Interleukin-6 blockade in ocular inflammatory diseases

Abstract

Interleukin-6 (IL-6) is a key cytokine featuring redundancy and pleiotropic activity. It plays a central role in host defence against environmental stress such as infection and injury. Dysregulated, persistent interleukin (IL)-6 production has been implicated in the development of various autoimmune, chronic inflammatory diseases and even cancers. Significant elevation of IL-6 has been found in ocular fluids derived from refractory/chronic uveitis patients. In experimental autoimmune uveitis models with IL-6 knock-out mice, IL-6 has shown to be essential for inducing inflammation. IL-6 blockade can suppress acute T helper type 17 (Th17) responses via its differentiation and, importantly, can ameliorate chronic inflammation. Tocilizumab, a recombinant humanized anti-IL-6 receptor antibody, has been shown to be effective in several autoimmune diseases, including uveitis. Herein, we discuss the basic biology of IL-6 and its role in development of autoimmune conditions, focusing particularly on non-infectious uveitis. It also provides an overview of efficacy and safety of tocilizumab therapy for ocular inflammatory diseases.

Biology of interleukin (IL)-6

IL-6 is a key cytokine featuring redundancy and pleiotropic activity [1]. It plays a central role in host defence against environmental stress such as infection and injury. Under physiological conditions, IL-6 is barely detectable in serum (1–5 pg/ml), although its levels can increase more than 100 000-fold during early phases of inflammation [1,2]. In infectious inflammation, IL-6 is promptly produced by monocytes and macrophages after the stimulation of Toll-like receptors (TLRs) with distinct pathogen-associated molecular patterns (PAMPs) [2]. In non-infectious inflammations such as burn or traumatic injury, damage-associated molecular patterns (DAMPs) from damaged or dying cells stimulate TLRs to produce IL-6 [3]. This acute IL-6 expression is key in host defence by stimulating various cell populations. When acting on hepatocytes, IL-6 strongly induces a wide variety of acute-phase proteins such as C-reactive protein (CRP), serum amyloid A, fibrinogen and haptoglobin, among others [4]. CRP is a good biomarker of inflammation and is used as such in clinical laboratory tests. Importantly, its expression depends principally upon IL-6 [5]. In lymphocytes, IL-6 induces B cell differentiation into immunoglobulin-producing cells [1]. IL-6, together with transforming growth factor (TGF)-β, preferentially promotes differentiation of IL-17-producing T helper cells (Th17) that play a crucial role in the induction of autoimmune tissue injury [6,7]. However, IL-6 inhibits TGF-β-induced regulatory T cell (T_reg) differentiation [8]. The resultant Th17/T_reg imbalance leads to breakage of immunological tolerance and is of pathological importance for the development of various autoimmune and chronic inflammatory diseases [9]. IL-6 also induces naive/rested CD8⁺ T cells to be activated and acquire cytotoxic function [10].

Aside from its role in host defence, IL-6 has many other important biological functions. In haematopoiesis, IL-6 induces maturation of megakaryocytes into platelets and activation of stem cells [11]. In bone marrow, IL-6 activates osteoclasts leading to bone resorption and osteoporosis [12]. Production of IL-6 in inflamed tissues induces excess vascular endothelial growth factor (VEGF), which causes increased angiogenesis and vascular permeability [13]. The access of IL-6 into dermal keratinocytes promotes their proliferation and dermal fibroblast collagen production, which may contribute to autoimmune diseases such as psoriasis, systemic sclerosis and thyroid eye disease [14–17]. Table 1 summarizes the principal IL-6 biological functions.

Table 1.

Biological functions of interleukin (IL)-6.

Immune response and inflammation	Induction of final maturation of B cells into antibody-producing cells
	Activation and proliferation of T cells
	Induction of cytotoxic T cell differentiation
	IL-6 together with TGF-β preferentially promotes differentiation of Th17 cells
	IL-6 inhibits TGF-β-induced regulatory T cell (Treg) differentiation
	IL-6 induces excess of VEGF, which causes increased angiogenesis and vascular permeability
Haematopoiesis	Induction of haematopoietic stem cells from G0 to G1
	Maturation of megakaryocytes into platelets
	In bone marrow, IL-6 activates osteoclasts leading to bone resorption and osteoporosis
Stimulation of cell growth	Induction of the growth of myeloma/plasmocytoma cells
	Induction of mesangial cell growth
Inhibition of cell growth	Growth inhibition of myeloid leukaemia cells and breast carcinoma cell lines
Neural system	Induction of neural cell (PC12) differentiation
Acute-phase reaction proteins	IL-6 could induce a variety of acute phase proteins such as fibrinogen, alpha-1-anti-chymotrypsin, alpha-1-acid glycoprotein, and haptoglobin
	IL-6 induces serum A amyloid, C-reactive protein and alpha-1-anti-trypsin in human hepatocytes
	Serum levels of IL-6 correlate well with that of C-reactive protein and fever in patients with severe burns

TGF-β = transforming growth factor β; VEGF = vascular endothelial growth factor.

IL-6 signalling

IL-6 triggers signal transduction after binding to the IL-6 receptor (IL-6R) [18]. There are two forms of the IL-6R, the transmembrane receptor protein and the soluble form (sIL6-R). After binding of IL-6 to transmembrane IL-6R, the resultant IL-6/IL-6R complex associates with gp130 protein [18]. The activated IL-6R complex forms a hexameric structure consisting of two molecules each of IL-6, IL-6R and gp130 (so-called classical signalling). Expression of the transmembrane-spanning gp130 is found in almost all organs, including heart, kidney, spleen, liver, lung, placenta and brain. In contrast, cellular distribution of the cognate IL-6R is limited, and its expression is confined predominantly to hepatocytes and leucocyte subpopulations (monocytes, neutrophils, T cells and B cells). In addition to signalling through the membrane-bound IL-6R, IL-6 can provide signalling to cells lacking IL-6R through binding to the soluble IL-6R (sIL-6R) and association with the gp130 pathway, known as trans-signalling of IL-6. The IL-6R (sIL-6R) has been purified from human serum and urine. This soluble receptor binds IL-6 with an affinity similar to that of the cognate receptor (0·5–2 nM) and prolongs its plasma half-life. More importantly, the (sIL-6R/IL-6) complex is capable of activating cells via interaction with membrane-bound gp130. This feature makes the (sIL-6R/IL-6) complex an agonist for cell types that, although they express gp130, would not inherently respond to IL-6 alone. Hence, the sIL-6R has the ability to widen the repertoire of cell types that are responsive to IL-6. This is in contrast to the function of most soluble cytokine receptors that bind their ligand and antagonize cellular signalling by preventing the interaction of the cytokine with their respective plasma membrane-bound cognate receptor [1,2,18].

Pathological role of IL-6 in development of autoimmune diseases

Dysregulated, persistent IL-6 production has been implicated in the development of various autoimmune, chronic inflammatory diseases and even cancers [1,2,16,17]. The reason(s) why such dysregulated, continuous IL-6 production is induced remains to be clarified. Elucidation of the mechanisms underlying persistent IL-6 synthesis in such different diseases is of particular importance to tailor treatment. Such investigations are now in progress. Indeed, numerous animal models of diseases have disclosed the pathological role of IL-6 in disease development, including mouse models of rheumatoid arthritis [19], systemic lupus erythematosus [20], systemic sclerosis [21], Castleman's disease [22], experimental autoimmune uveoretinitis (EAU) [23,24] and experimental autoimmune encephalomyelitis [25]. In those animal models, IL-6 blockade by means of gene knock-out mice or administration of anti-IL-6 or anti-IL-6R antibody can suppress such disease development either preventively or therapeutically [19,25]. Table 2 summarizes clinical diseases in which a dysregulated IL-6/IL-6R can be found.

Table 2.

Systemic conditions where interleukin (IL)-6 plays a role in the disease pathogenesis.

Inflammatory disorders

Rheumathoid chronic arthritis

Juvenile arthritis

Adult Still disease

Castleman disease

Grave's disease

Osteoarthritis

Inflammatory bowel disease

Interstitial lung disease

Systemic sclerosis

Intraocular inflammation

Relapsing polychondritis

Ankylosing spondylitis

Sepsis

Asthma

Endometriosis

Neurological disorders

Multiple sclerosis

Alzheimer's disease

Schizophrenia

Depression and mania

Psychological stress

Cancers

Breast cancer

Prostate cancer

Metastatic renal cell carcinoma

Multiple myeloma

Colorectal cancer

Infections

HIV

HTLV-1

Cerebral malaria

Meningococcal infection

Urinary tract infection

Modified from: Simon A. Therapeutic strategies for clinical blockade of IL-6/gp 130 signaling. J Clin Invest 2011; 121:3375–83.

Targeting IL-6

Tocilizumab [Actemra outside the European Union (EU) and RoActemra inside the EU] is a humanized monoclonal antibody, developed by grafting the complementary-determining regions of mouse anti-human IL-6R antibody onto human IgG1.

Tocilizumab blocks IL-6-mediated signalling by binding to both soluble and transmembrane IL-6 receptors [17]. In this way it reduces IL-6 pleiotropic actions such as T cell activation, T helper type 17 (Th17) differentiation (and the resultant Th17/T_reg imbalance), antibody secretion and hepatic acute-phase protein production (CRP) [26,27]. Indeed, CRP level is a hallmark for checking whether or not IL-6 activity is blocked completely in vivo [17].

Tocilizumab: current and future indications

Tocilizumab has been approved by the Food and Drug Administration (FDA) for use in patients with rheumatoid arthritis who have active disease, despite having been treated with one or more disease-modifying anti-rheumatic drugs (also called DMARDs), including other biological response modifiers such as tumour necrosis factor (TNF) inhibitors or methotrexate [28]. It is also approved for use in children more than 2 years of age with the systemic form of juvenile idiopathic arthritis (JIA) [29], and for Castleman disease in Japan and India [30]. Recent pilot studies have suggested that tocilizumab may have broad application for other chronic, immune-mediated diseases such as systemic lupus erythematosus [31], systemic sclerosis [32], polymyositis [33], systemic vasculitis [34], Behçet's disease [35,36], Still's disease [37], Crohn's disease [38], relapsing polychondritis [39], polymyalgia rheumatica [40] and uveitis and its associated ocular complications [41–44]. It has been suggested that IL-6 blockade may also be useful as a treatment of organ-specific immune diseases such as acquired haemophilia A [45], autoimmune haemolytic anaemia [46], amyloid A amyloidosis [47] and graft-versus-host disease [48], as well as other non-organ specific autoimmune conditions [49,50]. Finally, it is expected that long-term treatment with tocilizumab may offer protection against the progression of atherosclerosis, as it was observed that during tocilizumab treatment of patients with rheumatoid arthritis, HbA1c levels and insulin resistance indices improved [51]. Table 3 shows the approved and off-label uses of tocilizumab. Table 4 shows the concluded and ongoing clinical trials on efficacy of tocilizumab in diseases other than rheumatoid arthritis.

Table 3.

Approved and off-label uses of tocilizumab.

Approved indication	Region where approved
Rheumatoid arthritis	> 100 countries worldwide
Castleman's disease	Japan, India
Systemic juvenile idiopathic arthritis	Japan, India, United States, Europe

Off-label applications	Type of scientific evidence
Systemic lupus erythematosus	Case series
Systemic sclerosis	Case series
Polymyositis	Case series
Vasculitis syndrome	Case report and series
Spondyloarthritis	Case reports
Crohn's disease	Case reports
Relapsing polychondritis	Case reports
Acquired haemophilia A	Case reports
Autoimmune haemolytic anaemia	Case reports
Adult-onset Still's disease	Case reports and series
Amyloid A amyloidosis	Case reports
Polymyalgia rheumatica	Case reports and series
Remitting seronegative, symmetrical synovitis with pitting oedema	Case reports
Behçet's disease	Case reports and series
Uveitis	Case reports and series
Graft-versus-host disease	Case reports and series
Tumour necrosis factor associated periodic syndrome	Case reports
Spondyloarthritis	Case reports
Pulmonary arterial hypertension	Case reports
Atopic dermatitis	Case reports
Sciatica	Case reports

Table 4.

Concluded and ongoing trials on efficacy of tocilizumab in diseases other than rheumatoid arthritis (RA).

Targeted diseases	Trial identifier
ClinicalTrials.gov (United States)
Adult-onset Still's disease	NCT01002781
Relapsing polychondritis	NCT01041248
Type II diabetes, obesity	NCT01073826
Grave's ophthalmopathy	NCT01297699
Cardiovascular disease in RA	NCT01331837
Polymialgia rheumatica	NCT01396317
Giant cell arteritis	NCT01450137
	NCT01910038
Acute graft versus host disease	NCT01475162
Non-ST elevation myocardial infarction	NCT01491074
Systemic sclerosis	NCT01532869
Transplant rates in highly sensitized patients awaiting kidney transplantation	NCT01594424
Schizophrenia	NCT01696929
Non-infectious posterior, intermediate or panuveitis	NCT01717170
Castleman's disease	NCT01441063
Juvenile idiopathic arthritis	NCT01734382
Ovarian cancer	NCT01637532
Fibrous dysplasia of bone	NCT01791842
Primary Sjögren's syndrome	NCT01782235
European Union Clinical Trials Registry
Ankylosing spondylitis	2009-017488-40, 2009-017443-34
Cardiovascular disease in RA	2010-020065-24
Grave's ophthalmopathy	2010-023841-31
Systemic sclerosis	2011-001460-22
Erdheim Chester disease	2012-003151-11
Polyarticular-course juvenile idiopathic arthritis	2011-001097-25
Giant cell arteritis	2011-006022-25
UMIN-CTR clinical trial (Japan)
ANCA-associated vasculitis	UMIN00002892
Systemic sclerosis	UMIN00005550
Neuromyelitis optica	UMIN00005889
Chronic glomerulonephritis	UMIN00006080
Colorectal cancer	UMIN00007493
Takayasu arteritis	UMIN00007845

ANCA = anti-neutrophil cytoplasmic antibodies; UMIN-CTR = University Hospital Medical Information Network Clinical Trials Registry.

IL-6 blockade in ocular inflammatory diseases

Suppressing the immune response with steroids or with conventional immunosuppressive drugs forms the mainstay of treatment of non-infectious uveitis. This achieves disease control and prevents vision-threatening complications in most patients, but a significant proportion of patients remain unresponsive to conventional immunosuppression and have a diminished quality of life. During the last two decades, advances in the understanding of the pathogenesis of autoimmune disease, as well as improved biotechnology, have enabled the development of a new class of drugs called biologicals, which provide selective targeting of the immune mediators of the inflammation cascade.

Different studies have found significant elevation of IL-6 in ocular fluids derived from refractory/chronic uveitis patients and animal models [52,53]. Experimental autoimmune uveitis (EAU) is a rodent model of human uveoretinitis, and recent studies have revealed that highly proinflammatory IL-17-producing Th17 cells play a pivotal role in the development of EAU, human uveitis and other experimental autoimmune diseases [54]. Several lines of evidence have shown that autoreactive Th1 and Th17 cells mediate EAU, and IL-6 is recognized as an essential factor in inducing the early phase of Th17 differentiation from naive T cells in combination with TGF-β [55]. Th17 cells further produce IL-17, IL-6 and TNF-α, and these cytokines perpetuate inflammation by stimulating fibroblasts, endothelial cells and macrophages to produce chemokines, with the subsequent recruitment of more neutrophils and macrophages to the retina, which results in tissue damage and chronic inflammation [55,56]. Several studies have demonstrated that invalidation of the IL-6 gene or blockage of the IL-6 molecule inhibited the development of uveitis by suppression of the Th17 response [57]. Yoshimura et al. [58] studied the role of Th17 cells on EAU by using IL-6-and IL-23-deficient mice, and confirmed that EAU development was reduced in these animals. They found that systemic administration of recombinant anti-IL-6-receptor antibody ameliorates EAU interfering with antigen-specific Th17 differentiation/expansion, and concluded that IL-6 blockade can suppress acute Th17 responses and ameliorate chronic/refractory intraocular inflammation.

Conversely, TGF-β alone promotes naive T cells to differentiate into T_reg, which are considered immunosuppressive helper T cells [57]. Thus, Th17 and T_reg cells are distinct subsets of helper T cells, and IL-6 signalling promotes Th17 cells and inhibits T_reg cell differentiation. Haruta et al. [24] found that the IL-6 signalling blockade not only inhibited Th17 cell differentiation, but also promoted antigen-specific T_reg cells which, in turn, suppressed the inflammatory effects of antigen-specific Th1 cells. Thus, the inhibitory effect of the IL-6 blockade in the development of EAU is associated with suppression of the induction of both Th1 and Th17 cells and their dominant proinflammatory effects in this disease [24].

To date, reports on tocilizumab efficacy in uveitis remain sparse. Adán et al. [59] reported the efficacy of tocilizumab in eight eyes of five uveitis patients with cystoid macular oedema (CME) refractory to conventional immunosuppressive drugs and anti-TNF therapy. After 6 months of tocilizumab infusions CME resolved in all eyes. These authors suggest that early use of tocilizumab in refractory uveitis patients could lead to better functional results than when indicated after long-term disease duration. Similarly, Muselier et al. [44] found that tocilizumab was effective in two uveitis patients diagnosed with Birdshot chorioretinopathy and idiopathic granulomatous panuveitis who were refractory to conventional immunosuppressive drugs. Tocilizumab induced uveitis control in both patients and also macular oedema resolution in one case. Tappeiner et al. [43] reported that tocilizumab was effective for the treatment of ocular inflammation in two out of three patients suffering uveitis associated with juvenile idiopathic arthritis refractory to several disease-modifying anti-rheumatic drugs and anti-TNF agents. Efficacy of tocilizumab in patients with uveitis accompanied with Behçet's and Castelman disease has also been reported [35,60,61]. A case has been reported regarding tocilizumab efficacy for Cogan's syndrome with iritis and aortitis [62]. Recently, Kieseier et al. reported a case of neuromyelitis optica refractory to diverse immunosuppressants and other biologicals that responded well to tocilizumab therapy [63].

To date, there are two ongoing Phase I–II clinical trials to study tocilizumab therapy for uveitis: the STOP-UVEITIS Study (NCT01717170), which is a study of the safety, tolerability and bioactivity of tocilizumab on patients with non-infectious uveitis, and another study about tocilizumab in the management of juvenile idiopathic arthritis-associated uveitis (NCT01603355).

Another ocular inflammatory disease, the aetiology of which was shown to be associated with IL-6 action, is thyroid eye disease. This condition is caused by crossed immunological activity between thyroid gland and orbital tissue antigens, due to the expression of thyroid-stimulating hormone receptor by orbital fibroblasts. Collectively, orbital fibroblasts are unique, in the sense that they not only manifest an intense inflammatory response but are also involved actively in the process by secreting various cytokines and chemoattractants. It has been observed that the incited fibroblasts produce a dysregulated, increased secretion of IL-6 that induces orbital adipogenesis. Mature adipocytes formation stimulated by IL-6 augments the expression of thyrotrophin receptor, and contributes significantly to the maintenance of the disease process [15,64]. Moreover, Slowik et al. [65] proved that in patients with thyroid eye disease the IL-6 and soluble IL-6 receptor levels were significantly higher than in normal controls. They also showed that after efficient treatment soluble IL-6 receptor levels decreased in thyroid eye disease patients. Due to these findings, tocilizumab was pointed out as a potential treatment for thyroid eye disease resistant to corticosteroid treatment. To date, there is one ongoing Phase III study on tocilizumab efficacy in thyroid eye disease refractory to corticosteroids (NCT01297699). The purpose of this study is to investigate tocilizumab administration in patients with moderate to severe or sight-threatening thyroid eye disease without response to treatment with corticoid intravenous pulses. Currently, these patients only have surgery as a therapeutic alternative.

Dosing

Tocilizumab is given as intravenous infusions every 4 weeks. Although some patients may improve during the weeks after the first infusion, it may take as long as 6–12 weeks to see results. For children with systemic JIA, dosing can be as frequent as every 2 weeks. Tocilizumab dose is adjusted according to the patient's weight. The starting dose in adults is 4 mg tocilizumab/kg of body weight, but the dose can be increased to 8 mg/kg if needed to control arthritis. In children, the dose is 8 mg/kg in those weighing more than 30 kg (66 pounds) and 12 mg/kg in those weighing less than 30 kg. Outside the United States, tocilizumab is licensed to be used at 8 mg/kg every 4 weeks for patients with rheumatoid arthritis. Tocilizumab should not be given in combination with another biological agent [66].

Safety

In clinical trials, adverse events associated with tocilizumab have included infections, infusion reactions and gastrointestinal perforation [67,68].

Laboratory abnormalities have included hyperlipidaemia, transaminaemia and neutropaenia. Special attention should also be paid to a possible increase in the risk of neurological disorders and malignancies although, to date, clinical trials have not shown a statistically significant relation between tocilizumab and those diseases. There is no sufficient evidence on safety of tocilizumab in infants and pregnant women [69].

Infections

Reactions to tocilizumab infusions, including fever and chills, can occur, but these are rare. Perhaps the most concerning potential side effect with regular therapy is the risk of infection, as it is with most biological therapies. The primary concern is for common bacterial infections. Reactivation of tuberculosis (TB) has not been seen frequently during tocilizumab treatment, compared with that during anti-TNF biological treatment. However, it still remains a concern, and screening for prior exposure to TB is recommended before starting tocilizumab therapy. Screening and monitoring for TB and other important but unusual infections, including fungal infections, is important during treatment with tocilizumab. Overall, the rate of infection seen in clinical trials with tocilizumab was similar to that seen with other biological drugs used in the treatment of rheumatoid arthritis [68]. In a recent meta-analysis of six randomized, controlled trials of tocilizumab (4 mg/kg and 8 mg/kg) revised by Campbell et al. [69] the risk of infection was significantly higher than in placebo or control groups [odds ratio (OR) 1·30, 95% confidence interval (CI) 1·07–1·58]. Although opportunistic infections in patients treated with tocilizumab are rare, cases reported in the literature include ophthalmic herpes zoster virus infection, allergic bronochopulmonary aspergillosis and cytomegalovirus-associated pneumonitis [68]. In patients treated with tocilizumab, active infections should be discarded before the treatment is commenced. It is recommended to perform hepatitis B serology and tuberculin skin before starting the treatment. Patients diagnosed with latent TB should undergo prophylaxis treatment before starting tocilizumab infusions. In the case of developing a severe active infection once treatment with tocilizumab has been initiated, therapy should be interrupted. No live or live attenuated vaccines should be administered simultaneously with tocilizumab treatment, as its clinical safety has not yet been established [69].

Gastrointestinal complications

Twenty-six cases of gastrointestinal perforation have been reported among clinical trials on tocilizumab with an incidence of 2·8 cases per 1000 patients per year (with no cases reported in control groups) [69]. Therefore, tocilizumab should be used with precautions in patients with history of intestinal ulceration or diverticulitis. In the case of signs or symptoms of abdominal pain, gastrointestinal haemorrhage, fever or changes in bowel movements habits prompt evaluation should be performed in order to discard gastrointestinal disease and a risk of concomitant perforation [69].

Active hepatic disease and insufficiency

Tocilizumab – especially when associated with methotrexate – may cause an increase in hepatic transaminase levels. Although no increased risk of clinical hepatitis was noted, the initiation of treatment with tocilizumab should be evaluated carefully in patients with hepatic transaminase levels 1·5-fold higher than normal serum values, and is not recommended at all when the serum levels are fivefold higher than the normal range [69]. The transaminase values should be checked every 4–8 weeks in the first 6 months of treatment with tocilizumab and then every 12 weeks. If the transaminase levels are threefold higher than normal values, the treatment should be interrupted. If the levels fall to below the mentioned limits, the treatment may be reinitiated with a dose between 4 and 8 mg/kg [69].

Haematological alterations

The initiation of treatment with tocilizumab should be evaluated carefully in patients with serum neutrophils and low platelet counts. Treatment is not recommended when absolute neutrophils and platelets levels are below 500/μl and 50·000/ml, respectively. The neutrophils and platelets count should be performed every 4–8 weeks at commencement of the treatment. The risk of neutropenia is higher in patients treated previously with anti-TNF agents [69].

Serum lipid alterations

The serum lipid levels should be evaluated 4–8 weeks after starting treatment with tocilizumab, and if needed hyperlipidaemia should be treated.

Neurological disorders

Currently, the risk of central demyelinating process in patients treated with tocilizumab is not known. Therefore, the clinicians should pay special attention to possible signs of a demyelinating disease in patients receiving tocilizumab [69].

Malignant tumours

There was no increased risk of malignancies noted in clinical trials, although the risk : benefit ratio should be evaluated personally in patients with history of cancers [69].

Use in pregnancy, children and elderly people

Tocilizumab is not recommended in children, due to limited data on its safety and efficacy in this group of patients. There are no sufficient data on the use of tocilizumab in pregnant women. Studies on animals have shown an increase in miscarriage and embryo–fetal death with high doses. Women in the fertile age group should be using effective contraceptive methods to prevent pregnancy during the treatment period and up to 6 months after its termination. There are no studies on tocilizumab excretion in human or animal milk, and therefore the treatment is not recommended in breastfeeding women [70].

Use in renal and hepatic insufficiency

Dose adjustment is not needed in patients with mild renal insufficiency. To date, there are no studies on use of tocilizumab in patients with moderate to severe renal failure or hepatic insufficiency [69].

Interactions with other drugs

In-vitro studies have shown that expression of hepatic CYP450 enzymes is suppressed by IL-6. This inhibition may be reverted in patients treated with tocilizumab due to the action of IL-6 suppression. This can affect the metabolism of drugs metabolized by CYP450, 3A4, 1A2, 2C9 or 2C19 enzymes such as simvastatin, atorvastatin, calcium antagonists, theophylline, acenocoumarol, phenytoin, cyclosporin and benzodiazepines. It may be necessary to increase the dose of the aforementioned drugs to maintain their therapeutic effect [69].

Cost of treatment with tocilizumab

The price of 80 and 200 mg tocilizumab vials is €139·6 and €349, respectively. The habitual dosage of tocilizumab is 8 mg/kg every 4 weeks. The annual cost of treatment is €11·726 for a single patient with an average weight of 67 kg. Additionally, the costs of intravenous administration must be summed, which require 13 days of hospital ambulatory admission per patient.

Discussion

IL-6 is a pleiotropic cytokine that is produced by a variety of cell types during infection, trauma and immunological challenge. IL-6 promotes inflammatory events through the expansion and activation of T cells, differentiation of B cells and the induction of acute-phase reactants by the liver. IL-6 increases vascular permeability early in acute disease, leading to vascular leakage and an influx of cytokines and inflammatory cells. In contrast, IL-6 also performs a protective role during disease and counteracts the manifestation of certain inflammatory responses. IL-6 contributes to the host defence against acute environmental stress. IL-6, as an important mediator of the acute-phase response, induces fever in response to infections. Aside from its role in host defence, IL-6 has many other important biological functions. For example, it is highly produced by smooth muscle and functions as a myokine. IL-6, in addition to work on T and B cells and hepatocytes, also stimulates production of neutrophils and cytotoxic T cells. IL-6 is also involved in the homeostasis of the immune response at a later stage, and can remain elevated during remission.

Dysregulated, persistent IL-6 production has been demonstrated to play a pathological role in various autoimmune and chronic inflammatory diseases.

Serum and intraocular levels of IL-6 have been shown to be elevated significantly in patients with active non-infectious uveitis disease and decrease during remission, playing an active role in the modulation of inflammation in chronic disease. In addition, it probably plays a key role in uveitis and in the pathogenesis of uveitis-related macular oedema. Targeting IL-6 is thus a rational approach for the treatment of non-infectious uveitis. Furthermore, inhibition of the IL-6 receptor diminishes Th17 responses and ameliorates experimental autoimmune uveitis. Anti-IL-6 receptor antibodies have proved to be effective in experimental models of autoimmune arthritis, encephalomyelitis and also uveitis. Tocilizumab is a fully humanized antibody that binds both to soluble and membrane bound IL-6 receptors. It has been approved for the treatment of rheumatoid arthritis and JIA, and is currently under investigation in several clinical trials for a wide variety of autoimmune conditions, including uveitis and thyroid eye disease. Although preliminary reports are scarce, results seem to be very promising and further studies on IL-6 inhibition in uveitis are warranted.

Disclosure

All authors report no disclosures.