Interleukin-6 inhibition in inflammatory diseases: results achieved and tasks to accomplish


Interleukin-6 (IL-6) is a prototypical cytokine featuring functional pleiotropy and redundancy. Under situations of stress, such as infection or tissue injury, IL-6 is rapidly synthesized and plays a major role in host defense. However, uncontrolled excessive or persistent production of IL-6 has a pathological effect in various diseases. Thus, IL-6 blockade was expected to become a novel therapeutic strategy for IL-6–mediated inflammatory diseases, and the first-in-class IL-6 inhibitor tocilizumab, which blocks IL-6 activity by inhibiting IL-6 binding to its receptor, was developed. Clinical trials of tocilizumab have verified its efficacy and tolerable safety profile in several diseases, and it has been approved for the treatment of patients with rheumatoid arthritis, Castleman’s disease, systemic and polyarticular juvenile idiopathic arthritis, and giant cell arteritis. Off-label use and clinical trials strongly indicate that tocilizumab will be applicable for a wide variety of acute and chronic inflammatory diseases.

J scleroderma relat disord 2017; 2(Suppl. 2): 20 - 28

Article Type: REVIEW




Toshio Tanaka, Masashi Narazaki

Article History


Financial support: Medical writing and editorial assistance was funded by F. Hoffmann-La Roche Ltd.
Conflict of interest: TT is an employee of the Department of Clinical Application of Biologics of Osaka University Graduate School of Medicine, which is an endowment department supported by an unrestricted grant from Chugai Pharmaceutical Co., Ltd. MN has received payment for lectures, including services for speaker bureaus, from Chugai Pharmaceutical Co., Ltd.

This article is available as full text PDF.

Download any of the following attachments:


Progress in bioengineering techniques has led to dramatic changes in the clinical application of biological agents, from low-molecular-weight compounds to development of therapeutic drugs (1). Techniques that enable the conversion of a mouse monoclonal antibody to a humanized or fully human antibody have facilitated this progress. The most important characteristic of a therapeutic antibody is its high specificity and affinity to the targeted molecule. Therefore, if a molecule is identified as a key component of disease development, an antibody can bind to the molecule with high affinity and can specifically inhibit its pathological action.

Interleukin-6 (IL-6) plays a key role in the pathology underlying various autoimmune and inflammatory diseases (2, 3). When infections or tissue injuries occur, IL-6 is promptly produced and plays a major role in host defense against these environmental stresses (4). However, dysregulated excessive or persistent production of IL-6 during this process leads to the onset or the progression of systemic inflammatory response syndrome (SIRS) and various chronic diseases (5, 6). The first-in-class IL-6 inhibitor tocilizumab (TCZ) was developed using molecular cloning techniques (7). Clinical trials have verified the efficacy and tolerable safety profile of TCZ in rheumatoid arthritis (RA), systemic and polyarticular juvenile idiopathic arthritis (JIA), Castleman’s disease, and giant cell arteritis (GCA), and TCZ is approved for the treatment of patients with any of these diseases. This review focuses on recent findings from clinical trials and the off-label use of TCZ in various inflammatory diseases other than systemic sclerosis, which are discussed in other articles in this supplement, and raises the possibility that TCZ will be widely applicable for the management of acute and chronic inflammatory diseases.

Tocilizumab molecule, structure, and history of development

After the successful cloning of the human IL-6 gene in 1986 (8), IL-6 was characterized as a prototypical cytokine featuring functional pleiotropy and redundancy (3). Immediate and transient expression of IL-6 is generated in response to infection or tissue injury (4). IL-6 stimulates the acute phase response, including immune and hematologic responses to environmental stressors; therefore IL-6 is essential in the maintenance of homeostasis. However, dysregulated excessive or persistent IL-6 production in certain cell types leads to the development of some acute and chronic inflammatory diseases (5, 6). Association of IL-6 with disease development was first demonstrated in a patient with cardiac myxoma (9). The patient presented with fever, polyarthritis with positivity for anti-nuclear factor, elevated C-reactive protein (CRP) levels and hypergammaglobulinemia, and highly elevated levels of IL-6, suggesting that IL-6 might contribute to chronic inflammation and autoimmunity. Subsequent studies have revealed dysregulation of IL-6 production in the synovial fluid of patients with RA (10), swollen lymph nodes of patients with Castleman’s disease (11), peripheral blood cells or tissue involved in various other autoimmune and chronic inflammatory diseases, and malignant cancer cells (2, 3). Moreover, the pathological role of IL-6 in disease development has been demonstrated in animal models of diseases. For example, IL-6 blockade prevented joint destruction in a mouse model of RA (12) and prevented skin sclerosis in a bleomycin-induced systemic sclerosis mouse model (13).

These findings led to the expectation that targeting IL-6 would constitute a novel treatment strategy for various immune-mediated diseases. TCZ, a humanized anti–IL-6 receptor monoclonal antibody of the immunoglobulin 1 (IgG1) class, was generated by grafting the complementarity determining regions of a mouse antihuman IL-6 receptor antibody onto human IgG1 (7). TCZ blocks IL-6–mediated signal transduction by inhibiting IL-6 binding to its membrane-bound or soluble IL-6 receptor (Fig. 1).

Structures of IL-6, IL-6R, and signal-transducer gp130. Four helix bundles (labeled A to D) and three loops (A-B, B-C, and C-D) of the IL-6 structure are shown to the left of the figure. IL-6 binds to mIL-6R or sIL-6R. IL-6R consists of an immunoglobulin-like domain (D1) and a cytokine binding homology region (D2 and D3). The IL-6/IL-6R (or IL-6/sIL-6R) complex associates with signal transducer gp130, which consists of an immunoglobulin-like domain (D1), the cytokine binding homology region (D2 and D3), and the membrane proximal domains (D4, D5, and D6). The binding of IL-6/IL-6R (or IL-6/sIL-6R) to gp130 causes the formation of a gp130 homodimer, resulting in an IL-6(2):IL-6R(2):gp130(2) hexamer structure with two molecules each. Homodimerized gp130 allows the two cytoplasmic regions of gp130 to come into close proximity and transduces signaling. IL-6 has three interface sites: I, II, and III. IL-6 site I interacts with IL-6R D2-D3, site II interacts with D2-D3 of one gp130, and site III interacts with D1 of the other gp130. The view of hexamer structure from above is also shown. Strategies for blocking the IL-6 activation pathway consist of biologics targeting IL-6, IL-6R, and the IL-6/sIL-6R complex. Siltuximab is a chimeric anti–IL-6 monoclonal antibody that has been approved for the treatment of Castleman’s disease. Sirukumab and MEDI5117 are fully human anti–IL-6 antibodies. Clazakizumab, olokizumab, and EBI-029 are humanized anti–IL-6 antibodies. Olokizumab binds to site III, EBI-029 binds to site II, and other agents bind to site I of IL-6. Tocilizumab is a humanized anti–IL-6R antibody that is approved for the treatment of Castleman’s disease, rheumatoid arthritis, systemic and polyarticular juvenile idiopathic arthritis, and giant cell arteritis. Sarilumab and NI-1201 are fully human anti–IL-6R antibodies. SA237 is a humanized recycling anti–IL-6R antibody that was derived from tocilizumab. ALX-0061 is a high-affinity anti–IL-6R heavy chain. SA237 is a soluble gp130-Fc fusion protein that targets the IL-6/sIL-6R complex. Ab = antibody; IL-6 = interleukin 6; IL-6R = interleukin 6 receptor; mIL-6R = membrane-bound interleukin 6 receptor; sIL-6R = soluble interleukin 6 receptor; TCZ = tocilizumab.

Data from clinical trials to date for approved indications

TCZ is approved for the management of RA in more than 130 countries; of systemic and polyarticular JIA in Japan, the USA, the EU, and India; of Castleman’s disease in Japan and India; and of GCA in the USA (5, 6, 14). Key results from clinical trials for approved indications for TCZ are reviewed in this article.

Rheumatoid arthritis

The pathological role of IL-6 in RA is depicted in Figure 2. It plays a major role in the development of RA by inducing immunologic dysfunction and joint inflammation as well as systemic complications (15). The first randomized controlled trial of TCZ for RA was performed in 45 patients, each of whom received a single intravenous dose of 0.1, 1, 5, or 10 mg/kg TCZ or placebo (16). At week 2, a significant difference was observed between the group treated with 5 mg/kg TCZ and the placebo group. Five patients (56%) in the TCZ cohort and none in the placebo cohort achieved American College of Rheumatology 20% (ACR20) improvement. Subsequently, a 12-week, multicenter, double-blind, placebo-controlled, phase 2 trial was performed in Japan (17). In this trial, 164 patients with RA were randomly assigned to receive 8 mg/kg or 4 mg/kg TCZ or placebo intravenously once every 4 weeks. By week 12, ACR20 response was attained for 78%, 57%, and 11% of the patients infused with TCZ 8 mg/kg, TCZ 4 mg/kg, and placebo, respectively. Subsequent results from phase 3 clinical trials confirmed the efficacy of TCZ for the suppression of disease activity and the slowing of joint damage progression, leading to worldwide approval of TCZ for the treatment of patients with moderate to severe RA (15).

Pathological role of IL-6 in rheumatoid arthritis. Symptoms and complications due to IL-6 are observed in rheumatoid arthritis, which is a typical inflammatory disease. IL-6 supports the differentiation of naive CD4+ T cells into Th17 cells and suppresses their differentiation into Treg cells, thus shifting the Th17/Treg balance toward Th17 dominance and promoting inflammation. IL-6 supports the survival of plasmablasts and promotes the differentiation of B cells into immunoglobulin-producing plasma cells. IL-6 acts on vascular endothelial cells to promote vascular permeability directly or indirectly by the induction of VEGF, which leads to increased synovial fluid, joint swelling, synovial growth, and neovascularization. Systemic effects are rapid induction of the production of the acute phase proteins, C-reactive protein, serum amyloid A, complement C3, fibrinogen, hepcidin, and thrombopoietin and the reduction in albumin and cytochrome p450. Persistently high levels of serum amyloid A result in secondary amyloidosis. Hepcidin and thrombopoietin induced by IL-6 in the liver promote inflammatory anemia and thrombocytosis, respectively. Persistently high levels of fibrinogen and thrombocytosis are associated with risk for cardiovascular disease. IL-6 stimulates osteoblasts and synoviocytes to produce RANKL, which activates osteoclasts resulting in osteoporosis and joint destruction. Finally, IL-6 induces tissue factor on monocytes, resulting in the promotion of coagulation. CRP = C-reactive protein; IL-6 = interleukin 6; RANKL = receptor activator of nuclear factor kappa B ligand; Tfh = T follicular helper cells; Th = T-helper cell; VEGF = vascular endothelial growth factor. Adapted from (15) Narazaki M, Tanaka T, Kishimoto T. The role and therapeutic targeting of IL-6 in rheumatoid arthritis. Expert Rev Clin Immunol. 2017;13(6):535-551, by permission of the publisher (Taylor & Francis Ltd,

The safety profile of TCZ in phase 3 clinical trials was reported in 2011 by analyzing 8580 patient-years (PY) of exposure (18). The overall rates of adverse events (AEs) and serious AEs (SAE) were 278.2/100 PY and 14.4/100 PY, respectively, and included serious infections (4.7/100 PY), opportunistic infections (0.23/100 PY), and gastrointestinal perforations (0.28/100 PY). Post-marketing surveillance of 7901 patients for 28 weeks in Japan demonstrated that 9.6% of patients reported SAEs, and the most common event was infection (3.8%) (19).

Guidelines published by the European League Against Rheumatism recommend TCZ as one of the first-line biologics to be used for RA patients with inadequate responses to the conventional synthetic disease-modifying antirheumatic drug (csDMARD) methotrexate (MTX) (20). However, TCZ is the only biologic that has been shown to be more efficacious as monotherapy than MTX (21). Tumor necrosis factor (TNF) inhibitors require the concomitant use of MTX to achieve their maximal effects (22), whereas TCZ is as effective as monotherapy as it is in combination therapy with MTX for the suppression of disease activity (23, 24). A head-to-head comparison of TCZ and adalimumab, a human anti-TNFα antibody, demonstrated that TCZ monotherapy was superior to adalimumab monotherapy, as assessed by several indices of disease activity (25).

Systemic juvenile idiopathic arthritis

Systemic JIA (sJIA) is a subtype of chronic childhood arthritis that leads to joint destruction and functional disability and is accompanied by systemic inflammation (26). A clinical trial consisting of a 6-week, open-label, lead-in phase and a 12-week, double-blind phase that enrolled 56 children with sJIA was performed in Japan (27). By week 6, TCZ treatment (8 mg/kg intravenously every 2 weeks) resulted in ACR Pediatric (ACR Pedi) 30, 50, and 70 response rates of 91%, 86%, and 68%, respectively. Forty-three patients entered the double-blind phase, and 16 of the 20 patients (80%) in the TCZ group maintained an ACR Pedi 30 response and a CRP concentration <15 mg/L, compared with four of the 23 patients (17%) in the placebo group. Subsequently, a global phase 3 trial of 112 children with active sJIA demonstrated that TCZ is effective for the suppression of sJIA disease activity (28). These results led to the approval of TCZ for the treatment of sJIA in the USA, the EU, Japan, and India (5, 6, 14).

Polyarticular juvenile idiopathic arthritis

Polyarticular JIA (pJIA) is defined as JIA with five or more arthritic joints (26). The clinical efficacy and tolerable safety profile of TCZ was initially demonstrated in 17 patients with pJIA who had ACR Pedi 30, 50, 70, and 90 response rates of 95%, 95%, 58%, and 11% at week 12 and of 100%, 94%, 88%, and 65% at week 48, respectively (29). Furthermore, mean Disease Activity Score based on 28 joint counts (DAS28) remained below the remission cutoff of 2.6 from week 24. TCZ was approved in Japan in 2008 for the treatment of patients with pJIA. A 3-part, randomized, double-blind, phase 3 withdrawal trial was performed in 188 patients who had active pJIA for 6 months and inadequate responses to MTX (30). In part 1, patients received TCZ every 4 weeks (8 mg/kg or 10 mg/kg for body weight <30 kg; 8 mg/kg for body weight ≥30 kg). At week 16, patients who attained ACR Pedi 30 response entered part 2, the 24-week, double-blind portion of the trial, and received either TCZ or placebo. In part 3, patients who experienced flares or completed part 2 received open-label TCZ. In part 1, 188 patients received TCZ, and 163 patients entered part 2 and were randomly assigned to continue TCZ (82 patients) or switch to placebo (81 patients). JIA flare occurred in 48% of the placebo group and 26% of the TCZ group (p<0.01). At the end of part 2, 78% and 49% of patients receiving TCZ attained ACR Pedi 70 and 90 responses, respectively.

Castleman’s disease

Castleman’s disease is a chronic lymphoproliferative disorder in which persistent IL-6 production occurs in the germinal centers of swollen lymph node(s), indicating its pathological involvement (11). The first clinical trial of TCZ for Castleman’s disease was performed in seven patients, who presented with severe inflammatory symptoms such as fever and laboratory findings including anemia, increased levels of acute phase proteins, hypoalbuminemia, and hypergammaglobulinemia (31). The administration of TCZ ameliorated clinical symptoms and laboratory parameters. The efficacy of TCZ was confirmed in a subsequent clinical trial, which enrolled 28 patients with Castleman’s disease (32), leading to the approval of TCZ in Japan in 2005.

Giant cell arteritis

GCA is a vasculitis syndrome that involves both large and medium-sized arteries (33). The precise pathogenesis of GCA remains unclear, but IL-6 is pathologically involved (34). Subsequent to reports regarding favorable effects of TCZ for the treatment of GCA (35), a randomized, double-blind, placebo-controlled, phase 2 trial was performed in Switzerland (36). Thirty patients with new-onset or relapsing GCA were randomly assigned (2:1) to receive TCZ (8 mg/kg every 4 weeks) or placebo intravenously until week 52. Both groups received oral prednisolone, starting at 1 mg/kg/day and tapered to 0 mg/kg/day. Relapse-free survival was achieved by 17 (85%) patients in the TCZ group and two (20%) patients in the placebo group (p=0.001). The mean time difference to discontinuation of corticosteroids was 12 weeks in favor of TCZ (p<0.0001), leading to a cumulative prednisolone dose of 43 mg/kg in the TCZ group versus 110 mg/kg in the placebo group (p=0.0005) after 52 weeks. These results demonstrate the efficacy of TCZ for the induction and maintenance of remission in patients with GCA. A phase 3 trial of TCZ for the treatment of patients with GCA reported that subcutaneous TCZ weekly or every other week plus a 26-week prednisolone taper led to sustained remission at 12 months in 56% and 53% of patients, respectively, compared with 14% of patients who received the 26-week prednisolone taper alone (p<0.0001) (37). The proportion of patients in sustained remission in each TCZ group was also superior to that of patients who received a 52-week prednisolone taper (17.6%; p≤0.0002). This led to the US approval of TCZ for treatment of adult patients with GCA (38).

Data from trials in nonapproved indications other than systemic sclerosis

Ankylosing spondylitis

Ankylosing spondylitis (AS) is a subtype of the spondyloarthritides and is characterized by rheumatologic manifestations such as axial involvement, peripheral arthritis and enthesopathy, extra-articular features, negativity for rheumatoid factor, and a genetic background with higher than normal HLA-B27 positivity (39). IL-6 plays a pathological role in AS, and several case reports demonstrated clinical benefits of TCZ for patients with AS (40, 41). A phase 2/3 parallel-group trial in patients with AS naive to TNF inhibitors (BUILDER-1) was performed (42). One hundred and two patients were enrolled in the BUILDER-1 trial and were randomly assigned to receive placebo or TCZ (8 mg/kg every 4 weeks). The primary end point was the proportion of patients achieving 20% improvement in the Assessments in Axial SpondyloArthritis International Society (ASAS). Ninety-nine patients (48 TCZ, 51 placebo) completed 12 weeks; the ASAS 20% response rates were 37% and 28% in the TCZ and placebo groups, respectively (p=0.28). No significant difference in the ASAS 20% response rate was found between the TCZ and placebo groups, resulting in the termination of part 2 of BUILDER-1 and of the phase 3 trial, BUILDER-2, both of which had been initially planned to follow part 1 of BUILDER-1. The ALIGN study, in which the efficacy and safety of sarilumab, an IL-6 receptor antagonist, were evaluated for patients with AS who were naive to TNF inhibitors, also failed to demonstrate effectiveness according to ASAS 20% response rates at week 12 (43).

Data from investigator-sponsored trials

Graves’ ophthalmopathy

Graves’ ophthalmopathy (GO) is an autoimmune inflammatory disorder of extraocular muscles and orbital fat or connective tissue, complicated by Graves’ disease (44). A prospective, open-label study of TCZ was conducted in patients with GO, as defined by Clinical Activity Score (CAS) ≥4, who were resistant to previous intravenous steroids (45). Eighteen patients were enrolled and treated with 8 mg/kg TCZ every 4 weeks. All patients had significant CAS improvement with a reduction in mean CAS score of -5.89 ± 1.41 (p<0.00027) at 9 months. Mean thyroid-stimulating immunoglobulin levels were also significantly lowered by TCZ treatment (-76.2% ± 17.8%; p<0.00007). Moreover, 13 patients (72%) experienced reduced proptosis and 15 patients (83%) experienced improvement in extraocular motility.

Polymyalgia rheumatica

Polymyalgia rheumatica (PMR) is a chronic inflammatory disease that affects the elderly and is characterized by aching and morning stiffness in the shoulders, neck, and pelvic girdle (33). Onset of this disorder often occurs in association with GCA (33). IL-6 has been recognized as a highly sensitive marker of disease activity (34). In a prospective, open-label study (TENOR), 20 steroid-free patients with symptom onset within the previous 12 months and PMR activity score (PMR-AS) >10 received three infusions each of 8 mg/kg TCZ every 4 weeks, followed by prednisolone from weeks 12 to 24 (0.15 mg/kg/day if PMR-AS was ≤10 and 0.30 mg/kg/day otherwise) (46). Baseline median PMR-AS was 36.6; by week 12, the score was ≤10 in all patients, and they all subsequently received low-dose prednisolone. Median PMR-AS was 4.5 by week 12 and 0.95 by week 24. In another open-label clinical trial, 10 patients with newly diagnosed PMR who previously received treatment with glucocorticoids for <1 month received 8 mg/kg TCZ every 4 weeks intravenously plus a standardized rapid steroid taper (47). The primary end point was the proportion of patients in relapse-free remission without glucocorticoids at 6 months. One patient withdrew after 2 months, but the other nine patients attained the primary end point and remained in remission without relapse throughout the 15-month study. These findings indicate that TCZ is effective for recent-onset PMR. A phase 3 trial ( identifier, NCT02908217) to evaluate the safety and efficacy of TCZ in PMR with glucocorticoid dependence is under way.

Steroid-refractory acute graft-versus-host disease

Acute graft-versus-host disease (GVHD) is a frequent, and in some cases lethal, complication of allogeneic hematopoietic stem cell transplantation (SCT) (48). Based on the suggested involvement of IL-6 in acute GVHD, a phase 1/2 clinical trial was performed in Australia (49). Forty-eight patients who underwent T-cell–replete, HLA-matched allogeneic SCT from unrelated or sibling donors received one intravenous dose of TCZ (8 mg/kg) on the day before allogeneic SCT with standard GVHD prophylaxis regimens (cyclosporine plus methotrexate). The incidence of grades 2-4 acute GVHD at day 100 in patients who received TCZ was 12%, whereas the incidence of grades 3-4 acute GVHD was 4%. The incidence was well below that of acute GVHD without TCZ treatment from the same hospital, which was at 52%-54% for grades 2-4 acute GVHD and 22%-43% for grades 3-4 acute GVHD (50). Immune reconstitution was preserved in recipients of TCZ treatment. In a retrospective study, nine patients with grade 3 or 4 steroid-refractory GVHD received TCZ (8 mg/kg) every 3 to 4 weeks intravenously. Median time from acute GVHD onset to TCZ administration was 44 days (51). Four patients (44%) experienced a response; two were complete and two were partial. These results suggest that IL-6 blockade is promising for prophylaxis or therapy for acute GVHD.


Autoimmune and inflammatory uveitis constitute a group of potentially blinding intraocular inflammatory diseases that arise without a known infectious trigger (52). They are often associated with immunologic responses to unique proteins and often occur in conjunction with systemic inflammatory diseases such as JIA and Behçet disease. Retrospective data have been reported from 17 patients with JIA receiving TCZ treatment for uveitis (53). All these patients were refractory to previous treatment regimens, including corticosteroids, MTX, other csDMARDs, and TNF inhibitors. Uveitis inactivity was achieved in 10 patients after a mean of 5.7 months of TCZ treatment and persisted in 7 patients. In a multicenter retrospective study, 25 patients with JIA-associated uveitis refractory to conventional immunosuppressive drugs and at least one TNF inhibitor were enrolled (54). The TCZ dosage regimen was 8 mg/kg intravenously every 4 weeks (n=21), every 2 weeks (n=2), or every 8 weeks (n=1) or 2.9 mg/kg subcutaneously every week (n=1). TCZ treatment resulted in rapid and sustained improvement in all ocular parameters. Six months of therapy resulted in improvement in anterior chamber cell numbers in 79% of patients, whereas best-corrected visual acuity increased from 0.56 ± 0.35 to 0.64 ± 0.32 (p<0.01). After a median follow-up of 12 months, visual improvement persisted and complete remission of uveitis was observed in 19 of 25 patients, leading to significant reduction in the prednisolone dosage. Interim analysis of the STOP-UVEITIS trial, a randomized open-label study of intravenous TCZ in 37 patients with noninfective uveitis, showed that repeated infusions of TCZ were well tolerated. The mean change in visual acuity (ETDRS letters) from baseline to month 6 was +10.9 with TCZ 4 mg/kg and +5.5 with TCZ 8 mg/kg; vitreous haze decreased by one step or more in 73% and 81% of patients, respectively, and the mean change in foveal thickness was -131.5 μm and -38.91 μm, respectively, suggesting that TCZ was effective for improving visual acuity and reducing vitreous haze and foveal thickness in patients with noninfective uveitis (55). Furthermore, several case reports and case series have reported the ameliorative effects of TCZ in idiopathic or Behçet disease–related uveitis (56, 57).

Desensitization for kidney transplantation

Alloimmune responses to transplants are responsible for most allograft failures, and IL-6 is involved in this process (58). A phase 1/2 trial of TCZ was performed in 10 patients who had been unresponsive to a desensitization method with intravenous immunoglobulin (IVIg) plus rituximab (59). Patients received IVIg 2 g/kg on days 0 and 30 and TCZ 8 mg/kg on day 15, then TCZ monthly for 6 months. If they received a transplant, patients received IVIg once and TCZ monthly for 6 months. Five of 10 patients received transplants. Six-month protocol biopsies showed no antibody-mediated rejection, and donor-specific antibody strength and titers were reduced with TCZ treatment. Subsequently, 36 renal transplant patients with chronic active antibody-specific antibodies and transplant glomerulopathy who did not respond to IVIg plus rituximab, with or without plasma exchange, received TCZ with monthly infusions (60). TCZ treatment led to significant reductions in donor-specific antibodies and stabilization of renal function at 2 years. Furthermore, patients treated with TCZ showed good long-term outcomes compared with historical published treatments, with graft survival and patient survival rates of 80% and 91%, respectively, at 6 years. These findings suggest that IL-6 blockade may represent a novel strategy to stabilize allograft function.

Other potential indications

Cytokine storm

Cytokine storm is a potentially fatal immune reaction with highly elevated levels of various cytokines caused by highly activated immune cells, such as T cells, macrophages, and/or histiocytes in response to infection, tissue injury, or autoimmune reaction. Cytokine release syndrome (CRS) entails severe acute complications and is induced by non-physiological T-cell activation after T-cell–engaging therapies such as chimeric antigen receptor–modified T cells (CAR-T) and a CD19/CD3 bispecific antibody (blinatumomab) (61). IL-6, IL-8, IL-10, monocyte chemoattractant protein-1 (MCP-1), and interferon-γ levels are markedly elevated in patients with CRS. A single administration of TCZ in a patient with CRS treated with CAR-T therapy dramatically and unexpectedly resolved the condition (62). In a subsequent study, 30 patients with acute lymphoblastic leukemia treated with CAR-T therapy had mild to severe CRS, with the latter accounting for 27% of the patients (63). In the patients with severe CRS, serum IL-6 levels were >1000 pg/mL. TCZ treatment resulted in rapid and pronounced improvement in the patients’ severe clinical manifestations in 1 to 3 days. These findings suggest that IL-6 blockade may constitute a novel therapeutic strategy for emergent fatal complications mediated by a cytokine storm, including SIRS, macrophage activation syndrome, and hemophagocytic lymphohistiocytosis in addition to CRS. SIRS comprises a variety of diseases, among them infection-induced SIRS (sepsis) and noninfectious SIRS, such as trauma, burns, acute pancreatitis, heat stroke, crush syndrome, blast injury, and GVHD. Indeed, IL-6 is an excellent biomarker of severity and a prognostic indicator of outcome for patients with sepsis and noninfectious SIRS (64). Given that the affinity of IL-6 to the soluble IL-6 receptor is about 1 nanomolar and the resultant complex binds with an affinity of 10 picomolar to gp130, highly elevated levels of IL-6 can activate various cells, particularly vascular endothelial cells, resulting in further secretion of IL-6, IL-8, and MCP-1. Thus, as seen in CRS managed with T cell–engaging therapy, IL-6 blockade may become a novel therapeutic approach for a wide variety of acute, severe, systemic inflammatory diseases manifesting as a cytokine storm, though future clinical studies are essential to verify this possibility (64).


IL-6 blockade therapy was pioneered by the development of TCZ, which is used for the treatment of patients with RA, sJIA, pJIA, GCA, and Castleman’s disease. Further research will inform on the role of TCZ in various, as yet intractable, diseases, including systemic sclerosis, polymyalgia rheumatica, Graves’ ophthalmopathy, GVHD, uveitis, allograft rejection, and cytokine storm (Fig. 3). Results of ongoing clinical trials or further clinical evaluations will be essential to achieve the realization of TCZ therapy.

TCZ for the treatment of various diseases. The diseases approved for the use of TCZ are shown on the blue arrow. Diseases in ongoing or completed phase 2/3 clinical trials are shown on the red arrow. TCZ is approved for the treatment of rheumatoid arthritis, systemic and polyarticular juvenile idiopathic arthritis, Castleman’s disease, and giant cell arteritis. Phase 2/3 trials for ankylosing spondylitis failed to show effectiveness of TCZ, whereas results from phase 2 trials for systemic sclerosis, polymyalgia rheumatica, GVHD, and desensitization of kidney transplantation are promising. Reports of off-label use of TCZ suggest that it is expected to constitute a novel therapeutic strategy for a wide range of diseases, shown in the box. AML = acute myelogenous leukemia; B-CLL = B-cell chronic lymphocytic leukemia; GCA = giant cell arteritis; GVHD = graft-versus-host disease; HIV = human immunodeficiency virus; IgG4 = immunoglobulin G4; IL-6 = interleukin 6; LNs = lymph nodes; pJIA = polyarticular juvenile idiopathic arthritis; RA = rheumatoid arthritis; RS3PE = remitting seronegative symmetrical synovitis with pitting edema; sJIA = systemic juvenile idiopathic arthritis; TCZ = tocilizumab.


Medical writing and editorial assistance was provided by Renee Gordon, PhD, and Sara Duggan, PhD, of ApotheCom (Yardley, PA, USA).


Financial support: Medical writing and editorial assistance was funded by F. Hoffmann-La Roche Ltd.
Conflict of interest: TT is an employee of the Department of Clinical Application of Biologics of Osaka University Graduate School of Medicine, which is an endowment department supported by an unrestricted grant from Chugai Pharmaceutical Co., Ltd. MN has received payment for lectures, including services for speaker bureaus, from Chugai Pharmaceutical Co., Ltd.
  • 1. An Z Monoclonal antibodies - a proven and rapidly expanding therapeutic modality for human diseases. Protein Cell 2010 1 4 319 330 Google Scholar
  • 2. Akira S Taga T Kishimoto T Interleukin-6 in biology and medicine. Adv Immunol 1993 54 1 78 Google Scholar
  • 3. Kishimoto T Interleukin-6: from basic science to medicine40 years in immunology. Annu Rev Immunol 2005 23 1 1 21 Google Scholar
  • 4. Tanaka T Narazaki M Masuda K Kishimoto T Regulation of IL-6 in immunity and diseases. Adv Exp Med Biol 2016 941 79 88 Google Scholar
  • 5. Tanaka T Narazaki M Kishimoto T Therapeutic targeting of the interleukin-6 receptor. Annu Rev Pharmacol Toxicol 2012 52 1 199 219 Google Scholar
  • 6. Tanaka T Narazaki M Kishimoto T IL-6 in inflammation, immunity, and disease. Cold Spring Harb Perspect Biol 2014 6 10 a016295. Google Scholar
  • 7. Sato K Tsuchiya M Saldanha J et al. Reshaping a human antibody to inhibit the interleukin 6-dependent tumor cell growth. Cancer Res 1993 53 4 851 856 Google Scholar
  • 8. Hirano T Yasukawa K Harada H et al. Complementary DNA for a novel human interleukin (BSF-2) that induces B lymphocytes to produce immunoglobulin. Nature 1986 324 6092 73 76 Google Scholar
  • 9. Hirano T Taga T Yasukawa K et al. 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 1 228 231 Google Scholar
  • 10. Hirano T Matsuda T Turner M et al. Excessive production of interleukin 6/B cell stimulatory factor-2 in rheumatoid arthritis. Eur J Immunol 1988 18 11 1797 1801 Google Scholar
  • 11. Yoshizaki K Matsuda T Nishimoto N et al. Pathogenic significance of interleukin-6 (IL-6/BSF-2) in Castlemans disease. Blood 1989 74 4 1360 1367 Google Scholar
  • 12. Ohshima S Saeki Y Mima T et al. Interleukin 6 plays a key role in the development of antigen-induced arthritis. Proc Natl Acad Sci USA 1998 95 14 8222 8226 Google Scholar
  • 13. Kitaba S Murota H Terao M et al. Blockade of interleukin-6 receptor alleviates disease in mouse model of scleroderma. Am J Pathol 2012 180 1 165 176 Google Scholar
  • 14. Tanaka T Kishimoto T The biology and medical implications of interleukin-6. Cancer Immunol Res 2014 2 4 288 294 Google Scholar
  • 15. Narazaki M Tanaka T Kishimoto T The role and therapeutic targeting of IL-6 in rheumatoid arthritis. Expert Rev Clin Immunol 2017 13 6 535 551 Google Scholar
  • 16. Choy EHS Isenberg DA Garrood T et al. Therapeutic benefit of blocking interleukin-6 activity with an anti-interleukin-6 receptor monoclonal antibody in rheumatoid arthritis: a randomized, double-blind, placebo-controlled, dose-escalation trial. Arthritis Rheum 2002 46 12 3143 3150 Google Scholar
  • 17. Nishimoto N Yoshizaki K Miyasaka N et al. Treatment of rheumatoid arthritis with humanized anti-interleukin-6 receptor antibody: a multicenter, double-blind, placebo-controlled trial. Arthritis Rheum 2004 50 6 1761 1769 Google Scholar
  • 18. Schiff MH Kremer JM Jahreis A Vernon E Isaacs JD van Vollenhoven RF Integrated safety in tocilizumab clinical trials. Arthritis Res Ther 2011 13 5 R141. Google Scholar
  • 19. Koike T Harigai M Inokuma S et al. Effectiveness and safety of tocilizumab: postmarketing surveillance of 7901 patients with rheumatoid arthritis in Japan. J Rheumatol 2014 41 1 15 23 Google Scholar
  • 20. Smolen JS Landewé R Bijlsma J et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update. Ann Rheum Dis 2017 76 6 960 977 Google Scholar
  • 21. Jones G Sebba A Gu J et al. Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis: the AMBITION study. Ann Rheum Dis 2010 69 1 88 96 Google Scholar
  • 22. Tanaka T Hishitani Y Ogata A Monoclonal antibodies in rheumatoid arthritis: comparative effectiveness of tocilizumab with tumor necrosis factor inhibitors. Biologics 2014 8 141 153 Google Scholar
  • 23. Bykerk VP Östör AJ Alvaro-Gracia J et al. Comparison of tocilizumab as monotherapy or with add-on disease-modifying antirheumatic drugs in patients with rheumatoid arthritis and inadequate responses to previous treatments: an open-label study close to clinical practice. Clin Rheumatol 2015 34 3 563 571 Google Scholar
  • 24. Dougados M Kissel K Sheeran T et al. Adding tocilizumab or switching to tocilizumab monotherapy in methotrexate inadequate responders: 24-week symptomatic and structural results of a 2-year randomised controlled strategy trial in rheumatoid arthritis (ACT-RAY). Ann Rheum Dis 2013 72 1 43 50 Google Scholar
  • 25. Gabay C Emery P van Vollenhoven R et al; ADACTA Study Investigators. Tocilizumab monotherapy versus adalimumab monotherapy for treatment of rheumatoid arthritis (ADACTA): a randomised, double-blind, controlled phase 4 trial. Lancet 2013 381 9877 1541 1550 Google Scholar
  • 26. Ravelli A Martini A Juvenile idiopathic arthritis. Lancet 2007 369 9563 767 778 Google Scholar
  • 27. Yokota S Imagawa T Mori M et al. Efficacy and safety of tocilizumab in patients with systemic-onset juvenile idiopathic arthritis: a randomised, double-blind, placebo-controlled, withdrawal phase III trial. Lancet 2008 371 9617 998 1006 Google Scholar
  • 28. De Benedetti F Brunner HI Ruperto N et al. PRINTO; PRCSG. Randomized trial of tocilizumab in systemic juvenile idiopathic arthritis. N Engl J Med 2012 367 25 2385 2395 Google Scholar
  • 29. Imagawa T Yokota S Mori M et al. Safety and efficacy of tocilizumab, an anti-IL-6-receptor monoclonal antibody, in patients with polyarticular-course juvenile idiopathic arthritis. Mod Rheumatol 2012 22 1 109 115 Google Scholar
  • 30. Brunner HI Ruperto N Zuber Z et al. Paediatric Rheumatology International Trials Organisation PRINTO; Pediatric Rheumatology Collaborative Study Group (PRCSG). Efficacy and safety of tocilizumab in patients with polyarticular-course juvenile idiopathic arthritis: results from a phase 3, randomised, double-blind withdrawal trial. Ann Rheum Dis 2015 74 6 1110 1117 Google Scholar
  • 31. Nishimoto N Sasai M Shima Y et al. Improvement in Castlemans disease by humanized anti-interleukin-6 receptor antibody therapy. Blood 2000 95 1 56 61 Google Scholar
  • 32. Nishimoto N Kanakura Y Aozasa K et al. Humanized anti-interleukin-6 receptor antibody treatment of multicentric Castleman disease. Blood 2005 106 8 2627 2632 Google Scholar
  • 33. Salvarani C Pipitone N Versari A Hunder GG Clinical features of polymyalgia rheumatica and giant cell arteritis. Nat Rev Rheumatol 2012 8 9 509 521 Google Scholar
  • 34. Roche NE Fulbright JW Wagner AD Hunder GG Goronzy JJ Weyand CM Correlation of interleukin-6 production and disease activity in polymyalgia rheumatica and giant cell arteritis. Arthritis Rheum 1993 36 9 1286 1294 Google Scholar
  • 35. Seitz M Reichenbach S Bonel HM Adler S Wermelinger F Villiger PM Rapid induction of remission in large vessel vasculitis by IL-6 blockade. A case series. Swiss Med Wkly 2011 141 w13156. Google Scholar
  • 36. Villiger PM Adler S Kuchen S et al. Tocilizumab for induction and maintenance of remission in giant cell arteritis: a phase 2, randomised, double-blind, placebo-controlled trial. Lancet 2016 387 10031 1921 1927 Google Scholar
  • 37. Stone JH Tuckwell K Dimonaco S et al. Trial of tocilizumab in giant-cell arteritis. N Engl J Med 2017 377 4 317 328 Google Scholar
  • 38. Actemra (tocilizumab) injection for intravenous infusion, injection for subcutaneous use. San Francisco, CA: Genentech, Inc. 2017. Available from: Accessed September 6, 2017. Google Scholar
  • 39. Sieper J Poddubnyy D Axial spondyloarthritis. Lancet 2017 390 10089 73 84 Google Scholar
  • 40. Brulhart L Nissen MJ Chevallier P Gabay C Tocilizumab in a patient with ankylosing spondylitis and Crohns disease refractory to TNF antagonists. Joint Bone Spine 2010 77 6 625 626 Google Scholar
  • 41. Henes JC Horger M Guenaydin I Kanz L Koetter I Mixed response to tocilizumab for ankylosing spondylitis. Ann Rheum Dis 2010 69 12 2217 2218 Google Scholar
  • 42. Sieper J Porter-Brown B Thompson L Harari O Dougados M Assessment of short-term symptomatic efficacy of tocilizumab in ankylosing spondylitis: results of randomised, placebo-controlled trials. Ann Rheum Dis 2014 73 1 95 100 Google Scholar
  • 43. Sieper J Braun J Kay J et al. Sarilumab for the treatment of ankylosing spondylitis: results of a Phase II, randomised, double-blind, placebo-controlled study (ALIGN). Ann Rheum Dis 2015 74 6 1051 1057 Google Scholar
  • 44. Wiersinga WM Advances in treatment of active, moderate-to-severe Graves ophthalmopathy. Lancet Diabetes Endocrinol 2017 5 2 134 142 Google Scholar
  • 45. Pérez-Moreiras JV Alvarez-López A Gómez EC Treatment of active corticosteroid-resistant graves orbitopathy. Ophthal Plast Reconstr Surg 2014 30 2 162 167 Google Scholar
  • 46. Devauchelle-Pensec V Berthelot JM Cornec D et al. Efficacy of first-line tocilizumab therapy in early polymyalgia rheumatica: a prospective longitudinal study. Ann Rheum Dis 2016 75 8 1506 1510 Google Scholar
  • 47. Lally L Forbess L Hatzis C Spiera R Brief Report: a prospective open-label phase IIa trial of tocilizumab in the treatment of polymyalgia rheumatica. Arthritis Rheum (Munch) 2016 68 10 2550 2554 Google Scholar
  • 48. Blazar BR Murphy WJ Abedi M Advances in graft-versus-host disease biology and therapy. Nat Rev Immunol 2012 12 6 443 458 Google Scholar
  • 49. Kennedy GA Varelias A Vuckovic S et al. Addition of interleukin-6 inhibition with tocilizumab to standard graft-versus-host disease prophylaxis after allogeneic stem-cell transplantation: a phase 1/2 trial. Lancet Oncol 2014 15 13 1451 1459 Google Scholar
  • 50. Morton J Hutchins C Durrant S Granulocyte-colony-stimulating factor (G-CSF)-primed allogeneic bone marrow: significantly less graft-versus-host disease and comparable engraftment to G-CSF-mobilized peripheral blood stem cells. Blood 2001 98 12 3186 3191 Google Scholar
  • 51. Roddy JV Haverkos BM McBride A et al. Tocilizumab for steroid refractory acute graft-versus-host disease. Leuk Lymphoma 2016 57 1 81 85 Google Scholar
  • 52. Caspi RR A look at autoimmunity and inflammation in the eye. J Clin Invest 2010 120 9 3073 3083 Google Scholar
  • 53. Tappeiner C Mesquida M Adán A et al. Evidence for tocilizumab as a treatment option in refractory uveitis associated with juvenile idiopathic arthritis. J Rheumatol 2016 43 12 2183 2188 Google Scholar
  • 54. Calvo-Río V Santos-Gómez M Calvo I et al. Anti-interleukin-6 receptor tocilizumab for severe juvenile idiopathic arthritis-associated uveitis refractory to anti-tumor necrosis factor therapy: a multicenter study of twenty-five patients. Arthritis Rheum (Munch) 2017 69 3 668 675 Google Scholar
  • 55. Sepah YJ Sadiq MA Hassan M et al. Interim analyses of study of safety and bioactivity of tocilizumab in patients with non-infectious UVEITIS: STOP-UVEITIS. Invest Ophthalmol Vis Sci 2016 57 12 6124 Available from: = 2557672&resultClick = 1. Accessed September 6, 2017. Google Scholar
  • 56. Hirano T Ohguro N Hohki S et al. A case of Behçets disease treated with a humanized anti-interleukin-6 receptor antibody, tocilizumab. Mod Rheumatol 2012 22 2 298 302 Google Scholar
  • 57. Muselier A Bielefeld P Bidot S Vinit J Besancenot JF Bron A Efficacy of tocilizumab in two patients with anti-TNF-alpha refractory uveitis. Ocul Immunol Inflamm 2011 19 5 382 383 Google Scholar
  • 58. Jordan SC Choi J Kim I et al. Interleukin-6, a cytokine critical to mediation of inflammation, autoimmunity and allograft rejection: therapeutic implications of IL-6 receptor blockade. Transplantation 2017 101 1 32 44 Google Scholar
  • 59. Vo AA Choi J Kim I et al. A phase I/II trial of the interleukin-6 receptor-specific humanized monoclonal (tocilizumab) + intravenous immunoglobulin in difficult to desensitize patients. Transplantation 2015 99 11 2356 2363 Google Scholar
  • 60. Choi J Aubert O Vo A et al. Assessment of tocilizumab (anti-interleukin-6 receptor monoclonal) as a potential treatment for chronic antibody-mediated rejection and transplant glomerulopathy in HLA-sensitized renal allograft recipients. Am J Transplant 2017 17 9 2381 2389 Google Scholar
  • 61. Maude SL Barrett D Teachey DT Grupp SA Managing cytokine release syndrome associated with novel T cell-engaging therapies. Cancer J 2014 20 2 119 122 Google Scholar
  • 62. Grupp SA Kalos M Barrett D et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med 2013 368 16 1509 1518 Google Scholar
  • 63. Maude SL Frey N Shaw PA et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med 2014 371 16 1507 1517 Google Scholar
  • 64. Tanaka T Narazaki M Kishimoto T Immunotherapeutic implications of IL-6 blockade for cytokine storm. Immunotherapy 2016 8 8 959 970 Google Scholar



  • Osaka Prefectural Hospital Organization, Osaka Habikino Medical Center, Osaka - Japan
  • Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Osaka - Japan

Article usage statistics

The blue line displays unique views in the time frame indicated.
The yellow line displays unique downloads.
Views and downloads are counted only once per session.

No supplementary material is available for this article.