Sage Journals: Discover world-class research

Abstract

Interleukin-6 (IL-6), produced by a variety of cells, is a typical cytokine featuring redundancy and pleiotropic activity. IL-6 is promptly and transiently synthesized in response to infections or injuries, and participates in host defense by inducing immune responses, hematopoiesis, and acute-phase reactions. However, since its abnormal persistent production of mostly unknown etiology plays an important pathological role in the development of various immune-mediated diseases, a humanized anti-IL-6 receptor monoclonal antibody, tocilizumab, was developed and is now used as an innovative biologic for rheumatoid arthritis in more than 90 countries. Several factors strongly suggest that a IL-6 blockade strategy may have a broad application for the treatment of various immune-mediated diseases. These factors include favorable results of pilot or case studies with off-label use of tocilizumab, pathological analyses of the contribution of IL-6 to the development of immune-mediated diseases, and the potential capability of tocilizumab to both repair an imbalance of effector T cell subsets and to suppress pathologic autoantibody production. However, clinical trials to evaluate the efficacy and safety of tocilizumab for these diseases are essential. Furthermore, clarification of the cell source of IL-6 production and of the mechanisms through which dysregulated continuous IL-6 synthesis is induced constitutes an important issue for future studies into the pathogenesis of diseases.

Keywords

anti-IL-6 receptor antibody IL-6 immune-mediated diseases rheumatoid arthritis tocilizumab

Interleukin-6

In the early stages of research into the soluble factor interleukin-6 (IL-6), its various and distinct functions were being studied and each research group had its own name for this cytokine. One was B cell stimulatory factor 2 (BSF-2) because it induces B-cell differentiation into antibody (Ab) producing cells. Another was hepatocyte-stimulating factor (HSF) because it induces synthesis of acute phase proteins in hepatocytes. Yet another was hybridoma growth factor (HGF) due to its promotion of growth of fusion cells with myeloma, or IFNβ2 due to its IFN anti-viral activity. Later, it was discovered that these diverse functions reflect the wide range of target organs for IL-6.¹ In 1986, two groups independently reported on the molecular structures of IFNβ2 and BSF-2.^2,3 Since these two molecules were found to be identical, the cytokine was renamed IL-6. Human IL-6 (GenBank: X04602) consists of 212 amino acids, includes a 28-amino-acid signal peptide, and its gene has been mapped to chromosome 7p21. The structure of IL-6 includes four helix bundles, which are arranged in an up-up-down-down topology (Fig. 1: A to D), and three loops (two long ones, A–B and C–D, and a short one, B–C).⁴

Figure 1

Schematic representation of the domain structure of human IL-6.

IL-6 mediates inflammatory signals from infected or injured lesions to other parts of the body in order to generate protection against emergent events. There are many cytokines that are involved in and regulate inflammation, but IL-6 is the most imoprtant for mediating systemic inflammation. The clinical function of IL-6 was discovered first by observing and examining patients with cardiac myxoma or Castleman's disease in whom IL-6 was persistently produced from myxoma tissues or involved lymph nodes, respectively.^5,6 These patients presented with symptoms of systemic inflammation and autoimmunity (eg, fever, arthralgia, fatigue) and laboratory findings of inflammation such as elevated C-reative protein (CRP), serum amyloid A (SAA), and fibrinogen levels, as well as thrombocytosis. As a result of chronic inflammation, anemia, autoantibody production, hypergammaglobulinemia and hypoalbuminemia were also detected. The fact that all of these signs and laboratory data became normalized after surgical removal of cardiac myxoma suggested that IL-6 played a role in systemic inflammation. An IL-6 deficient mouse model was thus compared with its IL-6 transgenic expression counterpart. The IL-6 deficient mice could develop almost normally and were fertile,⁷ indicating that IL-6 is not essential for organ development, whereas mice with persistent IL-6 expression showed chronic inflammation accompanied by swollen lymph nodes and spleen.⁸ Similarly, healthy human individuals feature almost undetectable serum IL-6 levels, whereas in those with infection, trauma or burn IL-6 levels increase and inflammatory symptoms appear.⁹ These findings indicate that production of IL-6 provides an SOS signal to indicate occurrence of an emergent infection or injury in an organ.

In infectious stress, IL-6 is promptly produced by monocytes and macrophages through the stimulation of Toll-like receptors (TLRs) by microbial motifs.¹⁰ IL-6, when acting on hepatocytes, induces a wide spectrum of acute phase proteins, such as CRP, SAA, fibrinogen, and hepcidin, and inhibits the synthesis of albumin (Fig. 2).¹¹ High levels of hepcidin cause increased internalisation of iron transporter ferro-portin molecules on cell membranes, which inhibits release from iron stores and leads to anemia of chronic disease.¹² Induction of zinc transporter Zip14 by IL-6 in liver increases zinc uptake into hepatocytes, resulting in hypozincemia.¹³ IL-6 in the bone marrow promotes maturation of megakaryocytes, which leads to the production of platelets.¹⁴ These changes in acute phase serum protein levels and red blood cell and platelet counts are in fact used in clinical practice for the diagnosis and evaluation of inflammatory severity. After the infiltration of neutrophils into the focus of acute infection, IL-6 orchestrates the switch in leukocyte recruitment from neutrophils to more sustained monocytic cells that develop acquired immune responses.¹⁵ IL-6 thus performs an important function in acquired immunity. In lymphocytes, CD4-positive T-helper cells display distinct effector functions after their differentiation.¹⁶ IL-6, together with TGF-β, has been shown to be essential for Th17 differentiation from naive CD4-positive T cells.¹⁷ On the other hand, IL-6 inhibits the generation of regulatory T cells (Treg) induced by TGF-β.^16,17 The resultant Th17/Treg imbalance leads to a rupture in immunological tolerance and is thus essential for the development of autoimmune or chronic inflammatory diseases.¹⁸ IL-6 also acts on CD8-positive T cells to induce cytotoxic T cells,¹⁹ and on activated B cells for differentiation into Ab producing cells.²⁰ Besides its effects on hepatocytes and lymphocytes, IL-6 has various effects that are associated with inflammatory symptoms. For example, IL-6 production in bone marrow stromal cells induces the receptor activator of NF-kappaB ligand (RANKL), which is an essential factor for the differentiation and activation of osteoclasts and bone resorption.^21,22 IL-6 production by bone marrow stromal cells is suppressed by 17 beta-estradiol and in mice the loss of estrogen due to ovariectomy increased the number of osteoclasts in trabecular bone. Conversely, the administration of 17 beta-estradiol or anti-IL-6 Ab prevented such an increase,²³ suggesting that estrogen loss results in an IL-6-mediated bone resorption in postmenopausal osteoporosis and affects the development of rheumatoid arthritis (RA) in postmenopausal women.²⁴ Furthermore, enhanced angiogenesis and increased vascular permeability are pathological features of chronic inflammatory sites such as synovial tissue of RA; these pathological changes are due to the excess production of vascular endothelial growth factor (VEGF), which is induced by IL-6.²⁵ Finally, IL-6 has been demonstrated to promote the proliferation of keratinocytes²⁶ and collagen production²⁷ in dermal fibroblasts.

Figure 2

Pleiotropic activity of IL-6.

The IL-6 receptor (IL-6R) system consists of two chains, IL-6-binding chain IL-6R and gp130, both of which belong to the cytokine receptor family.²⁸ The latter transduces the IL-6 signal into cells.²⁹ The broad range of expression of gp130 on various cells suggests that IL-6 has pleiotropic effects because the soluble form of IL-6R (sIL-6R) is present in human serum.³⁰ The IL-6/sIL-6R complex can transduce the IL-6 signal on gp130-expressing cells even in cells lacking transmembrane IL-6R. The IL-6/IL-6R complex in turn induces homodimerization of gp130 to trigger downstream events in cytoplasm (Fig. 3). The activated IL-6 receptor complex is formed as a hexameric structure comprising two molecules each of IL-6, IL-6R, and gp130.³¹ In this complex, IL-6 provides one IL-6R binding site (site I) and two gp130 binding sites (sites II and III) (Fig. 1). IL-6R is a unique binding receptor for IL-6 and its expression is restricted to certain cells, including leukocytes and hepatocytes, whereas signal-transducing chain gp130 is expressed in almost all cells and is shared by members of the IL-6 family of cytokines.³² These members include leukemia inhibitory factor (LIF), oncostatin M (OSM), ciliary neurotrophic factor (CNTF), IL-11, cardiotrophin 1 (CTF1), cardiotrophin-like cytokine (CLC), IL-27, and IL-35.³³ These cytokines bind to their unique binding receptors but use their common gp130 to transduce their signal. The only exception is virus-encoded IL-6 (vIL-6), which is the product of Kaposi's sarcoma-associated herpes virus (also known as human herpes virus 8) and directly binds to and activates gp130.³⁴ It is known that the activities of the IL-6 family of cytokines often overlap with those of IL-6. The model in which IL-6 family members use the common signal-transducing chain makes it clear why different cytokines show functional redundancy. Activated gp130 triggers activation of the JAK (Janus kinase)-STAT3 (signal transducer and activator of transcription 3) pathway and the JAK-SH2-domain containing protein tyrosine phosphatase-2 (SHP-2)-mitogen-activated protein (MAP) kinase pathway. In this context, STAT3 is the transcriptional factor that regulates various sets of IL-6 responsive genes, including acute phase proteins.²⁸

Figure 3

IL-6 receptor system.

IL-6 is produced from inflammatory lesions. The synthesis of IL-6 is strictly regulated both through levels of gene transcription and the stability of mRNA. The transcriptional factors NF-kB and NF-IL-6 (also known as C/EBPβ) promote transcription of IL-6 mRNA in response to various stimuli.^35,36 Some RNA binding proteins or micro-RNAs bind to the 3‘-untranslated regions of the IL-6 mRNA so as to control the stability of mRNA.^37,38 However, dysregulated and persistent expression of IL-6 has been implicated in the development of various autoimmune diseases, chronic inflammatory diseases, and even cancers; the IL-6 signal pathway could therefore be an appropriate target for the treatment of such diseases.³⁹ Inhibition of this function of IL-6 consists of four strategies–-inhibition of any of IL-6, IL-6R, gp130, or the cytoplasmic signaling cascade via gp130. The humanized anti-IL-6R monoclonal Ab, tocilizumab (TCZ),⁴⁰ is the first drug that successfully blocks the IL-6 signal and has been approved worldwide for the treatment of RA.

Tocilizumab, a Humanized Anti-IL-6 Receptor Monoclonal Antibody

TCZ blocks IL-6-mediated signal transduction by inhibiting IL-6-binding to transmembrane and soluble IL-6R. If concentration of free TCZ is maintained at more than 1 μg/mL, CRP remains negative⁴¹ and the serum CRP level becomes a hallmark for in vivo confirmation of whether IL-6 activity is completely blocked. TCZ is currently approved for the treatment of RA in more than 90 countries, for the treatment of systemic juvenile idiopathic arthritis (JIA) in Japan, India, the EU, and the USA, and of polyarticular JIA and Castleman's disease in Japan and India.^42–44 For RA, the recommended TCZ posology is 8 mg/kg once every 4 weeks in Japan and the EU. The recommended starting dose in the USA is 4 mg/kg once every 4 weeks, followed by an increase to 8 mg/kg, depending on clinical response. TCZ is used for the treatment of Castleman's disease and systemic JIA at 8 mg/kg once every 2 weeks in Japan, while in the USA the recommended TCZ dosing for systemic JIA patients weighing less than 30 kg is 12 mg/kg and 8 mg/kg for those weighing more than 30 kg, intravenously once every 2 weeks.

Efficacy and Safety of Tocilizumab for Rheumatoid Arthritis

RA is an inflammatory arthritis which causes joint destruction. Inflammatory cytokines including IL-6 play an important role in the pathogenesis of RA; treatment options which inhibit IL-6 activity for patients with RA have advanced significantly over the past decade. Among these, TCZ is the first approved IL-6 signaling inhibitor.

The key mechanism by which TCZ affects RA is thought to be interference with systemic inflammation, which can normalize imbalance in the effector CD4-positive T cell subsets that generate autoimmune reactions. Interestingly, IL-6 blockade inhibits arthritis in type II collagen-induced arthritis (CIA), which requires the presence of CD4-positive T cells, and leads to the production of antitype II collagen IgG.⁴⁵ It does not, however, inhibit the development of antitype II collagen Ab-induced arthritis (CAIA), which skips the priming phase of T cell-dependent Ab generation.⁴⁶ These observations suggest that IL-6 is required primarily for the activation of T cell responses, as well as the production of Abs specific to joint components (the priming phase).⁴⁷ TCZ has little effect on spondyloarthritides such as psoriatic arthritis and ankylosing spondylitis,^48,49 for which the autoimmune process appears not to be required. Additionally, the onset of the anti-arthritic effect of TCZ is slow compared with that of TNF inhibitors. These observations suggest that TNF contributes to local inflammation, a direct cause of joint destruction, and IL-6 mainly contributes to immune activation, synovitis, and systemic inflammation (Fig. 4).

Figure 4

Pathological role of IL-6 in rheumatoid arthritis.

The efficacy of TCZ on RA was evaluated in seven major phase III clinical trials. Its efficacy was found to be outstanding for RA patients either as monotherapy or in combination with disease-modifying antirheumatic drugs (DMARDs).^42,43 The efficacy of TCZ administered alone or in combination with methotrexate (MTX) was also confirmed for RA patients of various backgrounds. The results of these trials are summarized in Table 1. The findings of three phase III trials of TCZ monotherapy have been reported. The AMBITION trial was performed with MTX- or biologic-naïve patients,⁵⁰ the SAMURAI trial with patients with an inadequate response to DMARDs,⁵¹ and the SATORI trial with patients with an inadequate response to MTX.⁵² These studies showed that TCZ monotherapy is better than MTX and DMARD monotherapy for patients who are naïve to MTX and other biologics and that it is also effective for those who are resistant to MTX and other DMARDs. All studies showed that after 24 weeks patients treated with TCZ showed superior ACR20 (American College of Rheumatology) responses and reduction in disease activity score 28 (DAS28) when compared to controls treated with MTX or other DMARDs.^50–52 In addition, four phase III trials of TCZ combination therapy have been performed. The OPTION trial was designed to evaluate the efficacy of TCZ in combination with MTX and showed that TCZ combination therapy was effective for and well tolerated by patients with moderate-to-severe active RA and with an inadequate response to MTX.^53,54 The TOWARD trial, with an enrollment of 1,220 RA patients, demonstrated that TCZ combined with DMARDs such as MTX, chloroquine, gold, sulphasalazine, azathioprine, and leflunomide was effective for reducing RA disease activity in patients with an inadequate response to monotherapy with any one of the DMARDs.⁵⁵ The RADIATE trial proved that TCZ plus MTX was effective for achieving rapid and sustained improvements in signs and symptoms of patients with RA refractory to TNF inhibitors; it also showed that it had a manageable safety profile.⁵⁶ The LITHE trial, which was designed to evaluate not only disease activity but also structural joint damage, demonstrated that TCZ plus MTX was effective for the suppression of disease activity and symptoms. The LITHE trial also showed that at 52 weeks TZ plus MTX significantly inhibited radiographic progression for patients with an inadequate clinical response to MTX.^57,58 In short, all these studies enrolled patients with an inadequate response to all previous treatments–-including MTX, TNF inhibitors, and other DMARDs–-and all showed that TCZ combination therapy was effective for these populations. In addition, the OPTION, RADIATE, and LITHE studies reported that the efficacy of TCZ was dose dependent (4 mg/kg and 8 mg/kg).^53,56,57

Table 1

Summary of phase III clinical trials of tocilizumab in rheumatoid arthritis.

Study	Population	Day at evaluation	Treatment arms	Patient number	Response rate (%)	Remission rate (%)	Radiological progression from baseline
					ACR20	DAS28 < 2.6	∆ TSS
AMBITION	MTX, TNFi-naïve	24 W	TCZ (8 mg/kg) MTX	286 284	70 53	34 12
SAMURAI	DMARDs-IR	52 W	TCZ (8 mg/kg) DMARDs	157 145	78 34	59 3	2.3 6.1
SATORI	MTX-IR	24 W	TCZ (8 mg/kg) MTX	61 64	80 25	43 2
TOWARD	DMARDs-IR	24 W	TCZ (8 mg/kg) + DMARDs DMARDs	803 413	61 25	30 3
RADIATE	TNFi-IR	24 W	TCZ (4 mg/kg) + MTX	161	30	8
			TCZ (8 mg/kg) + MTX	170	50	30
			MTX	158	10	2
OPTION	MTX-IR	24 W	TCZ (4 mg/kg) + MTX	186	48	13
			TCZ (8 mg/kg) + MTX	191	59	27
			MTX	189	26	1
LITHE	MTX-IR	52 W	TCZ (4 mg/kg) + MTX	394	47	30	0.34
			TCZ (8 mg/kg) + MTX	398	56	47	0.29
			PBO	393	26	8	1.13

Abbreviations: MTX, methotrexate; TCZ, tocilizumab; IR, inadequate response; DMARDs, disease-modifying antirheumatic drugs; TNFi, TNF inhibitor; PBO, placebo; ACR20, ACR criteria for 20% improvement; DAS28, disease activity score 28; TSS, total sharp score.

Recently many phase IIIb/IV studies have been conducted in clinical settings as well. The ACT-RAY trial compared TCZ plus MTX therapy with TCZ monotherapy in a setting that closely resembled real-life clinical practice.⁵⁹ The trial was a double-blind, 2-year study in which active RA patients being treated with MTX were randomly assigned either to continue MTX with the addition of TCZ 8 mg/kg every 4 weeks or to switch to TCZ plus placebo. Of 556 randomly assigned patients, 512 (92%) completed 24 weeks. ACR20/50/70 response rates were 71.5%/45.5%/24.5% for the TCZ plus MTX group and 70.3%/40.2%/25.4% for the TCZ plus placebo group. TCZ plus MTX combination therapy was therefore shown not to be clinically superior to TCZ monotherapy. The ACT-SURE trial was a phase IIIb, open-label, single-arm, 6-month study which was conducted with a patient population resembling one to be expected in clinical practice.⁶⁰ Patients, who were categorised as TNF inhibitor-naïve (never received TNF inhibitor), TNF inhibitor-previous (washout: TNF inhibitor therapy discontinued for more than 2 months) or TNF inhibitor-recent (TNF inhibitor discontinued for less than 2 months), received open-label TCZ 8 mg/kg every 4 weeks, with or without DMARDs, for 24 weeks. Overall, 1,681 (976 TNF inhibitor-naïve, 298 TNF inhibitor-previous, and 407 TNF inhibitor-recent) patients were treated. ACR20/50/70 rates by week 24 were 70.5%/51.9%/31.8%, 60.7%/35.2%/17.8% and 62.7%/42.3%/19.7% for TNF inhibitor-naïve patients, TNF inhibitor-previous, TNF inhibitor-recent patients, respectively. The ACT-STAR study was a 24-week, prospective, open-label study conducted in the USA.⁶¹ Of 886 patients enrolled, 163 were assigned to TCZ 8 mg/kg monotherapy. The remaining 723 patients were assigned to combination therapy, with 363 randomized to receive a starting dose of TCZ 4 mg/kg plus DMARDs and 360 to receive a starting dose of TCZ 8 mg/kg plus DMARDs. In the initial TCZ 4 mg/kg plus DMARDs group, 152 patients (41.9%) at week 8 and 68 patients (18.7%) after 8 week escalated to TCZ 8 mg/kg plus DMARDs. Overall, the 24-week study was completed by 82.5% of patients. By week 24, 49.7%, 27.1%, and 10.3% of the patients in the 8 mg/kg TCZ plus DMARDs group and 47.9%, 24.5%, and 7.4% of the patients in the 8 mg/kg TCZ monotherapy group had attained ACR20/50/70 responses. The safety profiles and efficacy were similar for the TCZ monotherapy and the TCZ plus DMARD groups. Therefore, the efficacy of TCZ monotherapy and combination therapy with MTX or DMARDs was similar, demonstrating that TCZ monotherapy can provide patients who cannot use MTX with a good quality of life (QoL).

In addition, TCZ showed a good continuation rate and could induce drug-free remission. Reduced efficacy is one of the issues when using a treatment for RA that includes biologics. In the Danish DANBIO registry, the drug adherence rate after 48 months was 64%.⁶² In another multicentre registry, the Japanese REAL, the continuation rate for TCZ at 2.5 years was 67%.⁶³ The DREAM study reported findings on the maintenance of TCZ-free remission in TCZ monotherapy;⁶⁴ remisson rates following the cessation of TCZ were 35.1% and 13.4% at 24 and 52 weeks, respectively. Even if recurrence was noted after TCZ cessation, TCZ re-administration could re-induce remission.⁶⁵ The OPTION trial reported on maintenance of TCZ-free remission for combination therapy with MTX; efficacy after the cessation of TCZ was 52.5% at 12 months.⁶⁶ Relapses occurred in 47.5% patients, half of which were noted during the first 3 months after the final TCZ administration.

The systemic effects of TCZ enhance the satisfaction of RA patients; health-related QoL (HRQoL) was reportedly improved with TCZ therapy.^67,68 Depression, fatigue, and quality of sleep in patients treated with TCZ also improved.^69–71

The safety profile of TCZ monotherapy was first published in 2010.⁷² The overall incidence of adverse events (AE) and serious AE (SAE) rates were 465.1/100 patient-year (PY) and 6.22/100 PY, respectively. As for the risk of AEs for RA patients treated with TCZ, pooled odds ratios (ORs) indicate a statistically significantly increased risk of AEs (OR = 1.53; 95% confidence interval (CI) = 1.26–1.86) in addition to a heightened risk of infection (OR = 1.30; 95% CI = 1.07–1.58). The safety profile of TCZ combination therapy was first published in 2011.⁷³ Overall AE and SAE rates were 278.2/100 PY and 14.4/100 PY, respectively. These events included serious infections (4.7/100 PY), opportunistic infections (0.23/100 PY), and gastrointestinal perforations (0.28/100 PY). Pooled ORs revealed a significantly increased risk of AEs (OR = 1.53; 95% CI = 1.26–1.86) and infection (OR = 1.30; 95% CI = 1.07 = 1.58) for patients treated with 8 mg/kg TCZ plus MTX compared with that for controls.

TCZ blocks IL-6 function and has been shown to have excellent efficacy and tolerability when used in the treatment of RA. The efficacy of TCZ monotherapy appears to be similar to that of combination therapy with DMARDs or MTX. In addition, the recent development of the option of subcutaneous administration of TCZ may also be beneficial for patients with RA. Because of the outstanding efficacy of TCZ, other new biological agents that target IL-6 are also being developed. These IL-6 inhibitors can be expected to constitute a new class of antirheumatic drugs in the future.

The clinical efficacy of TCZ in RA is mediated by the inhibition of IL-6-induced RANKL induction followed by osteoclastogenesis and suppression of IL-6-induced production of matrix metalloproteinases.⁷⁴ Moreover, it has been shown that TCZ corrects Th17 (CD4⁺IL-17⁺)/Treg (CD4⁺CD25^highFoxp3⁺) imbalance in RA patients.⁷⁵ Other studies have found both that TCZ induced a significant reduction in the peripheral pre-switch and post-switch memory B cells of RA patients⁷⁶ and that TCZ but not TNF inhibitors significantly reduced somatic hypermutation in immunoglobulin gene rearrangements in pre-switch memory B cells.⁷⁷ These findings thus indicate that modulation of memory B cells may constitute a potential target for TCZ.

Additional Applications of Tocilizumab for other Immune-Mediated Diseases

In addition to the diseases for which it has been approved, IL-6 blockade strategy is expected to come into extensive use for the treatment of various other immune-mediated diseases; several clinical studies to evaluate the efficacy and safety of TCZ for such diesases are in progress.

Systemic sclerosis

Systemic sclerosis (SSc) is a connective tissue disease, characterized by skin and tissue fibrosis, vasculopathy, and immune abnormalities.⁷⁸ Numerous studies have analyzed the pathogenic mechanisms of SSc, but no effective treatment has been established yet.⁷⁹ IL-6 is a potential target for SSc therapy for several reasons.^80,81 IL-6 levels in the sera of SSc patients are elevated and these levels correlate well with skin severity scores.^82–86 Indeed, the culture supernatants of peripheral blood mononuclear cells and skin tissues from patients with SSc were found to contain higher concentrations of IL-6 than did those from controls.^87–89 Furthermore, in vitro studies indicate that IL-6 may contribute to fibrosis by inducing collagen production²⁷ by dermal fibroblasts and induce their differentiation into myofibroblasts.⁹⁰ Moreover, anti-IL-6 Ab suppressed procollagen type 1 production in vitro in fibroblasts derived from SSc patients.⁹¹ Another reason for targeting IL-6 in SSc is that SSc serum mediated largely by IL-6 was found to induce endothelial cell activation and apoptosis in endothelial cell-neutrophil co-cultures.⁹² Loss of IL-6 expression led to amelioration of skin and lung fibrosis in a mouse model immunized with DNA topoisomerase 1 and Freund's complete adjuvant.⁹³ Meanwhile, IL-6 deficiency produced by either administration of anti-IL-6R Ab or gene knockout in a bleomycin-induced mouse model of SSc suppressed fibroblast activation, which resulted in a reduction of dermal thickness and hardness.⁹⁴

We reported our clinical findings for two patients with SSc who responded well to TCZ.⁹⁵ The skin became softer as indicated by the modified Rodnan total skin score and a novel device known as Vesmeter, which can measure viscosity, elasticity, and hardness of the skin.⁹⁶ Histological analysis showed that collagen fibre bundles had become thinner and activated myofibroblasts reduced in the dermis after a 6-month treatment with TCZ.^94,95 These findings indicate that IL-6 blockade strategy is a promising approach for the treatment of SSc. A phase II/III, multicenter, randomized, double-blind, placebo-controlled study is in progress to assess the efficacy and safety of TCZ as compared with a placebo for patients with SSc.

Polymyositis

Inflammatory myopathies encompass a group of acquired muscle disorders that includes polymyositis (PM), dermatomyositis, and inclusion body myositis; these disorders share the clinical features of progressive symmetrical muscle weakness and mononuclear inflammatory cell infiltrating muscle tissue.⁹⁷ PM appears to be another suitable target disease for TCZ for three reasons. Firstly, excessive IL-6 expression has been found in the sera and in the infiltrating mononuclear cells in the muscles of PM patients.^98–101 Secondly, infiltrating cytotoxic T cells are thought to be involved in muscle fiber damage and IL-6 reportedly functions as a helper factor in the induction of cytotoxic T cells.¹⁹ Thirdly, in a model of myosin-induced experimental myositis it was shown that control mice developed clinically manifest muscle damage, whereas IL-6-deficient mice showed no clinical or histological signs of muscle damage.¹⁰² In another model of PM, known as C protein-induced myositis, intraperitoneal administration of anti-IL-6R Ab reduced the severity of myositis.¹⁰³

We therefore administered TCZ to two PM patients who had been refractory to corticosteroids and immunosuppressive drugs for more than 5 years. Creatine phosphokinase levels of both patients normalized and magnetic resonance images showed that high-intensity zones in the thigh muscles had disppeared,¹⁰⁴ indicating that TCZ administration may also be an option for the treatment of refractory PM.

Vasculitis syndrome and polymyalgia rheumatica

Vasculitis syndrome refers to a heterogeneous group of disorders featuring inflammation and damage of blood vessel walls, leading to tissue necrosis.^105,106 According to the 2012 revised international Chapel Hill Consensus Conference nomenclature of primary vasculitis syndrome, large vessel vasculitis includes giant cell arteritis (GCA) and Takayasu arteritis (TA), medium vessel vasculitis comprises polyarteritis nodosa and Kawasaki disease, and small vessel vasculitis includes anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, immune complex small vessel vasculitis, and hypocomplementary urticarial vasculitis. The pathological significance of IL-6 for large vessel vasculitis has been well documented.^107,108 It was found that the serum concentrations of IL-6 were elevated at the onset and during clinical relapse and correlated with the disease activity of GCA and TA,^109–115 while tissue-infiltrating cells reportedly produced major quantities of IL-6 in patients with GCA and TA.^116–119

Nishimoto et al were the first to report that TCZ treatment for a 20 year old woman with refractory active TA improved clinical manifestations and abnormal laboratory findings.¹²⁰ It was subsequently reported that TCZ treatment induced a rapid remission in five patients with GCA and two patients with TA, so that cumulative corticosteroid doses could be reduced substantially.¹²¹ Corticosteroid treatment is currently recognized as the mainstay therapy for GCA, but interestingly, TCZ as monotherapy without corticosteroids was effective for two of the patients with GCA in the study. Furthermore, recent case reports and case series of off-label use of TCZ have demonstrated its outstanding efficacy for refractory GCA and TA.^122–132 It has been reported to date that the treatment had rapid beneficial effects on 22 patients with GCA and 12 patients with TA, resulting in the successful tapering of corticosteroids, with the exception of one GCA patient. Instrumental examination of the arteries involved by determining the vascular ¹⁸F-fluorodeoxyglucose (FDG) uptake on positron emission tomography by means of CT and ultrasonographic resolution, showed improvement in all cases evaluated. These results strongly suggest that IL-6 inhibition may become a novel therapeutic strategy for large vessel vasculitis. As of this study, a phase II, randomized, double-blind, placebo controlled study of TCZ for patients with GCA has just been initiated.

In addition to the clinical effect of TCZ on large vessel vasculitis, the treatment reportedly improved clinical symptoms in a patient with a chimeric anti-CD20 antibody rituximab-refractory cryoglobulinemic vasculitis.¹³³ A patient with myeloperoxidase-ANCA-associated crescentic glomerulonephritis complicated by RA also showed improvements.¹³⁴

Polymyalgia rheumatica (PMR) is a chronic inflammatory disorder that affects the elderly and is characterized by aching and morning stiffness in the shoulders, neck, and pelvic girdles.¹⁰⁷ PMR can occur in its isolated form or may be associated with GCA. Although the pathogenesis of this disorder remains unknown, IL-6 has been identified as the only cytokine occurring at a consistently high level in patients with the active form of the disease; it is recognized as the most sensitive indicator of disease activity and course.^{107,109–111,135} IL-6 was also reported to be elevated in the synovial fluid¹³⁶ and in the muscle interstitial concentrations of cytokines.¹³⁷ IL-6 inhibition with TCZ may thus constitute a novel strategy for the treatment of PMR. Low doses (15–20 mg/day) of corticosteroids are effective for PMR, but 43%–65% of patients with this disease reportedly experienced at least one steroid-related adverse event such as osteoporosis, fragility fracture, or arterial hypertension.^138,139

We found that TCZ had a significantly beneficial effect on a patient with long-standing steroid-refractory PMR complicated by diabetes, osteoporosis, and hypertension.¹⁴⁰ After five injections of TCZ, all symptoms such as pain and morning stiffness improved and the patient was judged to be in remission; improvements were such that the prednisolone dose could be reduced. In addition, TCZ treatment was found to produce a disease-free status for four patients with PMR complicated with GCA.¹²¹ As mentioned before, two patients with PMR treated with TCZ but not with corticosteroids also attained remission. Moreover, recent studies have demonstrated the ameliorative and steroid-sparing effects of TCZ for patients with PMR,^126,130 while a phase IIa clinical trial of tocilizumab for the treatment of polymyalgia rheumatica is in progress.

Systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease of unknown etiology that mainly affects young women.¹⁴¹ While pathogenesis of SLE remains unclear, cytokine dysregulation is pervasive in SLE and its expression profiles may serve as a marker of disease activity and severity. Recent findings have highlighted the presence of the type I interferon pathway¹⁴² or the activation of Th17 cell¹⁴³ in the pathogenesis of SLE. IL-6 has also been shown to play a role in the development of SLE,¹⁴⁴ since it was found that serum IL-6 levels of SLE patients were elevated,^145–147 urinary excretion of IL-6 had increased in SLE patients with active proliferating lupus nephritis,^146,148 and IL-6 levels were elevated in the cerebrospinal fluid of SLE patients with central nervous system (CNS) involvement.¹⁴⁹ A comparison with healthy controls showed that SLE patients have significantly more IL-6 secreting peripheral blood mononuclear cells.¹⁵⁰ Moreover, lymphoblastoid cells isolated from SLE patients produced higher levels of IL-6 and blocking of IL-6 inhibited anti-double-stranded DNA (dsDNA) production in vitro.^151,152 In murine SLE models, IL-6 administration exacerbated glomerulonephritis,^153,154 while IL-6 blockade by means of anti-IL-6R or anti-IL-6 Ab prevented the onset and progression of the disease.^155,156 Mice with epidermal loss of JunB reportedly developed an SLE phenotype associated with enhanced epidermal IL-6 secretion.¹⁵⁷ Facial skin biopsies of SLE patients displayed low levels of JunB protein expression and high levels of IL-6 and activated STAT3 within lupus lesions.¹⁵⁷

An open-label phase I dosage-escalation study (2 mg/kg, 4 mg/kg or 8 mg/kg of TCZ, every 2 weeks for 12 weeks) with an enrollment of 16 SLE patients with mild-to-moderate disease activity showed significant improvement in disease activity in 8 of the 15 evaluable patients, with a median reduction of 47% in levels of anti-dsDNA antibodies.¹⁵⁸ The percentage of CD38^highCD19^lowIgD^negative plasma cells in the peripheral blood, which was higher for SLE patients than for normal controls (mean 5.3% vs. 1.2%), had been significantly reduced to 3.1% after 6 weeks. Moreover, according to two case reports, TCZ was efficacious for a patient with intractable SLE complicated by RA and treated in combination with tacrolimus.¹⁵⁹ TCZ was also efficacious for a multiple drug-refractory SLE patient with cutaneous lupus and urticarial vasculitis.¹⁶⁰ These results indicate that TCZ represents a promising therapeutic biologic for SLE.

Relapsing polychondritis

Relapsing polychondritis is a very rare disease, characterized by recurrent inflammation and cartilage destruction;^161,162 the cartilaginous structures of ear, nose, joints and respiratory tract are especially affected.¹⁶³ Autoimmune reactions to antigens present in cartilage, for example, type II, IX and XI collagen and matrilin and excess generation of proinflammatory cytokines and chemokines, are thought to evoke the disease symptoms.¹⁶⁴ The involvement of laryn-gotracheal cartilage causes severe airway destruction and thus requires vigorous treatments with corticosteroids and immunosuppressive drugs. Biologics including TNF inhibitors, rituximab, and IL-1R antagonist anakinra, have been successfully used for refractory relapsing polychondritis.¹⁶⁵ Two patients with relapsing polychondritis, who had been refractory to conventional regimens, were treated with TCZ.¹⁶⁶ The treatment ameliorated clinical symptoms related to the upper and lower airways. In one patient, airway narrowing of the bronchi was improved within one year of treatment while in the other patient Gallium citrate uptake in the involved cartilages had disappeared 21 months after the treatment. The TCZ treatment for these two patients has continued for more than five years without any signs of relapse so that the prednisolone dose could be reduced. Moreover, in a patient with relapsing polychondritis, tocilizumab caused a complete resolution of all clinical symptoms, which had been refractory to conventional therapy and adalimumab, a TNF inhibitor.¹⁶⁷ Because of the very rare occurrence of the disease it is difficult to perform a randomized controlled trial and in order to evaluate its efficacy for this disorder there is therefore an urgent need for reports on clinical experience with the use of TCZ for relapsing polychndritis.

Neuromyelitis optica

Neuromyelitis optica (NMO) is a chronic inflammatory CNS disorder predominantly affecting the spinal cord and optic nerves, in which anti-aquaporin-4 (AQP4) autoantibodies perform a pathologic function.^168,169 AQP4, which belongs to the aquaporin family of integral membrane proteins that conduct water through the cell membrane, is constitutively expressed in astrocytes and is upregulated in response to direct insult to the CNS.¹⁷⁰ Several studies have reported a marked increase of IL-6 in cerebrospinal fluid of patients with NMO.^171–174 Moreover, it has been found that the population of plasmablasts showing the CD19^intCD27^highCD38^highCD180^negative phenotype was selectively increased in the peripheral blood of NMO patients and that anti-AQP4 Abs were mainly produced by the plasmablasts.¹⁷⁵ IL-6 enhanced the survival of plasmablasts, as well as anti-AQP4 Ab secretion, whereas anti-IL-6R Ab diminished their survival and, indeed, clinical improvement and reduced serum levels of anti-AQP4 Abs were observed in a patient with NMO following therapy with TCZ.¹⁷⁶ Moreover, the prominent positive effect of TCZ was reported in a patient with NMO who had failed to respond to numerous immunosuppressive interventions, including high-dose corticosteroids, mitoxantrone, plasma exchange, rituximab and anti-CD52 Ab, alemtuzumab.¹⁷⁷

Crohn's disease

Crohn's disease (CD) is a chronic inflammatory bowel disease of unknown etiology. However, both Th1 and Th17 cells are believed to play a central role in its development.^178,179 IL-6 also contributes to its development, since elevated levels of IL-6 have been detected in the blood and in the cultures of colonic mucosal specimens from CD patients.^180–182 In a colitis mouse model generated by transfer of CD45RB^highCD4^positive T cells into SCID mice, anti-IL-6R Ab prevented the occurrence of signs and symptoms of colitis.¹⁸³

A randomized pilot trial of TCZ for 36 patients with active CD demonstrated that 80% of the patients given 8 mg/kg every 2 weeks showed a clinical response, as compared with only 31% of placebo-injected patients.¹⁸⁴ Colitis-associated intestinal perforation is one of the most serious complications of inflammatory bowel diseases, but there was no event of gastrointestinal perforation in TCZ- or placebo-injected patients in the clinical trial for CD.

Adult-onset still's disease

Adult-onset Still's disease (AOSD) is a chronic inflammatory disease characterized by four cardinal symptoms, namely spiking fever, evanescent maculopapular rash, arthritis, and leukocytosis.^185,186 Pathologically it resembles systemic JIA; IL-6 levels are elevated and correlate with disease activity in patients with AOSD.^187–190 Although the efficacy and safety of TCZ for AOSD have not yet been evaluated in a randomized controlled trial, numerous case and pilot studies have shown that TCZ treatment improved clinical symptoms and signs of AOSD in patients who had been refractory to conventional treatment regimens and biologics, including TNF inhibitors and anakinra.^191–207 These findings indicate that TCZ may become a first-line biologic for the treatment of AOSD.

Amyloid A amyloidosis

Amyloid A amyloidosis is a serious complication of chronic inflammatory diseases in which amyloid fibril deposition causes progressive deterioration in various organs.²⁰⁸ SAA, an acute phase protein produced in the liver, is an amyloid fibril precursor protein and sustained high concentrations of SAA have been found to correlate with progression of renal amyloid diseases.²⁰⁹ Several therapeutic strategies have been proposed for the treatment of amyloid A amyloidosis, but the inhibition of SAA appears to be the most suitable approach, since long-term suppression of its level (less than 10 mg/L) was found to lead to a regression or stabilization of the amyloid load.²¹⁰ Activation of the SAA1 gene depends primarily on IL-6,^211,212 and indeed, TCZ administration was found to cause a marked reduction of serum SAA concentrations, irrespective of the underlying diseases.^53,213–215 Case studies of amyloid A amyloidosis complicated with RA, JIA, or latent tuberculosis reported that TCZ had an ameliorative clinical effect on gastrointestinal symptoms and renal function.^216–222 Surprisingly, amyloid A fibril deposits were found to have disappeared in two cases after only three injections of TCZ.^217,219 This suggests that IL-6 blocking may be an innovative strategy for amyloid A amyloidosis complicated with chronic inflammatory diseases.²²³

Behcet's disease and uveitis

Behcet's disease (BD) is a systemic inflammatory disease of unknown etiology, characterized by relapsing episodes of oral aphthous ulcers, genital ulcers, skin lesions, ocular lesions, and other manifestations that include neurological, gastrointestinal, and vascular involvement.²²⁴ The involvement of IL-6 has been demonstrated in the pathological development of BD.^225–228 We administered TCZ in the treatment of one BD patient with posterior uveitis who had been suffering from BD for 10 years and had been treated with colchicine, prednisolone, and ciclosporin.²²⁹ Treatment with infliximab used for recurrent posterior uveitis brought the uveitis attacks under satisfactory control. When a severe relapse of posterior uveitis occurred 16 months later, however, TCZ was initiated and continuous treatment for 1 year reduced the number of ocular attacks and the BD Current Activity Form score.²²⁹ IL-6 may well be the most important inflammatory cytokine involved in both acute and chronic progressive neuro-BD,^230–232 and a case report of off-label use with TCZ noted outstanding and beneficial effects in a patient with neuro-BD refractory to all previous treatment regimens.²³³

Autoimmune and inflammatory uveitis refers to a group of potentially blinding intraocular inflammatory diseases that arise without a known infectious trigger and which are often associated with immunological responses to unique proteins; they are also known to frequently occur in conjunction with systemic diseases.²³⁴ IL-6 is known to be elevated in the vitreous body of patients with active intermediate and posterior uveitis,^235–239 and both Th1 and Th17 cells have been found to play a pathologic role in experimental autoimmune uveoretinitis, an animal model of uveitis.²⁴⁰ Blockade of IL-6 signaling reportedly suppresses autoimmune uveoretinitis and its protective effect is mediated by Treg induction and by Th17 and Th1 inhibition.^240–242 This indicates that TCZ may constitute a therapeutic option for uveitis; a recent case report on the clinical efficacy of TCZ for two patients with anti-TNFα refractory uveitis has suggested this possibility.²⁴³ In this context, an open-label trial has just been started to assess the efficacy and safety of TCZ in the management of JIA-associated vision-threatening uveitis refractory to other modes of systemic immunosuppression.

Other candidate diseases

Case series or reports of off-label use of TCZ have also raised the possibility that TCZ might be applicable for the treatment of other diseases. These include graft-versus-host disease,^244,245 acquired hemophilia A,²⁴⁶ autoimmune hemolytic anemia,^247–249 remitting seronegative, symmetrical synovitis with pitting edema,²⁵⁰ pulmonary arterial hypertension,^251–253 tumor necrosis factor receptor-associated periodic syndrome,²⁵⁴ atopic dermatitis,²⁵⁵ interstitial granulomatous dermatitis,²⁵⁶ and sciatica.²⁵⁷ Moreover, some studies have reported the efficacy of TCZ for spondyloarthritides such as ankylosing spondylitis^258–262 and reactive arthritis.^263,264 However, recent clinical trials of TCZ⁴⁹ and sarilumab,²⁶⁵ a fully human anti-IL-6R Ab, could not detect any favorable effect on ankylosing spondylitis, nor did our study of the clinical effect of TCZ on skin and joint lesions in two patients with psoriasis.⁴⁸ Observational studies of RA patients complicated with type 2 diabetes mellitus treated with TCZ found a reduction in hemoglobin A1c (HbA1c) levels.²⁶⁶ Moreover, a study of 11 non-diabetic patients with RA detected, after 3 months of tocilizumab treatment, a significant decrease in insulin resistance indexes such as the homeostasis model assessment of insulin resistance (HOMA-IR) and the leptin-to-adiponectin ratio.²⁶⁷ Serum levels of reactive oxygen metabolites also decreased in RA patients treated with TCZ.²⁶⁸ It can thus be expected that long-term TCZ treatment may offer protection against the progression of atherosclerosis leading to cardiovascular events.²⁶⁹ A randomized, open-label, parallel-group, multicenter study is in progress to determine and assess the rate of cardiovascular events for patients with RA following treatment with TCZ, with a comparison to treatment with etanercept, a TNF inhibitor, as a control.

Conclusions and Future Prospects

Currently TCZ is approved worldwide for the treatment of RA, Additionally, in several countries it is approved for treatment of Castleman's disease and systemic and polyarticular JIA. In view of the favorable results for off-label use of TCZ and the pathologic role of IL-6 in various immune-mediated diseases, TCZ is expected to be widely used in the treatment of such diseases. However, further clinical trials are required to achieve this goal.

The mechanisms through which TCZ exerts its therapeutic effects on various phenotypically different diseases are not yet well understood. It is possible that TCZ can rectify the imbalance of Th17/ Treg in various diseases,¹⁸ as seen in treatment of RA.⁷⁵ On the other hand, TCZ could exert its beneficial clinical effect by inhibiting pathological autoantibody production, since TCZ treatment was found to lead to a reduction in the pathologic CD38^highCD19^lowIgD^negative plasma cells of SLE patients¹⁵⁸ and to diminish the survival of plasmablasts–-that is, CD19^intCD180^negativeCD27⁺CD38⁺ cells, which produce the anti-AQP4 Ab seen in NMO.^175,176

Finally, as already mentioned, IL-6 synthesis is regulated by transcriptional levels and post-transcriptional mechanisms. It has already been shown that some viral products derived from Kaposi's sarcoma-associated herpes virus, human T lymphotropic virus-1, human immunodeficiency virus-1, or human hepatitis virus B, could constitutively activate transcriptional activation of the IL-6 gene and/or inhibit its mRNA degradation.^270–276 For these reasons, clarification of the cell source and the mechanism of dysregulated persistent IL-6 production is expected to aid and facilitate the investigation of the pathogenesis of a wide range of diseases.

Author Contributions

All authors contributed to the writing of the manuscript, reviewed and approved of the final manuscript.

Funding

Author(s) disclose no funding sources.

Competing Interests

TT has received grant and payment for lectures including service on speakers bureaus from Chugai Pharmaceutical Co, Ltd. AO has received a consulting fee as a medical adviser, grant and payment for lectures including service on speakers bureaus from Chugai Pharmaceutical Co, Ltd. MN has received grant and payment for lectures including service on speakers bureaus from Chugai Pharmaceutical Co, Ltd.

Disclosures and Ethics

As a requirement of publication author(s) have provided to the publisher signed confirmation of compliance with legal and ethical obligations including but not limited to the following: authorship and contributorship, conflicts of interest, privacy and confidentiality and (where applicable) protection of human and animal research subjects. The authors have read and confirmed their agreement with the ICMJE authorship and conflict of interest criteria. The authors have also confirmed that this article is unique and not under consideration or published in any other publication, and that they have permission from rights holders to reproduce any copyrighted material. Any disclosures are made in this section. The external blind peer reviewers report no conflicts of interest. Provenance: the authors were invited to submit this paper.

Footnotes

Acknowledgements

The authors gratefully acknowledge the valuable discussion of Professor Tadamitsu Kishimoto, Professor Atsushi Kumanogoh, and Professor Kazuyuki Yoshizaki.

References

Kishimoto

Interleukin-6: from basic sciences to medicine-40 years in immunology. Annu Rev Immunol. 2005; 23: 1–21.

Zilberstein

, Ruggieri

, Korn

J.H.

, Revel

Structure and expression of cDNA and genes for human interferon-beta-2, a distinct species inducible by growth-stimulatory cytokines. EMBO J. 1986; 5: 2529–37.

Hirano

, Yasukawa

, Harada

Complementary DNA for a novel human interleukin (BSF-2) that induces B lymphocytes to produce immunoglobulin. Nature. 1986; 324: 73–6.

Somers

, Stahl

, Seehra

J.S.

1.9 A crystal structure of interleukin 6: implications for a novel mode of receptor dimerization and signaling. EMBO J. 1997; 16: 989–97.

Hirano

, Taga

, Yasukawa

Human B-cell differentiation factor defined by an anti-peptide antibody and its possible role in autoantibody production. Proc Natl Acad Sci USA. 1987; 84: 228–31.

Yoshizaki

, Matsuda

, Nishimoto

Pathogenic significance of interleukin-6 (IL-6/BSF-2) in Castleman's disease. Blood. 1989; 74: 1360–7.

Kopf

, Baumann

, Freer

Impaired immune and acute-phase responses in interleukin-6-deficient mice. Nature. 1994; 368: 339–42.

Suematsu

, Matsuda

, Aozasa

IgG1 plasmacytosis in interleukin 6 transgenic mice. Proc Natl Acad Sci USA. 1989; 86: 7547–51.

Ohzato

, Yoshizaki

, Nishimoto

Interleukin-6 as a new indicator of inflammatory status: detection of serum levels of interleukin-6 and C-reactive protein after surgery. Surgery. 1992; 111: 201–9.

10.

Akira

, Takeda

Toll-like receptor signalling. Nat Rev Immunol. 2004; 4: 499–511.

11.

Heinrich

P.C.

, Castell

J V.

, Andus

Interleukin-6 and the acute phase response. Biochem J. 1990; 265: 621–36.

12.

Nemeth

, Rivera

, Gabayan

IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J Clin Invest. 2004; 113: 1271–6.

13.

Liuzzi

J.P.

, Lichten

L.A.

, Rivera

Interleukin-6 regulates the zinc transporter Zip14 in liver and contributes to the hypozincemia of the acute-phase response. Proc Natl Acad Sci USA. 2005; 102: 6843–8.

14.

Asano

, Okano

, Ozawa

In vivo effects of recombinant human interleukin-6 in primates: stimulated production of platelets. Blood. 1990; 75: 1602–5.

15.

Hurst

S.M.

, Wilkinson

T.S.

, McLoughlin

R.M.

IL-6 and its soluble receptor orchestrate a temporal switch in the pattern of leukocyte recruitment seen during acute inflammation. Immunity. 2001; 14: 705–14.

16.

Bettelli

, Carrier

, Gao

Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature. 2006; 441: 235–8.

17.

Korn

, Bettelli

, Oukka

, Kuchroo

V.K.

IL-17 and Th17 cells. Annu Rev Immunol. 2009; 27: 485–517.

18.

Kimura

, Kishimoto

IL-6: regulator of Treg/Th17 balance. Eur J Immunol. 2010; 40: 1830–35.

19.

Okada

, Kitahara

, Kishimoto

, Matsuda

, Hirano

, Kishimoto

IL-6/BSF-2 functions as a killer helper factor in the in vitro induction of cytotoxic T cells. J Immunol. 1988; 141: 1543–9.

20.

Hirano

, Taga

, Nakano

Purification to homogeneity and characterization of human B-cell differentiation factor (BCDF or BSFp-2). Proc Natl Acad Sci USA. 1985; 82: 5490–4.

21.

Kotake

, Sato

, Kim

K.J.

Interleukin-6 and soluble interleukin-6 receptors in the synovial fluids from rheumatoid arthritis patients are responsible for osteoclast-like cell formation. J Bone Miner Res. 1996; 11: 88–95.

22.

Palmqvist

, Persson

, Conaway

H.H.

, Lerner

U.H.

IL-6, leukemia inhibitory factor, and oncostatin M stimulate bone resorption and regulate the expression of receptor activator of NF-kappa B ligand, osteoprotegerin, and receptor activation of NF-kappa B in mouse calvariae. J Immunol. 2002; 169: 3353–62.

23.

Jilka

R.L.

, Hangoc

, Girasole

Increased osteoclast development after estrogen loss: mediation by interleukin-6. Science. 1992; 257: 88–91.

24.

Islander

, Jochems

, Lagerquist

M.K.

, Forsblad-d'Elia

, Carlsten

Estrogens in rheumatoid arthritis; the immune system and bone. Mol Cell Endocrinol. 2011; 335: 14–29.

25.

Nakahara

, Song

, Sugimoto

Anti-interleukin-6 receptor antibody therapy reduces vascular endothelial growth factor production in rheumatoid arthritis. Arthritis Rheum. 2003; 48: 1521–9.

26.

Grossman

R.M.

, Krueger

, Yourish

Interleukin 6 is expressed in high levels in psoriatic skin and stimulates proliferation of cultured human keratinocytes. Proc Natl Acad Sci USA. 1989; 86: 6367–71.

27.

Duncan

M.R.

, Berman

Stimulation of collagen and glycosaminoglycan production in cultured human adult dermal fibroblasts by recombinant human interleukin 6. J Investig Dermatol. 1991; 97: 686–92.

28.

Kishimoto

, Akira

, Narazaki

, Taga

Interleukin-6 family of cytokines and gp130. Blood. 1995; 86: 1243–54.

29.

Taga

, Hibi

, Hirata

Interleukin-6 triggers the association of its receptor with a possible signal transducer, gp130. Cell. 1989; 58: 573–81.

30.

Narazaki

, Yasukawa

, Saito

Soluble forms of the interleukin-6 signal-transducing receptor component gp130 in human serum possessing a potential to inhibit signals through membrane-anchored gp130. Blood. 1993; 82: 1120–6.

31.

Boulanger

M.J.

, Chow

D.C.

, Brevnova

E.E.

, Garcia

K.C.

Hexameric structure and assembly of the interleukin-6/IL-6 alpha-receptor/gp130 complex. Science. 2003; 300: 2101–4.

32.

Kishimoto

, Akira

, Taga

Interleukin-6 and its receptor: a paradigm for cytokines. Science. 1992; 258: 593–7.

33.

Garbers

, Hermanns

H.M.

, Schaper

Plasticity and cross-talk of interleukin 6-type cytokines. Cytokine Growth Factor Rev. 2012; 23: 85–97.

34.

Aoki

, Narazaki

, Kishimoto

, Tosato

Receptor engagement by viral interleukin-6 encoded by Kaposi sarcoma-associated herpes virus. Blood. 2001; 98: 3042–9.

35.

Akira

, Kishimoto

IL-6 and NF-IL6 in acute-phase response and viral infection. Immunol Rev. 1992; 127: 25–50.

36.

Matsusaka

, Fujikawa

, Nishio

Transcription factors NF-IL6 and NF-kappa B synergistically activate transcription of the inflammatory cytokines, interleukin 6 and interleukin 8. Proc Natl Acad Sci USA. 1993; 90: 10193–7.

37.

Matsushita

, Takeuchi

, Standley

D.M.

Zc3h12a is an RNase essential for controlling immune responses by regulating mRNA decay. Nature. 2009; 458: 1185–90.

38.

Iwasaki

, Takeuchi

, Teraguchi

The IkB kinase complex regulates the stability of cytokine-encoding mRNA induced by TLR-IL-1R by controlling degradation of regnase-1. Nat Immunol. 2011; 12: 1167–75.

39.

Tanaka

, Narazaki

, Kishimoto

Therapeutic targeting of the interleukin-6 receptor. Annu Rev Pharmacol Toxicol. 2012; 52: 199–219.

40.

Sato

, Tsuchiya

, Saldanha

Reshaping a human antibody to inhibit the interleukin 6-dependent tumor cell growth. Cancer Res. 1993; 53: 851–6.

41.

Nishimoto

, Terao

, Mima

, Nakahara

, Takagi

, Kakehi

Mechanisms and pathologic significances in increase in serum interleukin-6 (IL-6) and soluble IL-6 receptor after administration of an anti-IL-6 receptor antibody, tocilizumab, in patients with rheumatoid arthritis and Castleman disease. Blood. 2008; 112: 3959–64.

42.

Tanaka

, Ogata

, Narazaki

Tocilizumab for the treatment of rheumatoid arthritis. Expert Rev Clin Immunol. 2010; 6: 843–54.

43.

Jones

, Ding

Tocilizumab: a review of its safety and efficacy in rheumatoid arthritis. Clin Med Insights Arthritis Musculoskelet Disord. 2010; 3: 81–9.

44.

Yokota

, Tanaka

, Kishimoto

Efficacy, safety and tolerability of tocilizumab in patients with systemic juvenile idiopathic arthritis. Ther Adv Musculoskelet Dis. 2012; 4: 387–97.

45.

Alonzi

, Fattori

, Lazzaro

Interleukin 6 is required for the development of collagen-induced arthritis. J Exp Med. 1998; 187: 461–8.

46.

Kagari

, Doi

, Shimozato

The importance of IL-1 beta and TNF-alpha, and the noninvolvement of IL-6, in the development of monoclonal antibody-induced arthritis. J Immunol. 2002; 169: 1459–66.

47.

Iwakura

, Nakae

, Saijo

, Ishigame

The roles of IL-17A in inflammatory immune responses and host defense against pathogens. Immunol Rev. 2008; 226: 57–79.

48.

Ogata

, Umegaki

, Katayama

, Kumanogoh

, Tanaka

Psoriatic arthritis in two patients with an inadequate response to treatment with tocilizumab. Joint Bone Spine. 2012; 79: 85–7.

49.

Sieper

, Porter-Brown

, Thompson

, Harari

, Dougados

Tocilizumab (TCZ) is not effective for the treatment of ankylosing spondylitis (AS): result of phase 2, international multicentre randomized double-blind placebo-controlled trial. Ann Rheum Dis. 2012; 71(Suppl 3): 110.

50.

Jones

, Sebba

, Gu

Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis: the AMBITION study. Ann Rheum Dis. 2010; 69: 88–96.

51.

Nishimoto

, Hashimoto

, Miyasaka

Study of active controlled monotherapy used for rheumatoid arthritis, an IL-6 inhibitor (SAMURAI): evidence of clinical and radiographic benefit from an x-ray reader-blinded randomized controlled trial of tocilizumab. Ann Rheum Dis. 2007; 66: 1162–7.

52.

Nishimoto

, Miyasaka

, Yamamoto

Study of active controlled tocilizumab monotherapy for rheumatoid arthritis patients with an inadequate response to methotrexate (SATORI): significant reduction in disease activity and serum vascular endothelial growth factor by IL-6 receptor inhibition therapy. Mod Rheumatol. 2009; 19: 12–9.

53.

Smolen

J.S.

, Beaulieu

, Rubbert-Roth

, Ramos-Remus

, Rovensky

, Alecock

; OPTION Investigators. Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomized trial. Lancet. 2008; 371: 987–97.

54.

Garnero

, Thompson

, Woodworth

, Smolen

J.S.

Rapid and sustained improvement in bone and cartilage turnover markers with anti-interleukin-6 receptor inhibitor tocilizumab plus methotrexate: results from a substudy of the multicenter double-blind, placebo controlled trial of tocilizumab in inadequate responders to methotrexate alone. Arthritis Rheum. 2010; 62: 33–43.

55.

Genovese

M.C.

, McKay

J.D.

, Nasonov

E.L.

Interleukin-6 receptor inhibition with tocilizumab reduces disease activity in rheumatoid arthritis with inadequate response to disease-modifying antirheumatic drugs: the tocilizumab in combination with traditional disease-modifying antirheumatic drug therapy study. Arthritis Rheum. 2008; 58: 2968–80.

56.

Emery

, Keystone

, Tony

H.P.

IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals: results from a 24-week multicentre randomised placebo-controlled trial. Ann Rheum Dis. 2008; 67: 1516–23.

57.

Kremer

J.M.

, Blanco

, Brzosko

Tocilizumab inhibits structural joint damage in rheumatoid arthritis patients with inadequate responses to methotrexate: results from the double-blind treatment phase of a randomized placebo-controlled trial of tocilizumab safety and prevention of structural joint damage at one year. Arthritis Rheum. 2011; 63: 609–21.

58.

Smolen

J.S.

, Avila

J.C.

, Aletaha

Tocilizumab inhibits progression of joint damage in rheumatoid arthritis irrespective of its anti-inflammatory effects: dissociation of the link between inflammation and destruction. Ann Rheum Dis. 2012; 71: 687–93.

59.

Dougados

, Kissel

, Sheeran

Adding tocilizumab or switching to tocilizumab monotherapy in methotrexate inadequate responders: 24-week symptomatic and structural results of a 2-year randomized controlled strategy trial in rheumatoid arthritis (ACT-RAY). Ann Rheum Dis. 2013; 72: 43–50.

60.

Bykerk

V.P.

, Ostör

A.J.

, Alvaro-Gracia

Tocilizumab in patients with active rheumatoid arthritis and inadequate responses to DMARDs and/or TNF inhibitors: a large, open-label study close to clinical practice. Ann Rheum Dis. 2012; 71: 1950–4.

61.

Weinblatt

M.E.

, Kremer

, Cush

Tocilizumab as monotherapy or in combination with nonbiologic DMARDs: 24-week results of an open-label, clinical practice study (ACT-STAR). Arthritis Care Res (Hoboken). Sep 12, 2012. [Epub ahead of print.]

62.

Hetland

M.L.

, Christensen

I.J.

, Tarp

All Departments of Rheumatology in Denmark. Direct comparison of treatment responses, remission rates, and drug adherence in patients with rheumatoid arthritis treated with adalimumab, etanercept, or infliximab: results from eight years of surveillance of clinical practice in the nationwide Danish DANBIO registry. Arthritis Rheum. 2010; 62: 22–32.

63.

Sakai

, Tanaka

, Nanki

for the REAL Study Group. Drug retention rates and relevant risk factors for drug discontinuation due to adverse events in rheumatoid arthritis patients receiving anticytokine therapy with different target molecules. Ann Rheum Dis. 2012; 71: 1820–6.

64.

Nishimoto

Japanese MRA study group for RA. Drug free remission after cessation of actemra monotherapy (DREAM Study). Ann Rheum Dis. 2010; 69(Suppl 3): 98.

65.

Nishimoto

Japanese MRA study group for RA. Retreatment efficacy and safety to tocilizumab in patients with rheumatoid arthritis at recurrence (RESTORE study). Ann Rheum Dis. 2010; 69(Suppl 3): 537.

66.

Aguilar-Lozano

, Padilla-Ibarra

, Sandoval-Castro

The length of remission and rate of relapse after tocilizumab withdrawal in rheumatoid arthritis patients. Ann Rheum Dis. 2012; 71(Suppl 3): 69.

67.

Fusama

, Nakahara

, Hamano

Improvement of health status evaluated by Arthritis Impact Measurement Scale 2 (AIMS-2) and Short Form-36 (SF-36) in patients with rheumatoid arthritis treated with tocilizumab. Mod Rheumatol. Jun 6, 2012. [Epub ahead of print.]

68.

Strand

, Burmester

G.R.

, Ogale

, Devenport

, John

, Emery

Improvements in health-related quality of life after treatment with tocilizumab in patients with rheumatoid arthritis refractory to tumour necrosis factor inhibitors: results from the 24-week randomized controlled RADIATE study. Rheumatology (Oxford). 2012; 51: 1860–9.

69.

Miwa

, Furuya

, Yanai

Comparison of efficacy of four biological agents for rheumatoid arthritis patients using the HRQoL questionnaire and depression scale. Ann Rheum Dis. 2012; 71(Suppl 3): 663.

70.

Foti

, Russo

, Malavolta

Effects of tocilizumab in combination with non biologic DMARDs on early improvement of anemia and fatigue in adult patients with moderate to severe active rheumatoid arthritis. Ann Rheum Dis. 2012; 71(Suppl 3): 671.

71.

Fragiadaki

, Tektonidou

M.G.

, Konsta

, Chrousos

G.P.

, Sfikakis

P.P.

Sleep disturbances and interleukin 6 receptor inhibition in rheumatoid arthritis. J Rheumatol. 2012; 39: 60–2.

72.

Nishimoto

, Ito

, Takagi

Safety and efficacy profiles of tocilizumab monotherapy in Japanese patients with rheumatoid arthritis: meta-analysis of six initial trials and five long-term extensions. Mod Rheumatol. 2010; 20: 222–32.

73.

Schiff

M.H.

, Kremer

J.M.

, Jahreis

, Vernon

, Isaacs

J.D.

, van Vollenhoven

R.F.

Integrated safety in tocilizumab clinical trials. Arthritis Res Ther. 2011; 13: R141.

74.

Hashizume

, Mihara

The roles of interleukin-6 in the pathogenesis of rheumatoid arthritis. Arthritis. 2011: Article ID 765624.

75.

Samson

, Audia

, Janikashvili

Brief report: inhibition of interleukin-6 function corrects Th17/Treg cell imbalance in patients with rheumatoid arthritis. Arthritis Rheum. 2012; 64: 2499–503.

76.

Roll

, Muhammad

, Schumann

In vivo effects of the anti-interleukin-6 receptor inhibitor tocilizumab on the B cell compartment. Arthritis Rheum. 2011; 63: 1255–64.

77.

Muhammad

, Roll

, Seibold

Impact of IL-6 receptor inhibition on human memory B cells in vivo: impaired somatic hypermutation in pre-switch memory B cells and mutational targeting in memory B cells. Ann Rheum Dis. 2011; 70: 1507–10.

78.

Gabrielli

, Avvedimento

E V.

, Krieg

Scleroderma. N Engl J Med. 2009; 360: 1989–2003.

79.

Hasegawa

, Takehara

Potential immunologic targets for treating fibrosis in systemic sclerosis: a review focused on leukocytes and cytokines. Semin Arthritis Rheum. 2012; 42: 281–96.

80.

Barnes

T.C.

, Anderson

M.E.

, Moots

R.J.

The many faces of interleukin-6: the role of IL-6 in inflammation, vasculopathy, and fibrosis in systemic sclerosis. Int J Rheumatol. 2011: 721608.

81.

O'Reilly

, Ciechomska

, Cant

, Hugle

, van Larr

J.M.

Interleukin-6, its role in fibrosing conditions. Cytokine Growth Factor Rev. 2012; 23: 99–107.

82.

Hasegawa

, Sato

, Fujimoto

, Ihn

, Kikuchi

, Takehara

Serum levels of interleukin 6 (IL-6), oncostatin M, soluble IL-6 receptor, and soluble gp130 in patients with systemic sclerosis. J Rheumatol. 1998; 25: 308–13.

83.

Sato

, Hasegawa

, Takehara

Serum levels of interleukin-6 and interleukin-10 correlate with total skin thickness score in patients with systemic sclerosis. J Dermatol Sci. 2001; 27: 140–6.

84.

Gourh

, Arnett

F.C.

, Assassi

Plasma cytokine profiles in systemic sclerosis: associations with autoantibody subsets and clinical manifestation. Arthritis Res Ther. 2009; 11: R147.

85.

Radstake

T.R.

, van Bon

, Broen

The pronounced Th17 profiles in systemic sclerosis (SSc) together with intracellular expression of TGFbeta and IFNgamma distinguishes SSc phenotype. Plos One. 2009; 4: e5903.

86.

Khan

, Xu

, Nihtyanova

Clinical and pathological significance of interleukin 6 overexpression in systemic sclerosis. Ann Rheum Dis. 2012; 71: 1235–42.

87.

Feghali

C.A.

, Bost

K.L.

, Boulware

D.W.

, Levy

L.S.

Mechanisms of pathogenesis in scleroderma. I. Overproduction of interleukin 6 by fibroblasts cultured from affected skin sites of patients with scleroderma. J Rheumatol. 1992; 19: 1207–11.

88.

Koch

A.E.

, Kronfeld-Harrington

L.B.

, Szekanecz

In situ expression of cytokines and cellular adhesion molecules in the skin of patients with systemic sclerosis: their role in early and late disease. Pathobiology. 1993; 61: 239–46.

89.

Gurram

, Pahwa

, Frieri

Augmented interleukin-6 secretion in collagen-stimulated peripheral blood mononuclear cells from patients with systemic sclerosis. Ann Allergy. 1994; 73: 493–6.

90.

Gallucci

R.M.

, Lee

E.G.

, Tomasek

J.J.

IL-6 modulates alpha-smooth muscle actin expression in dermal fibroblasts from IL-6-deficient mice. J Invest Dermatol. 2006; 126: 561–8.

91.

Kawaguchi

, Hara

, Wright

T.M.

Endogenous IL-1alpha from systemic sclerosis fibroblasts induces IL-6 and PDGF-A. J Clin Invest. 1999; 102: 1253–60.

92.

Barnes

T.C.

, Spiller

D.G.

, Anderson

M.E.

, Edwards

S.W.

, Moots

R.J.

Endothelial activation and apoptosis mediated by neutrophil-dependent interleukin 6 trans-signalling: a novel target for systemic sclerosis?

Ann Rheum Dis. 2011; 70: 368–72.

93.

Yoshizaki

, Yanaba

, Ogawa

, Asano

, Kadono

, Sato

Immunization with DNA topoisomerase I and Freund's complete adjuvant induces skin and lung fibrosis and autoimmunity via interleukin-6 signaling. Arthritis Rheum. 2011; 63: 3575–85.

94.

Kitaba

, Murota

, Terao

Blockade of interleukin-6 receptor alleviates disease in mouse model of scleroderma. Am J Pathol. 2012; 80: 165–76.

95.

Shima

, Kuwahara

, Murota

The skin of patients with systemic sclerosis softened during the treatment with anti-IL-6 receptor antibody tocilizumab. Rheumatology (Oxford). 2010; 49: 2408–12.

96.

Kuwahara

, Shima

, Shirayama

Quantification of hardness, elastic and viscosity of the skin of patients with systemic sclerosis using a novel sensing device (Vesmeter): a proposal for a new outcome measurement procedure. Rheumatology (Oxford). 2008; 47: 1018–24.

97.

Dalakas

M.C.

Immunotherapy of myositis: issues, concerns and future prospects. Nat Rev Rheumatol. 2010; 6: 129–37.

98.

Gabay

, Gay-Croisier

, Roux-Lombard

Elevated serum levels of interleukin-1 receptor antagonist in polymyositis/dermatomyositis. A biologic marker of disease activity with a possible role in the lack of acute-phase protein response. Arthritis Rheum. 1994; 37: 1744–51.

99.

Lundberg

, Ulfgren

A.K.

, Nyberg

, Andersson

, Klareskog

Cytokine production in muscle tissue of patients with idiopathic inflammatory myopathies. Arthritis Rheum. 1997; 40: 865–74.

100.

Lepidi

, Frances

, Figarella-Branger

, Bartoli

, Machado-Baeta

, Pellissier

J.F.

Local expression of cytokines in idiopathic inflammatory myopathies. Neuropathol Appl Neurobiol. 1998; 24: 73–9.

101.

Sugiura

, Kawaguchi

, Harigai

Increased CD40 expression on muscle cells of polymyositis and dermatomyositis: role of CD40-CD40 ligand interaction in IL-6, IL-8, IL-15, and monocyte chemoattractant protein-1 production. J Immunol. 2000; 164: 6593–600.

102.

Scuderi

, Mannella

, Marino

, Provenzano

, Bartoccioni

IL-6-deficient mice show impaired inflammatory response in a model of myosin-induced experimental myositis. J Neuroimmunol. 2006; 176: 9–15.

103.

Okiyama

, Sugihara

, Iwakura

, Yokozeki

, Miyasaka

, Kohsaka

Therapeutic effects of interleukin-6 blockade in a murine model of polymyositis that does not require interleukin-17A. Arthritis Rheum. 2009; 60: 2505–12.

104.

Narazaki

, Hagihara

, Shima

, Ogata

, Kishimoto

, Tanaka

Therapeutic effect of tocilizumab on two patients with polymyositis. Rheumatology (Oxford). 2011; 50: 1344–6.

105.

Langford

C.A.

Vasculitis. J Allergy Clin Immunol. 2010; 125: S216–25.

106.

Sharma

, Sharma

, Baltaro

, Hurley

Systemic vascultis. Am Fam Physician. 2011; 83: 556–65.

107.

Salvarani

, Cantini

, Hunder

G.G.

Polymyalgia rheumatica and giant-cell arteritis. Lancet. 2008; 372: 234–45.

108.

Mason

J.C.

Takayasu arteritis-advances in diagnosis and management. Nat Rev Rheumatol. 2010; 6: 405–15.

109.

Dasgupta

, Panayi

G.S.

Interleukin-6 in serum of patients with polymyalgia rheumatica and giant cell arteritis. Br J Rheumatol. 1990; 29: 456–8.

110.

Roche

N.E.

, Fulbright

J.W.

, Wagner

A.D.

, Hunder

G.G.

, Goronzy

J.J.

, Weyand

C.M.

Correlation of interleukin-6 production and disease activity in polymyalgia rheumatica and giant cell arteritis. Arthritis Rheum. 1993; 36: 1286–94.

111.

Caplanne

, Le Parc

J.M.

, Alexandre

J.A.

Interleukin-6 in clinical relapses of polymyalgia and giant cell arteritis. Ann Rheum Dis. 1996; 55: 403–4.

112.

Weyand

C.M.

, Fulbright

J.W.

, Hunder

G.G.

, Evans

J.M.

, Goronzy

J.J.

Treatment of giant cell arteritis: interleukin-6 as a biologic marker of disease activity. Arthritis Rheum. 2000; 43: 1041–8.

113.

Garcia-Martinez

, Hernandez-Rodriguez

, Espigol-Frigole

Clinical relevance of persistently elevated circulating cytokines (tumor necrosis factor alpha and interleukin-6) in the long-term followup of patients with giant cell arteritis. Arthritis Care Res. 2010; 62: 835–41.

114.

Noris

, Daina

, Gamba

, Bonazzola

, Remuzzi

Interleukin-6 and RANTES in Takayasu arteritis: a guide for therapeutic decisions?

Circulation. 1999; 100: 55–60.

115.

Park

M.C.

, Lee

S.W.

, Park

Y.B.

, Lee

S.K.

Serum cytokine profiles and their correlations with disease activity in Takayasu's arteritis. Rheumatology (Oxford). 2006; 45: 545–8.

116.

Wagner

A.D.

, Goronzy

J.J.

, Weyand

C.M.

Functional profile of tissue-infiltrating and circulating CD68+ cells in giant cell arteritis. Evidence for two components of the disease. J Clin Invest. 1994; 94: 1134–40.

117.

Weyand

C.M.

, Hicok

K.C.

, Hunder

G.G.

, Goronzy

J.J.

Tissue cytokine patterns in patients with polymyalgia and giant cell arteritis. Ann Intern Med. 1994; 121: 484–91.

118.

Hernandez-Rodriguez

, Segarra

, Vilardell

Tissue production of pro-inflammatory cytokines (IL-1beta, TNFalpha and IL-6) correlates with the intensity of the systemic inflammatory response and with corticosteroid requirements in giant-cell arteritis. Rheumatology (Oxford). 2004; 43: 294–301.

119.

Seko

, Sato

, Takagi

Restricted usage of T-cell receptor Valpha-Vbeta genes in infiltrating cells in aortic tissue of patients with Takayasu's arteritis. Circulation. 1996; 93: 1788–90.

120.

Nishimoto

, Nakahara

, Yoshio-Hoshino

, Mima

Successful treatment of a patient with Takayasu arteritis using a humanized anti-interleukin-6 receptor antibody. Arthritis Rheum. 2008; 58: 1197–200.

121.

Seitz

, Reichenbach

, Bonel

H.M.

, Adler

, Wermelinger

, Villiger

P.M.

Rapid induction of remission in large vessel vasculitis by IL-6 blockade. A case series. Swiss Med Wkly. 2011; 141: w13156.

122.

Beyer

, Axmann

, Sahinbegovic

Anti-interleukin 6 receptor therapy as rescue treatment for giant cell arteritis. Ann Rheum Dis. 2011; 70: 1874–5.

123.

Sciascia

, Rossi

, Roccatello

Interleukin 6 blockade as steroid-sparing treatment for 2 patients with giant cell arteritis. J Rheumatol. 2011; 38: 2080–1.

124.

Salvarani

, Magnani

, Catanoso

Tocilizumab: a novel therapy for patients with large-vessel vasculitis. Rheumatology (Oxford). 2012; 51: 151–6.

125.

Vinit

, Bielefeld

, Muller

, Besancenot

J.F.

Efficacy of tocilizumab in refractory giant cell arteritis. Joint Bone Spine. 2012; 79: 317–8.

126.

Christidis

, Jain

, Das Gupta

Successful use of tocilizumab in polymyalgic onset biopsy positive GCA with large vessel involvement. BMJ Case Reports. Jun 30, 2011: 2011.

127.

Besada

, Nossent

J.C.

Ultrasonographic resolution of the vessel wall oedema with modest clinical improvement in a large-vessel vasculitis patient treated with tocilizumab. Clin Rheumatol. 2012; 31: 1263–5.

128.

Salvarani

, Magnani

, Catanoso

Rescue treatment with tocilizumab for Takayasu arteritis resistant to TNF-α blockers. Clin Exp Rheumatol. 2012; 30(1 Suppl 70): S90–3.

129.

Bredemeier

, Rocha

, Barbosa

, Pitrez

One-year clinical and radiological evolution of a patient with refractory Takayasu's arteritis under treatment with tocilizumab. Clin Exp Rheumatol. 2012; 30(1 Suppl 70): S98–100.

130.

Unizony

, Arias-Urdaneta

, Miloslavsky

Tocilizumab for the treatment of large-vessel vasculitis (giant cell arteritis, Takayasu arteritis) and polymyalgia rheumatica. Arthritis Res Care. 2012; 64: 1720–9.

131.

Lurati

, Bertani

, Re

K.A.

, Marrazza

, Bompane

, Scarpellini

Successful treatment of a patient with giant cell vasculitis (horton arteritis) with tocilizumab a humanized anti-interleukin-6 receptor antibody. Case Report Rheumatol. 2012: 639612.

132.

Isik

, Kilic

, Dogan

, Calquneri

Tocilizumab for giant cell arteritis: an amazing result. Rheumatol Int. Sep 11, 2012. [Epub ahead of print.]

133.

Cohen

, Mekinian

, Saidenberg-Kermanach

Efficacy of tocilizumab in rituximab-refractory cryoglobulinemia vasculitis. Ann Rheum Dis. 2012; 71: 628–9.

134.

Sumida

, Ubara

, Suwabe

Complete remission of myeloperoxidase-antineutrophil cytoplasmic antibody-associated crescentic glomerulonephritis complicated with rheumatoid arthritis using a humanized anti-interleukin 6 receptor antibody. Rheumatology (Oxford). 2011; 50: 1928–30.

135.

Alvarez-Rodriguez

, Lopez-Hoyos

, Mata

Circulating cytokines in active polymyalgia rheumatica. Ann Rheum Dis. 2010; 69: 263–69.

136.

Zen-Nyoji

, Shimizu

, Ohtani

, Oshimoto

, Kobayashi

, Mori

Increased RAHA titer and interleukin-6 levels in the synovial fluid in a patient with polymyalgia rheumatica. Intern Med. 1993; 32: 484–6.

137.

Kreiner

, Langberg

, Galbo

Increased muscle interstitial levels of inflammatory cytokines in polymyalgia rheumatica. Arthritis Rheum. 2010; 62: 3768–75.

138.

Gabriel

S.E.

, Sunku

, Salvarani

, O'Fallon

W.M.

, Hunder

G.G.

Adverse outcomes of antiinflammatory therapy among patients with polymyalgia rheumatica. Arthritis Rheum. 1997; 40: 1873–8.

139.

Mazzantini

, Torre

, Miccoli

Adverse events during long-term low-dose glucocorticoid treatment of polymyalgia rheumatica: a retrospective study. J Rheumatol. 2012; 39: 552–7.

140.

Hagihara

, Kawase

, Tanaka

, Kishimoto

Tocilizumab ameliorates clinical symptoms in polymyalgia rheumatica. J Rheumatol. 2010; 37: 1075–6.

141.

Ruiz-Irastorza

, Khamashta

M.A.

, Castellino

, Hughes

G.R.

Systemic lupus erythematosus. Lancet. 2001; 357: 1027–32.

142.

Obermoser

, Pascual

The interferon-α signature of systemic lupus erythematosus. Lupus. 2010; 19: 1012–9.

143.

Shin

M.S.

, Lee

, Kang

Effector T-cell subsets in systemic lupus erythematosus: update focusing on Th17 cells. Curr Opin Rheumatol. 2011; 23: 444–8.

144.

Tackey

, Lipsky

P.E.

, Illei

G.G.

Rationale for interleukin-6 blockade in systemic lupus erythematosus. Lupus. 2004; 13: 339–43.

145.

Linker-Israeli

, Deans

R.J.

, Wallace

D.J.

, Prehn

, Ozeri-Chen

, Klinenberg

J.R.

Elevated levels of endogenous IL-6 in systemic lupus erythematosus: a putative role in pathogenesis. J Immunol. 1991; 147: 117–23.

146.

Peterson

, Robertson

A.D.

, Emlen

Serum and urinary interleukin-6 in systemic lupus erythematosus. Lupus. 1996; 5: 571–5.

147.

Grondal

, Gunnarsson

, Ronnelid

, Rogberg

, Klareskog

Lundberg I. Cytokine production, serum levels and disease activity in systemic lupus erythematosus. Clin Exp Rheumatol. 2000; 18: 565–70.

148.

Iwano

, Dohi

, Hirata

Urinary levels of IL-6 in patients with active lupus nephritis. Clin Nephrol. 1993; 40: 16–21.

149.

Hirohata

, Miyamoto

Elevated levels of interleukin-6 in cerebrospinal fluid from patients with systemic lupus erythematosus and central nervous system involvement. Arthritis Rheum. 1990; 33: 644–9.

150.

Hagiwara

, Gourley

M.F.

, Lee

, Klinman

D.K.

Disease severity in patients with systemic lupus erythematosus correlates with an increased ratio of interleukin-10: interferon-gamma-secreting cells in the peripheral blood. Arthritis Rheum. 1996; 39: 379–85.

151.

Klashman

D.J.

, Martin

R.A.

, Martinez-Maza

, Stevens

R.H.

In vitro regulation of B cell differentiation by interleukin-6 and soluble CD23 in systemic lupus erythematosus B cell subpopulations and antigen-induced normal B cells. Arthritis Rheum. 1991; 34: 276–86.

152.

Kitani

, Hara

, Hirose

Autostimulatory effects of IL-6 on excessive B cell differentiation in patients with systemic lupus erythematosus: analysis of IL-6 production and IL-6R expression. Clin Exp Immunol. 1992; 88: 75–83.

153.

Ryffel

, Car

B.D.

, Gunn

, Roman

, Hiestand

, Mihatsch

M.J.

Interleukin-6 exacerbates glomerulonephritis in (NZB x NZW)F1 mice. Am J Pathol. 1994; 144: 927–37.

154.

Finck

B.K.

, Chan

, Wofsy

Interleukin 6 promotes murine lupus in NZB/ NZW F1 mice. J Clin Invest. 1994; 94: 585–91.

155.

Mihara

, Takagi

, Takeda

, Ohsugi

IL-6 receptor blockage inhibits the onset of autoimmune kidney disease in NZB/W F1 mice. Clin Exp Immunol. 1998; 112: 397–402.

156.

Liang

, Gardner

D.B.

, Griswold

D.E.

, Bugelski

P.J.

, Song

X.Y.

Anti-interleukin-6 monoclonal antibody inhibits autoimmune responses in a murine model of systemic lupus erythematosus. Immunology. 2006; 119: 296–305.

157.

Pflegerl

, Vesely

, Hantusch

Epidermal loss of JunB leads to a SLE phenotype due to hyper IL-6 signaling. Proc Natl Acad Sci USA. 2009; 106: 20423–8.

158.

Illei

G.G.

, Shirota

, Yarboro

C.H.

Tocilizumab in systemic lupus erythematosus: data on safety, preliminary efficacy, and impact on circulating plasma cells from an open-label phase I dosage-escalation study. Arthritis Rheum. 2010; 62: 542–52.

159.

Maeshima

, Ishii

, Torigoe

Successful tocilizumab and tacrolimus treatment in a patient with rheumatoid arthritis complicated by systemic lupus erythematosus. Lupus. 2012; 21: 1003–6.

160.

Makol

, Gibson

L.E.

, Michet

C.J.

Successful use of interleukin 6 antagonist tocilizumab in a patient with refractory cutaneous lupus and urticarial vasculitis. J Clin Rheumatol. 2012; 18: 92–5.

161.

Rapini

R.P.

, Warner

N.B.

Relapsing polychondritis. Clin Dermatol. 2006; 24: 482–5.

162.

Lahmer

, Treiber

, von Werder

Relapsing polychondritis: an autoimmune disease with many faces. Autoimmu Rev. 2010; 9: 540–6.

163.

Arnaud

, Devilliers

, Peng

S.L.

The relapsing polychondritis disease activity index: development of a disease activity score for relapsing polychondritis. Autoimmun Rev. 2012; 12: 204–9.

164.

Stabler

, Piette

J.C.

, Chevalier

, Marini-Portugal

, Kraus

V.B.

Serum cytokine profiles in relapsing polychondritis suggest monocyte/ macrophage activation. Arthritis Rheum. 2004; 50: 3663–7.

165.

Kemta Lekpa

, Kraus

V.B.

, Chevalier

Biologics in relapsing polychondritis: a literature review. Semin Arthritis Rheum. 2012; 41: 712–9.

166.

Kawai

, Hagihara

, Hirano

Sustained response to tocilizumab, anti-interleukin-6 receptor antibody, in two patients with refractory relapsing polychondritis. Rheumatology (Oxford). 2009; 48: 318–9.

167.

Narshi

C.B.

, Allard

S.A.

Sustained response to tocilizumab, anti-IL-6 antibody, following anti-TNF-α failure in a patient with relapsing polychondritis complicated by aortitis. Rheumatology (Oxford). 2012; 51: 952–23.

168.

Lennon

V.A.

, Kryzer

T.J.

, Pittock

S.J.

, Verkman

A.S.

, Hinson

S.R.

IgG marker of optic-spinal multiple sclerosis binds to the aquaporin-4 water channel. J Exp Med. 2005; 202: 473–7.

169.

Ratelade

, Verkman

A.S.

Neuromyelitis optica: Aquaporin-4 based pathogenesis mechanisms and new therapies. Int J Biochem Cell Biol. 2012; 44: 1519–30.

170.

Benarroch

E.E.

Aquaporin-4, homeostatis, and neurologic disease. Neurology. 2007; 69: 2266–8.

171.

Uzawa

, Mori

, Ito

Markedly increased CSF interleukin-6 levels in neuromyelitis optica, but not in multiple sclerosis. J Neurol. 2009; 256: 2082–4.

172.

Icoz

, Tuzun

, Kurtuncu

Enhanced IL-6 production in aquaporin-4 antibody positive neuromyelitis optica patients. Int J Neurosci. 2010; 120: 71–5.

173.

Uzawa

, Mori

, Arai

Cytokine and chemokine profiles in neuromyelitis optica: significance of interleukin-6. Mult Scler. 2010; 16: 1443–52.

174.

Wang

, Wang

, Zhong

Notable increased cerebrospinal fluid levels of soluble interleukin-6 receptors in neuromyelitis optica. Neuroimmunomodulation. 2012; 19: 304–8.

175.

Chihara

, Aranami

, Sato

Interleukin 6 signaling promotes anti-aquaporin 4 autoantibody production from plasmablasts in neuromyelitis optica. Proc Natl Acad Sci USA. 2011; 108: 3701–6.

176.

Araki

, Aranami

, Matsuoka

, Nakamura

, Miyake

, Yamamura

Clinical improvement in a patient with neuromyelitis optica following therapy with the anti-IL-6 receptor monoclonal antibody tocilizumab. Mod Rheumatol. Jul 11, 2012. [Epub ahead of print.]

177.

Kieseier

B.C.

, Stuve

, Dehmel

Disease amelioration with tocilizumab in a treatment-resistant patient with neuromyelitis optica: implication for cellular immune responses. Arch Neurol. Dec 24, 2012. [Epub ahead of print.]

178.

Shanahan

Crohn's disease. Lancet. 2002; 359: 62–9.

179.

Perrier

, Rutgeerts

Cytokine blockade in inflammatory bowel diseases. Immunotherapy. 2011; 3: 1341–52.

180.

Holub

M.C.

, Mako

, Devay

Increased interleukin-6 levels, interleukin-6 receptor and gp130 expression in peripheral lymphocytes of patients with inflammatory bowel disease. Scand J Gastroenterol Suppl. 1998; 228: 47–50.

181.

Hosokawa

, Kusugami

, Ina

Interleukin-6 and soluble interleukin-6 receptor in the colonic mucosa of inflammatory bowel disease. J Gastroenterol Hepatol. 1999; 14: 987–96.

182.

Van Kemseke

, Belaiche

, Louis

Frequently relapsing Crohn's disease is characterized by persistent elevation in interleukin-6 and soluble interleukin-2 receptor serum levels during remission. Int J Colorectal Dis. 2000; 15: 206–10.

183.

Yamamoto

, Yoshizaki

, Kishimoto

, Ito

IL-6 is required for the development of Th1 cell-mediated murine colitis. J Immunol. 2000; 164: 4878–82.

184.

Ito

, Takazoe

, Fukuda

A pilot randomized trial of a human anti-interleukin-6 receptor monoclonal antibody in active Crohn's disease. Gastroenterology. 2004; 126: 989–96.

185.

Efthimiou

, Kontzias

, Ward

C.M.

, Ogden

N.S.

Adult-onset Still's disease: can recent advances in our understanding of its pathogenesis lead to targeted therapy?

Nat Clin Pract Rheumatol. 2007; 3: 328–35.

186.

Fautrel

Adult-onset Still disease. Best Pract Res Clin Rheumatol. 2008; 22: 773–92.

187.

Scheinberg

M.A.

, Chapira

, Fernades

M.L.

, Hubscher

Interleukin 6: a possible marker of disease activity in adult onset Still's disease. Clin Exp Rheumatol. 1996; 14: 653–5.

188.

Hoshino

, Ohta

, Yang

Elevated serum interleukin 6, interferon-gamma, and tumor necrosis factor-alpha levels in patients with adult Still's disease. J Rheumatol. 1998; 25: 396–8.

189.

Fujii

, Nojima

, Yasuoka

Cytokine and immunogenetic profiles in Japanese patients with adult Still's disease. Association with chronic articular disease. Rheumatology (Oxford). 2001; 40: 1398–404.

190.

Choi

J.H.

, Suh

C.H.

, Lee

Y.M.

Serum cytokine profiles in patients with adult onset Still's disease. J Rheumatol. 2003; 30: 2422–7.

191.

Iwamoto

, Nara

, Hirata

, Minota

, Nishimoto

, Yoshizaki

Humanized monoclonal anti-interleukin-6 receptor antibody for treatment of intractable adult-onset Still's disease. Arthritis Rheum. 2002; 46: 3388–9.

192.

Nakahara

, Mima

, Yoshio-Hoshino

, Matsushita

, Hashimoto

, Nishimoto

A case report of a patient with refractory adult-onset Still's disease who was successfully treated with tocilizumab over 6 years. Mod Rheumatol. 2009; 19: 69–72.

193.

De Bandt

, Saint-Marcoux

Tocilizumab for multirefractory adult-onset Still's disease. Ann Rheum Dis. 2009; 68: 153–4.

194.

Matsumoto

, Nagashima

, Takatori

Glucocorticoid and cyclosporine refractory adult onset Still's disease successfully treated with tocilizumab. Clin Rheumatol. 2009; 28: 485–7.

195.

Cunha

M.L.

, Wagner

, Osawa

, Scheinberg

The effect of tocilizumab on the uptake of 18FDG-PET imaging in patients with adult-onset Still's disease. Rheumatology (Oxford). 2010; 49: 1014–6.

196.

Sumida

, Ubara

, Hoshino

Etanercept-refractory adult-onset Still's disease with thrombotic thrombocytopenic purpura successfully treated with tocilizumab. Clin Rheumatol. 2010; 29: 1191–4.

197.

Yoshimura

, Makiyama

, Koga

, Miyashita

, Izumi

, Torigoshi

Successful treatment with tocilizumab in a patient with refractory adult-onset Still's disease (AOSD). Clin Exp Rheumatol. 2010; 28: 141–2.

198.

Perdan-Pirkmajer

, Praprotnik

, Tomsic

A case of refractory adult-onset Still's disease successfully controlled with tocilizumab and a review of the literature. Clin Rheumatol. 2010; 29: 1465–7.

199.

Naniwa

, Ito

, Watanabe

Case report: successful use of short-term add-on tocilizumab for multirefractory systemic flare of adult-onset Still's disease. Clin Rheumatol. Sep 15, 2010. [Epub ahead of print.]

200.

Kishida

, Okuda

, Onishi

Successful tocilizumab treatment in a patient with adult-onset Still's disease complicated by chronic active hepatitis B and amyloid A amyloidosis. Mod Rheumatol. 2011; 21: 215–8.

201.

Thonhofer

, Hiller

, Just

, Trummer

, Siegel

, Dejaco

Treatment of refractory adult-onset Still's disease with tocilizumab: report of two cases and review of the literature. Rheumatol Int. 2011; 31: 1653–6.

202.

Sabnis

G.R.

, Gokhale

Y.A.

, Kulkarni

U.P.

Tocilizumab in refractory adult-onset Still's diseases with aseptic meningitis-efficacy of interleukin-6 blockade and review of the literature. Semin Arthritis Rheum. 2011; 40: 365–8.

203.

Rech

, Ronneberger

, Englbrecht

Successful treatment of adult-onset Still's disease refractory to TNF and IL-1 blockade by IL-6 blockade. Ann Rheum Dis. 2011; 70: 390–2.

204.

Kobayashi

, Takahashi

, Yamashita

, Kaneko

, Mimori

Benefit and a possible risk of tocilizumab therapy for adult-onset Still's disease accompanied by macrophage-activation syndrome. Mod Rheumatol. 2011; 21: 92–6.

205.

Puechal

, DeBandt

, Berthelot

J.M.

Tocilizumab in refractory adult Still's disease. Arthritis Care Res. 2011; 63: 155–9.

206.

Sekkach

, Elqatni

, Khattabi

A.E.

Antagonists of interleukin-6 (tocilizumab) in adult refractory still disease. Presse Med. 2011; 40: e333–7.

207.

Suematsu

, Ohta

, Matsuura

Therapeutic response of patients with adult Still's disease to biologic agents: multicenter results in Japan. Mod Rheumatol. 2012; 22: 712–9.

208.

Perfetto

, Moggi-Pignone

, Livi

, Tempestini

, Bergesio

, Matucci-Cerinic

Systemic amyloidosis: a challenge for the rheumatologist. Nat Rev Rheumatol. 2010; 6: 417–29.

209.

Lachmann

H.J.

, Goodman

H.J.

, Gilbertson

J.A.

Natural history and outcome in systemic AA amyloidosis. N Engl J Med. 2007; 356: 2361–71.

210.

Gillmore

J.D.

, Lovat

L.B.

, Persey

M.R.

, Pepys

M.B.

, Hawkins

P.N.

Amyloid load and clinical outcome in AA amyloidosis in relation to circulating concentration of serum amyloid A protein. Lancet. 2001; 358: 24–9.

211.

Hagihara

, Nishikawa

, Isobe

, Song

, Sugamata

, Yoshizaki

IL-6 plays a critical role in the synergistic induction of human serum amyloid A (SAA) gene when stimulated with proinflammatory cytokines as analyzed with an SAA isoform real-time quantitative RT-PCR assay system. Biochem Biophys Res Commun. 2004; 314: 363–9.

212.

Hagihara

, Nishikawa

, Sugamata

Essential role of STAT3 in cytokine-driven NF-kappaB-mediated serum amyloid A gene expression. Genes Cells. 2005; 10: 1051–63.

213.

Nishimoto

, Yoshizaki

, Maeda

Toxicity, pharmacokinetics, and dose-finding study of repetitive treatment with the humanized anti-interleukin 6 receptor antibody MRA in rheumatoid arthritis. Phase I/II clinical study. J Rheumatol. 2003; 30: 1426–35.

214.

Nishimoto

, Yoshizaki

, Miyasaka

Treatment of rheumatoid arthritis with humanized anti-interleukin-6 receptor antibody: a multicenter, double-blind, placebo-controlled trial. Arthritis Rheum. 2004; 50: 1761–9.

215.

Nishimoto

, Kanakura

, Aozasa

Humanized anti-interleukin-6 receptor antibody treatment of multicentric Castleman disease. Blood. 2005; 106: 2627–32.

216.

Okuda

, Takasugi

Successful use of a humanized anti-interleukin-6 receptor antibody, tocilizumab, to treat amyloid A amyloidosis complicating juvenile idiopathic arthritis. Arthritis Rheum. 2006; 54: 2997–3000.

217.

Nishida

, Hagihara

, Shima

Rapid improvement of AA amyloidosis with humanised anti-interleukin 6 receptor antibody treatment. Ann Rheum Dis. 2009; 68: 1235–6.

218.

Sato

, Sakai

, Sugaya

Tocilizumab dramatically ameliorated life-threatening diarrhea due to secondary amyloidosis associated with rheumatoid arthritis. Clin Rheumatol. 2009; 28: 1113–6.

219.

Inoue

, Arima

, Kawanami

Excellent therapeutic effect of tocilizumab on intestinal amyloid a deposition secondary to active rheumatoid arthritis. Clin Rheumatol. 2010; 29: 1195–7.

220.

De La Torre

, Arboleya

, Pozo

, Pinto

, Velasco

Rapid and sustained response to tocilizumab, amti-interleukin-6 receptor antibody, in a patient with nephritic syndrome secondary to systemic juvenile idiopathic arthritis-related amyloidosis. NDT Plus. 2011; 4: 178–80.

221.

Magro-Checa

, Navas-Parejo Casado

, Borrego-Garcia

Successful use of tocilizumab in a patient with nephritic syndrome due to a rapidly progressing AA amyloidosis to latent tuberculosis. Amyloid. 2011; 18: 235–9.

222.

Hattori

, Ubara

, Sumida

Tocilizumab improves cardiac disease in a hemodialysis patient with AA amyloidosis secondary to rheumatoid arthritis. Amyloid. 2012; 19: 37–40.

223.

Tanaka

, Hagihara

, Hishitani

, Ogata

Tocilizumab for the treatment of AA amyloidosis. In: Guvenc

I.A.

, editor. Amyloidosis—An insight to disease of systems and novel therapies. Croatia: INTECH Open Access Publisher; 2011: 155–70.

224.

Mendes

, Correia

, Barbedo

, Vaio

, Mota

Behcet's disease-a contemporary review. J Autoimmun. 2009; 32: 178–88.

225.

Hirohata

, Oka

, Mizushima

Streptococcal-related antigens stimulate production of IL-6 and interferon-gamma by T cells from patients with Behcet's disease. Cell Immunol. 1992; 140: 410–9.

226.

Mege

J.L.

, Dilsen

, Sanguedolce

Overproduction of monocyte derived tumor necrosis factor alpha, interleukin (IL) 6, IL-8 and increased neutrophil superoxide generation in Behcet's disease. A comparative study with familial Mediterranean fever and healthy subjects. J Rheumatol. 1993; 20: 1544–9.

227.

Yamakawa

, Sugita

, Nagatani

Interleukin-6 (IL-6) in patients with Behcet's disease. J Dermatol Sci. 1996; 11: 189–95.

228.

Kulaber

, Tugal-Tutkun

, Yentur

S.P.

Pro-inflammatory cellular immune response in Behcet's disease. Rheumatol Int. 2007; 27: 1113–8.

229.

Hirano

, Ohguro

, Hohki

A case of Behcet's disease treated with a humanized anti-interleukin-6 receptor antibody, tocilizumab. Mod Rheumatol. 2012; 22: 298–302.

230.

Hirohata

, Isshi

, Oguchi

Cerebrospinal fluid interleukin-6 in progressive neuro-Behcet's syndrome. Clin Immunol Immunopathol. 1997; 82: 12–7.

231.

Akman-Demir

, Turun

, Icoz

Interleukin-6 in neuro-Behcet's disease: association with disease subsets and long-term outcome. Cytokine. 2008; 44: 373–6.

232.

Borhani Haghighi

, Ittehadi

, Nikseresht

A.R.

CSF levels of cytokines in neuro-Behcet's disease. Clin Neurol Neurosurg. 2009; 111: 507–10.

233.

Shapiro

L.S.

, Farrell

, Haghighi

A.B.

Tocilizumab treatment for neuro-Behcet's disease, the first report. Clin Neurol Neurosurgery. 2012; 114: 297–8.

234.

Caspi

R.R.

A look at autoimmunity and inflammation in the eye. J Clin Invest. 2010; 120: 3073–83.

235.

Murray

P.I.

, Hoekzema

, van Haren

M.A.

, de Hon

F.D.

, Kijlstra

Aqueous humor interleukin-6 levels in uveitis. Invest Ophthalmos Vis Sci. 1990; 31: 917–20.

236.

Benson

M.T.

, Shepherd

, Rees

R.C.

, Rennie

I.G.

Production of interleukin-6 by human retinal pigment epithelium in vitro and its regulation by other cytokines. Curr Eye Res. 1992; 11(Suppl): 173–9.

237.

Norose

, Yano

, Wang

X.C.

Dominance of activated T cells and interleukin-6 in aqueous humor in Vogt-Koyanagi-Harada disease. Invest Ophthalmol Vis Sci. 1994; 35: 33–9.

238.

Petrinovic-Doresic

, Mazuran

, Henc-Petrinovic

, Kuzmanovic

, Jovicic

Interleukin 6 and its soluble receptor are elevated in aqueous humor of patients with uveitis. Ocul Immunol Inflamm. 1999; 7: 75–84.

239.

Perez

V.L.

, Papaliodis

G.N.

, Chu

, Anzaar

, Christen

, Foster

C.S.

Elevated levels of interleukin 6 in the vitreous fluid of patients with pars planitis and posterior uveitis: the Massachusetts eye and ear experience and review of previous studies. Ocul Immunol Inflamm. 2004; 12: 193–201.

240.

Yoshimura

, Sonoda

, Ohguro

Involvement of Th17 cells and the effect of anti-IL-6 therapy in autoimmune uveitis. Rheumatology (Oxford). 2009; 48: 347–54.

241.

Hohki

, Ohguro

, Haruta

Blockade of interleukin-6 signaling suppresses experimental autoimmune uveoretinitis by the inhibition of inflammatory Th17 responses. Exp Eye Res. 2010; 91: 162–70.

242.

Haruta

, Ohguro

, Fujimoto

Blockade of interleukin-6 signaling suppresses not only Th17 but also interphotoreceptor retinoid binding protein-specific Th1 by promoting regulatory T cells in experimental autoimmune uveoretinitis. Invest Ophthalmol Vis Sci. 2011; 52: 3264–71.

243.

Muselier

, Bielefeld

, Bidot

, Vinit

, Besancenot

J.F.

, Bron

Efficacy of tocilizumab in two patients with anti-TNF-alpha refractory uveitis. Ocul Immunol Inflamm. 2011; 19: 382–3.

244.

Gergis

, Arnason

, Yantiss

Effectiveness and safety of tocilizumab, an anti-interleukin-6 receptor monoclonal antibody, in a patient with refractory GI graft-versus-host disease. J Clin Onocol. 2010; 28: e602–4.

245.

Drobyski

W.R.

, Pasquini

, Kovatovic

Tocilizumab for the treatment of steroid refractory graft versus host disease. Biol Blood Marrow Transplant. 2011; 17: 1862–8.

246.

Nishida

, Kawasaki

, Kashiwagi

Successful treatment of acquired hemophilia A, complicated by chronic GVHD, with tocilizumab. Mod Rheumatol. 2011; 21: 420–2.

247.

Kunitomi

, Konaka

, Yagita

, Nishimoto

, Kishimoto

, Takatsuki

Humanized anti-interleukin 6 receptor antibody induced long-term remission in a patient with life-threatening refractory autoimmune hemolytic anemia. Int J Hematol. 2004; 80: 246–9.

248.

Yuzuriha

, Saitoh

, Koiso

Successful treatment of autoimmune hemolytic anemia associated with multicentric Castleman disease by anti-interleukin-6 receptor antibody (tocilizumab) therapy. Acta Haematol. 2011; 126: 147–50.

249.

Garcia-Hernandez

F.J.

, Gonzalez-Leon

, Castillo-Palma

M.J.

, Ocana-Medina

, Sanchez-Roman

Tocilizumab for treating refractory haemolytic anaemia in a patient with systemic lupus erythematosus. Rheumatology (Oxford). 2012; 51: 1918–9.

250.

Tanaka

, Hagihara

, Shima

Treatment of a patient with remitting seronegative, symmetrical synovitis with pitting oedema with a humanized anti-interleukin-6 receptor antibody, tocilizumab. Rheumatology (Oxford). 2010; 49: 824–6.

251.

Furuya

, Satoh

, Kuwana

Interleukin-6 as a potential therapeutic target for pulmonary arterial hypertension. Int J Rheumatol. 2010: Article ID 720305.

252.

Taniguchi

, Shimazaki

, Fujimoto

Tocilizumab is effective for pulmonary hypertension associated with multicentric Castleman's disease. Int J Hematol. 2009; 90: 99–102.

253.

Arita

, Sakata

, Sudo

The efficacy of tocilizumab in a patient with pulmonary arterial hypertension associated with Castleman's disease. Heart Vessels. 2010; 25: 444–7.

254.

Vaitla

P.M.

, Radford

P.M.

, Tighe

P.J.

Role of interleukin-6 in a patient with tumor necrosis factor receptor-associated periodic syndrome: assessment of outcomes following treatment with the anti-interleukin-6 receptor monoclonal antibody tocilizumab. Arthritis Rheum. 2011; 63: 1151–5.

255.

Navarini

A.A.

, French

L.E.

, Hofbauer

G.F.L.

Interrupting IL-6-receptor signaling improves atopic dermatitis but associates with bacterial superinfection. J Allergy Clin Immunol. 2011; 128: 1128–30.

256.

Schanz

, Schmalzing

, Guenova

Interstitial granulomatous dermatitis with arthritis responding to tocilizumab. Arch Dermatol. 2012; 148: 17–20.

257.

Ohtori

, Miyagi

, Eguchi

Efficacy of epidural administration of anti-interleukin-6 receptor antibody onto spinal nerve for treatment of sciatica. Eur Spine J. 2012; 21: 2079–84.

258.

Henes

J.C.

, Horger

, Guenaydin

, Kanz

, Koetter

Mixed response to tocilizumab for ankylosing spondylitis. Ann Rheum Dis. 2010; 69: 2217–8.

259.

Wendling

, Bossert

, Prati

Short-term effect of IL-6 inhibition in spondylarthritis. Joint Bone Spine. 2010; 77: 624–5.

260.

Brulhart

, Nissen

M.J.

, Chevallier

, Gabay

Tocilizumab in a patient with ankylosing spondylitis and Crohn's disease refractory to TNF antagonists. Joint Bone Spine. 2010; 77: 625–6.

261.

Shima

, Tomita

, Ishii

Tocilizumab, a humanized anti-interleukin-6 receptor antibody, ameliorated clinical symptoms and MRI findings of a patient with ankylosing spondylitis. Mod Rheumatol. 2011; 21: 436–9.

262.

Cohen

J.D.

, Ferreira

, Jorgensen

Ankylosing spondylitis refractory to tumor necrosis factor blockade responds to tocilizumab. J Rheumatol. 2011; 38: 1527.

263.

Tanaka

, Kuwahara

, Shima

Successful treatment of reactive arthritis with a humanized anti-interleukin-6 receptor antibody, tocilizumab. Arthritis Rheum. 2009; 61: 1762–4.

264.

Kwan

, Bharadwaj

, Inderjeeth

Response to treatment with tocilizumab of reactive arthritis induced by intravesical bacillus Galmette-Guerin unresponsive to DMARDs. Int J Rheum Dis. 2012; 15: e73–5.

265.

Sieper

, Inman

R.D.

, Badalamenti

, Radin

, Braun

Sarilumab for the treatment of ankylosing spondylitis: results of phase 2, randomized double-blind, placebo-controlled, international study (ALIGN). Ann Rheum Dis. 2012; 71(Suppl 3): 111.

266.

Ogata

, Morishima

, Hirano

Improvement of HbA1c during treatment with humanised anti-interleukin 6 receptor antibody, tocilizumab. Ann Rheum Dis. 2011; 70: 1164–5.

267.

Schultz

, Oberhauser

, Saech

Effects of inhibition of interleukin-6 signalling on insulin sensitivity and lipoprotein (a) levels in human subjects with rheumatoid diseases. PLoS One. 2010; 5: e14328.

268.

Hirao

, Yamasaki

, Oze

Serum level of oxidative stress marker is dramatically low in patients with rheumatoid arthritis treated with tocilizumab. Rheumatol Int. 2012; 32: 4041–4015.

269.

Matthijs Boekholdt

, Stores

E.S.G.

The interleukin-6 pathway and atherosclerosis. Lancet. 2012; 379: 1176–8.

270.

Qin

, Keamey

, Plaisance

, Parsons

C.H.

Pivotal advance: Kaposi's sarcoma-associated herpesvirus (KSHV)-encoded microRNA specifically induce IL-6 and IL-10 secretion by macrophages and monocytes. J Leukoc Biol. 2010; 87: 25–34.

271.

Leung

, Nabel

G.J.

HTLV-1 transactivator induces interleukin-2 receptor expression through an NF-kappa B-like factor. Nature. 1988; 333: 776–8.

272.

Ballard

D.W.

, Bohnlein

, Lowenthal

J.W.

, Wano

, Franza

B.R.

, Greene

W.C.

HTLV-1 tax induces cellular proteins that activate the kappa B element in the IL-2 receptor alpha gene. Science. 1988; 241: 1652–5.

273.

Scala

, Ruocco

M.R.

, Ambrosino

The expression of the interleukin 6 gene is induced by the human immunodeficiency virus 1 TAT protein. J Exp Med. 1994; 179: 961–71.

274.

Ambrosino

, Ruocco

M.R.

, Chen

HIV-1 Tat induces the expression of the interleukin-6 (IL6) gene by binding to the IL6 leader RNA and by interacting with CAAT enhancer-binding protein beta (NF-IL6) transcription factors. J Biol Chem. 1997; 272: 14883–92.

275.

Mahe

, Mukaida

, Kuno

Hepatitis B virus X protein trans-activates human interleukin-8 gene through acting on nuclear factor kB and CCAAT/enhancer-binding protein-like cis-elements. J Biol Chem. 1991; 266: 13759–63.

276.

Ohno

, Kaneko

, Lin

, Kobayashi

, Murakami

Human hepatitis B virus X protein augments the DNA binding of nuclear factor for IL-6 through its basic-leucine zipper domain. J Med Virol. 1999; 58: 11–8.

Tocilizumab: An Updated Review of Its Use in the Treatment of Rheumatoid Arthritis and Its Application for Other Immune-Mediated Diseases

Abstract

Keywords

Interleukin-6

Tocilizumab, a Humanized Anti-IL-6 Receptor Monoclonal Antibody

Efficacy and Safety of Tocilizumab for Rheumatoid Arthritis

Additional Applications of Tocilizumab for other Immune-Mediated Diseases

Systemic sclerosis

Polymyositis

Vasculitis syndrome and polymyalgia rheumatica

Systemic lupus erythematosus

Relapsing polychondritis

Neuromyelitis optica

Crohn's disease

Adult-onset still's disease

Amyloid A amyloidosis

Behcet's disease and uveitis

Other candidate diseases

Conclusions and Future Prospects

Author Contributions

Funding

Competing Interests

Disclosures and Ethics

Footnotes

Acknowledgements

References