is a cytokine featuring redundancy and pleiotropic activity. While IL-6 contributes to host defense against acute environmental stress, continuous IL-6 production plays a significant pathological role in various autoimmune and chronic inflammatory diseases. To counter this drawback, tocilizumab, a humanized anti-IL-6 receptor antibody, was developed. Clinical trials have verified the efficacy of tocilizumab for patients with rheumatoid arthritis, Castleman's disease and systemic juvenile idiopathic arthritis, resulting in approval of this innovative biologic for their treatment. Moreover, a considerable number of case reports and pilot studies have indicated the beneficial effects of tocilizumab on other autoimmune and chronic inflammatory diseases. Further clinical studies to evaluate the efficacy and safety of tocilizumab for these diseases are essential.
[Show abstract][Hide abstract] ABSTRACT: Activation of fibroblasts by interleukin-6 (IL-6) is implicated in the pathogenesis of scleroderma, suggesting that the inhibition of fibroblast activation may be a promising scleroderma treatment. In this study, we used an IL-6 blocking antibody (Ab) and Il-6 knockout (Il-6KO) mice to examine the role of IL-6 in the bleomycin (BLM)-induced mouse model of scleroderma. BLM was administered to C57BL/6 and Il-6KO mice to induce dermal sclerosis. BLM-treated and control phosphate-buffered saline-treated mice were treated with anti-mouse IL-6 receptor monoclonal Ab (MR16-1). Disease severity was evaluated by measuring dermal thickness and skin hardness, by counting the numbers of α-smooth muscle actin-positive cells and mast cells, and by examining the cutaneous draining lymph nodes. C57BL/6 mice with BLM induced scleroderma had elevated serum IL-6 levels and more severe dermal sclerosis than Il-6KO mice. Weekly administration of MR16-1, but not control Ab, prevented and improved dermal sclerosis, and also attenuated swelling of the draining lymph nodes. MR16-1 suppressed α-smooth muscle actin induction in IL-6-stimulated Il-6KO fibroblasts. Our results indicate that IL-6 contributes to BLM induced dermal sclerosis and that IL-6 receptor-specific monoclonal Ab may improve the symptoms of scleroderma by suppressing fibroblast activation.
Full-text · Article · Nov 2011 · American Journal Of Pathology
[Show abstract][Hide abstract] ABSTRACT: Interleukin (IL)-6 has many biological functions. It induces acute-phase reactants (CRP, SAA) and suppresses albumin. It induces hepcidin, which regulates iron recycling and absorption, causing iron-deficiency anemia. It induces synovial cells to express receptor activator of nuclear factor-κB ligand (RANKL) and secrete vascular endothelial growth factor (VEGF), leading to osteoclast differentiation and neovascularization. In mice, it promotes development of Th17 cells (a new type of T cell) and inhibits Treg cells. Imbalance between these T cells may contribute to RA pathogenesis. In various clinical studies in RA, IL-6 signaling pathway blockade by a recombinant humanized anti-IL-6 receptor antibody, tocilizumab (TCZ), dramatically improved clinical symptoms. TCZ prevented radiographic progression of joint destruction by inhibiting synovial hyperplasia and cartilage/bone resorption. TCZ improved hematological abnormalities, including hypergammaglobulinemia, autoantibodies, and elevation of erythrocyte sedimentation rate and acute phase proteins. TCZ also improved systemic symptoms such as fatigue, anemia, anorexia and fever, improving quality of life. Many patients achieved clinical remission associated with decreased serum IL-6. These findings suggest that the pro-inflammatory cytokine, IL-6, also affects basic autoimmunity and they confirm that IL-6 hyper-production is responsible for joint destruction and the above clinical symptoms. Here, we discuss IL-6 signaling and its blockade by TCZ in RA.
No preview · Article · Nov 2011 · Current Rheumatology Reviews
[Show abstract][Hide abstract] ABSTRACT: Macrophages play a pivotal role in innate immune responses to pathogens via toll-like receptors. We previously demonstrated that aryl hydrocarbon receptor (Ahr) in combination with signal transducer and activator of transcription 1 (Stat1) negatively regulates pro-inflammatory cytokine production by inhibiting nuclear factor-κB activation in macrophages after LPS stimulation. Here, we show that Ahr also negatively regulates production of the pro-inflammatory cytokine IL-6 by suppressing histamine production in macrophages stimulated by LPS. We found that Ahr-Sp1 complex, independent of Stat1, represses histidine decarboxylase expression by inhibiting LPS-induced Sp1 phosphorylation on Ser residues in macrophages; this leads to suppression of histamine production. Moreover, we found that loratadine and chlorpromazine, histamine 1 receptor (H1R) antagonists, more effectively impair the production of LPS-induced IL-6 than that of other inflammatory cytokines in Ahr(-/-) macrophages. Collectively, these results demonstrate that Ahr negatively regulates IL-6 production via H1R signaling through the suppression of histamine production in macrophages following LPS stimulation.
No preview · Article · Sep 2011 · International Immunology
[Show abstract][Hide abstract] ABSTRACT: Malignant pleural mesothelioma (MPM) is an aggressive tumor with poor prognosis for which an effective therapy remains to be established. Our study investigated the therapeutic potential of the suppressor of cytokine signaling 3 (SOCS3), an endogenous inhibitor of intracellular signaling pathways, for treatment of MPM. We infected MPM cells (H226, EHMES-1, MESO-1 and MESO-4) with an adenovirus-expressing SOCS3 (AdSOCS3) to examine the effect of SOCS3 overexpression on MPM cells. SOCS3 overexpression reduced MPM proliferation and induced apoptosis and partial G0/G1 arrest. SOCS3 also inhibited the proliferation of MPM cells via multiple signaling pathways including Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3), extracellular signal-regulated kinase (ERK), focal adhesion kinase (FAK) and p53 pathways. Notably, AdSOCS3 treatment inhibited tumor growth in an MPM pleural xenograft model. These findings demonstrate that overexpression of SOCS3 has a potent antitumor effect against MPM both in vitro and in vivo and indicate the potential for clinical use of SOCS3 for MPM treatment.
Full-text · Article · Aug 2011 · International Journal of Cancer
[Show abstract][Hide abstract] ABSTRACT: The contributions of aryl hydrocarbon receptor (Ahr) to the pathogenesis of rheumatoid arthritis have not been elucidated. Here, we show that Ahr deficiency ameliorated collagen-induced arthritis, a mouse model of RA. Collagen-immunized Ahr KO mice showed decreased serum levels of such proinflammatory cytokines as IL-1β and IL-6. The Th17 and Th1 cell populations in lymph nodes from these mice decreased and increased, respectively, whereas the percentage of regulatory T cells was unchanged. Interestingly, a lack of Ahr specifically in T cells significantly suppressed collagen-induced arthritis development, whereas Ahr deficiency in macrophages had no effect. These finding indicate that the development of experimental autoimmune arthritis depends on the presence of Ahr in T cells, and that Th1/Th17 balance may be particularly important for this process.
Full-text · Article · Aug 2011 · Proceedings of the National Academy of Sciences
[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.
No preview · Article · Aug 2011 · Modern Rheumatology
[Show abstract][Hide abstract] ABSTRACT: A 47-year-old female patient with Beh double dagger et'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 Beh double dagger et's disease.
No preview · Article · Jul 2011 · Modern Rheumatology
[Show abstract][Hide abstract] ABSTRACT: Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by persistent synovitis and progressive destruction
of cartilage and bone in the multiple joints . The pathological features of the affected joints consist of hyperplasia of inflamed synovium and erosion of cartilage and
bone where the pannus tissue invades. There are numerous immunocompetent cells such as T cells, macrophages, dendritic cells
and plasma cells infiltrating in the synovium . Many small blood vessels are also observed and thought to be necessary to oxygenate the tissue . In addition to local inflammation of the joints, patients are associated with systemic inflammatory manifestations such
as fever, fatigue and anemia, and laboratory findings such as elevated erythrocyte sedimentation rate (ESR) and C-reactive
protein (CRP), hyper-γ-globulinemia, and thrombocytosis.
[Show abstract][Hide abstract] ABSTRACT: We evaluated the safety and efficacy of tocilizumab in polyarticular-course juvenile idiopathic arthritis (pJIA) with polyarticular or oligoarticular onset. Patients received 8 mg/kg tocilizumab every 4 weeks in the open-label studies: initial study (to week 12) and then an extension study (at least 48 weeks). Nineteen patients intractable to conventional methotrexate therapy were enrolled. Seventeen patients had polyarticular-onset pJIA; two had oligoarticular-onset pJIA. Mean age was 11.6 years; mean disease duration 5.3 years. American College of Rheumatology Pediatric (ACR Pedi) 30, 50, 70, and 90 response rates, respectively, were 94.7%, 94.7%, 57.9%, and 10.5% at week 12, and 100%, 94.1%, 88.2%, and 64.7% at week 48. Mean disease activity score (DAS28) remained below the remission level (2.6) from week 24. Administration was discontinued in two patients during the extension study because the ACR Pedi 50 response was judged insufficient (one patient) and antitocilizumab antibodies developed (one patient). Adverse events were generally mild, and the four serious adverse events resolved spontaneously or with treatment. In conclusion, tocilizumab showed early and sustained efficacy and tolerability for treating intractable pJIA, which suggests that it is a promising new treatment for this disease.
No preview · Article · Jun 2011 · Modern Rheumatology
[Show abstract][Hide abstract] ABSTRACT: Interleukin (IL)-17-producing helper T (Th17) cells have been proposed to participate in the pathogenesis of chronic inflammation, such as autoimmune myocarditis. IL-6 gene ablation confers the resistance to experimental autoimmune myocarditis (EAM). In this study, we have addressed the pathological roles of IL-6 in the regulation of Th17 cells in EAM.
To induce EAM, mice were immunized twice with α-myosin heavy chain peptide. Three weeks after the first injection, the cardiac expression of the Th17-specific transcription factor, retinoic acid receptor-related orphan nuclear receptor (ROR γt), was up-regulated. Consistently, Th17 cells were recruited into EAM hearts, as analysed by flow cytometry. Using the mice with enhanced green fluorescence protein (eGFP) gene knocked-in at RORγt locus (RORγt-eGFP mice), we observed Th17 cell infiltration into inflamed lesions. Pre-treatment with IL-6 receptor (IL-6R)-blocking antibody (anti-IL-6R Ab) inhibited EAM induction in terms of disease severity score (3.5 ± 0.8; IgG vs. 0.5 ± 0.8; anti-IL-6R Ab, n = 6, P< 0.01) and suppressed the myocardial expression of IL-17 and RORγt. In contrast, the administration of anti-IL-6R Ab 7 days after the first immunization failed to show the inhibitory effects, suggesting that IL-6 plays important roles in EAM initiation. Finally, by generating RORγt-eGFP homozygous mice, we revealed that RORγt gene ablation conferred the resistance to EAM induction.
IL-6-mediated induction of Th17 cells is critical for the onset of EAM, but not for its progression. IL-6/Th17 signalling could be a promising therapeutic target for the prevention of myocardial inflammation.
Full-text · Article · May 2011 · Cardiovascular Research
[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: Objective. Our aim was to investigate the effects of IL-6 blockade on the progression of Mycobacterium tuberculosis (TB) and compare them with those of TNF-α blockade in mice. Methods. Mice were intravenously infected with TB and injected with antibodies. Survival was monitored and histological and immunological studies were carried out. Results. All anti-IL-6R Ab-treated mice and 8 of 10 control mice survived until sacrificed 224 days after TB challenge, whereas anti-TNF-α Ab-treated mice all died between 120 and 181 days. Anti-IL-6R Ab-treated mice exhibited no significant differences in TB CFU in organs, including the lungs, and no deterioration in histopathology compared to control mice at 4 weeks. In contrast, anti-TNF-α Ab-treated mice exhibited increased TB CFU and greater progression of histopathological findings in organs than control mice. Spleen cells from anti-TNF-α Ab-treated mice had decreased antigen-specific response in IFN-γ release and proliferation assays. The results in anti-IL-6R Ab-treated mice suggest that spleen cell responses were decreased to a lesser degree. Similar results were obtained in IL-6 knockout (KO) mice, compared with TNF receptor 1 (TNFR1) KO and TNFR1/IL-6 double KO (DKO) mice. Conclusion. IL-6R blockade promotes the progression of TB infection in mice far less than TNF-α blockade.
Full-text · Article · Feb 2011 · Clinical and Developmental Immunology
[Show abstract][Hide abstract] ABSTRACT: Ankylosing spondylitis (AS) is a chronic inflammatory osteoarticular disease. Although the etiology remains unknown, proinflammatory cytokines, such as tumor necrosis factor α and interleukin-6, have been implicated in the development of AS. Here, we report that a patient with AS, whose disease had been refractory to conventional treatment regimens and who needed to receive continuous corticosteroid, responded well to tocilizumab. While further clinical evaluation is required, tocilizumab may be an optional treatment for AS.
No preview · Article · Feb 2011 · Modern Rheumatology