In the past decade, tocilizumab, an anti interleukin-6 agent, has been successfully developed as a therapeutic agent for the treatment of rheumatoid arthritis and systemic onset juvenile idiopathic arthritis. In addition to countering inflammation, tocilizumab is also known affect B cell as well as T cell function, thus modulating immune function, and impact osteoclasts, as well as vascular endothelial growth factor. As such, its efficacy is currently being explored in a large number of autoiommune conditions including a number of vasculitides, systemic lupus erythematosus, systemic sclerosis, polymyositis, graft versus host disease, relapsing polychondritis, as well as Behcet’s syndrome, spondyloarthropathies, and tumor necrosis factor receptor associated periodic syndrome.
Introduction
In the past decade, tocilizumab, an anti-interleukin-6 (IL-6) agent, has been successfully developed by the Chugai Pharmaceutical Co. Ltd., a subsidiary of Hoffman-LaRoche, as a therapeutic agent for the treatment of rheumatoid arthritis (RA) and systemic onset juvenile idiopathic arthritis (sJIA). The notable effectiveness of this agent in these two conditions, and consideration of its mode of action, has motivated new initiatives in applying this technology to a broad range of inflammatory/autoimmune conditions just in the last 2 years. This review surveys and updates the literature as it applies to the usefulness of tocilizumab in conditions other than RA and sJIA, restricting itself to experience in humans alone.
IL-6 and its receptor
IL-6, a pleiotropic cytokine secreted by T lymphocytes and macrophages, has a major impact on immune regulation, haematopoiesis and inflammation . Its broad action is related to its ubiquitous receptor, IL-6R. This receptor is composed of two units, one with a prominent extracellular domain and a short cytoplasmic domain and the other with an elongated cytoplasmic domain for transducing the IL-6 intracellular signal . A soluble IL-6 receptor (sIL-6R) also exists and the IL-6/sIL-6R complex can bind to cells lacking IL-6R.
In clinical practice, IL-6 is best appreciated for its potent pro-inflammatory action. It induces fever, fatigue and many of the clinical attributes associated with systemic inflammation. Its action on the liver enhances the production of a wide spectrum of acute phase proteins such as C-reactive protein (CRP), serum amyloid protein A (SAA), haptoglobin, fibrinogen and hepcidin, whereas it reduces albumin, transferrin and fibronectin ; its action on the bone marrow results in leucocytosis and thrombocytosis.
Less well known, but described already 25 years ago, is IL-6’s ability to induce B-cell differentiation into antibody-producing B cells, inducing immunoglobulin secretion and promoting autoantibody production. IL-6 acts not only on B-cells, but also on T cells by promoting differentiation of CD4 positive T-helper cells to IL-17-producing T-helper cells (Th17), as well as by differentiating CD8-positive T cells to activate cytotoxic cells .
Additional aspects of IL-6 action have been studied in RA pathogenesis: hypervascularity of the synovial tissue as a result of IL-6 induced increased production of vascular endothelial growth factor (VEGF), and erosions and bone resorption that follow its promotion of osteoclast differentiation and activation .
Considering the substantive role of IL-6 and its receptor in both inflammation as well as immune system dysregulation, as described above, it is compelling to see them as targets for therapeutic intervention in immune mediated inflammatory diseases.
IL-6 and its receptor
IL-6, a pleiotropic cytokine secreted by T lymphocytes and macrophages, has a major impact on immune regulation, haematopoiesis and inflammation . Its broad action is related to its ubiquitous receptor, IL-6R. This receptor is composed of two units, one with a prominent extracellular domain and a short cytoplasmic domain and the other with an elongated cytoplasmic domain for transducing the IL-6 intracellular signal . A soluble IL-6 receptor (sIL-6R) also exists and the IL-6/sIL-6R complex can bind to cells lacking IL-6R.
In clinical practice, IL-6 is best appreciated for its potent pro-inflammatory action. It induces fever, fatigue and many of the clinical attributes associated with systemic inflammation. Its action on the liver enhances the production of a wide spectrum of acute phase proteins such as C-reactive protein (CRP), serum amyloid protein A (SAA), haptoglobin, fibrinogen and hepcidin, whereas it reduces albumin, transferrin and fibronectin ; its action on the bone marrow results in leucocytosis and thrombocytosis.
Less well known, but described already 25 years ago, is IL-6’s ability to induce B-cell differentiation into antibody-producing B cells, inducing immunoglobulin secretion and promoting autoantibody production. IL-6 acts not only on B-cells, but also on T cells by promoting differentiation of CD4 positive T-helper cells to IL-17-producing T-helper cells (Th17), as well as by differentiating CD8-positive T cells to activate cytotoxic cells .
Additional aspects of IL-6 action have been studied in RA pathogenesis: hypervascularity of the synovial tissue as a result of IL-6 induced increased production of vascular endothelial growth factor (VEGF), and erosions and bone resorption that follow its promotion of osteoclast differentiation and activation .
Considering the substantive role of IL-6 and its receptor in both inflammation as well as immune system dysregulation, as described above, it is compelling to see them as targets for therapeutic intervention in immune mediated inflammatory diseases.
Tocilizumab, a humanised anti-IL-6 receptor antibody
Tocilizumab, a humanised anti-IL-6 receptor monoclonal antibody, IgG1 class, was developed in Japan. In several pivotal randomised placebo-controlled trials (e.g., OPTION, RADIATE and AMBITION studies), tocilizumab demonstrated significant efficacy in RA patients naive to methotrexate, methotrexate-inadequate responders, as well as those ‘failing’ an anti-tumour necrosis factor (TNF) agent . Studies conducted in parallel in children with sJIA gave even more dramatic results . In Japan, tocilizumab has been approved as a treatment for RA and sJIA since 2008. In the European Union and the USA, tocilizumab has been approved for RA treatment since 2009 and 2010, respectively.
The role of IL-6 in promoting the inflammatory reaction and its effect on immune regulation is an archetype pattern common to inflammatory and immune-mediated diseases other than RA. For most of these, only limited therapeutic options are available, thus encouraging clinician investigators to explore and extend the utility of tocilizumab in such conditions.
The growing interest in IL-6 blockade for its therapeutic potential in immune-mediated inflammatory disease has led just recently to the first reviews of what has been experimented so far in these disorders .
Amyloidosis
Reactive amyloidosis AA is a complication of chronic inflammatory disease or chronic infections, with amyloid deposits in tissues leading to progressive deterioration of various organs.
Serum amyloid A (SAA) is one of the acute phase proteins produced by the liver with activation of the SAA gene by IL-6 . A recent case of a long-standing RA patient whose course was complicated by amyloidosis AA deposits in the small and large intestines, manifest in dramatic diarrhoea and unresponsive to disease-modifying and remission inducing drugs (DMARDs) and anti-TNF agents, achieved a complete clinical and histologic remission from amyloidosis after only three infusions of tocilizumab .
Similar results were reported in secondary amyloidosis in a case of juvenile idiopathic arthritis . Thus, it seems that IL-6 blockade may be an option for this complication of RA, sJIA and other chronic inflammatory conditions.
Giant cell arteritis and Takayasu arteritis
Giant cell arteritis (GCA) and Takayasu arteritis (TA) are both primary systemic large vessel vasculitides involving the aorta and its branches, frequently dealt with together in the literature though there is a substantial disparity in the mean age at diagnosis between these two condition: GCA occurring in individuals above the age of 50, and typically over the age of 60, while TA is frequently reported in women in their 20s. Both conditions respond to glucocorticoid (GC) treatment but relapse is common after GC tapering and the overall treatment period may extend for years. The data about whether methotrexate has a steroid-sparing effect or efficacy in GCA and TA are limited and controversial . It has been shown that IL-6 plays an important role in the pathogenesis of GCA as well as in TA. Patient follow-up for sustained response/failure to the treatment of TA/GCA includes CRP and erythrocyte sedimentation rate levels which are directly affected by IL-6, and in both diseases, high levels of IL-6 measured directly have been found to be a marker for disease activity . In addition, increased IL-6 messenger RNA (mRNA) expression has been reported in aortic tissues of TA patients .
Use of tocilizumab for GCA and TA has been reported in recent small case series . In a series of seven patients with large cell vasculitis, a complete and prompt remission was achieved after only two infusions of tocilizumab. Half of the GCA group patients were GC dependent. Tocilizumab was well tolerated, exhibiting transient elevated liver enzymes in a few cases.
On the other hand, some emerging evidence indicates that patients with lower inflammatory response (and with lower levels of IL-6) in these vasculitides are prone to develop more ischaemic complications than other patients, since angiogenic activity of IL-6 seems to protect against ischaemia in GCA. . So, further clinical studies are needed to evaluate the efficacy and safety of tocilizumab in GCA and TA patients.
Polymyalgia rheumatica
Polymyalgia rheumatica (PMR) is a syndrome of pain and stiffness of the shoulder and pelvic girdle muscles, with evidence of a systemic inflammatory component, in elderly people. As it shares many features with GCA, PMR is often considered to be a smoldering form of GCA. Again, in this condition, the presence of high levels of IL-6 has been reported . Usually PMR is responsive to small doses of GC over 6–12 months, but 50% of the patients relapse during steroid tapering, so steroid-sparing treatment may required to avoid toxicity from its chronic administration . Only a few cases have been reported, confirming complete response to tocilizumab after only four or five monthly infusions .
ANCA-associated vasculitis/glomerulonephritis
Anti neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, including microscopic polyangiitis, Churg–Strauss vasculitis and granulomatosis with polyangiitis, represents a potentially lethal systemic clinical syndrome involving multiple organ systems, the result of inflammation of medium and small vessels. Its treatment, when vital organs are affected, usually requires remission induction with cyclophosphamide or rituximab.
Some evidence of high levels of IL-6 and TNFα has been found in patients suffering from P-ANCA-associated glomerulonephritis . One case of myeloperoxidase (representing P-ANCA) positive crescentic glomerulonephritis complicating a long course of RA, which completely responded to IL-6 blockade with tocilizumab, after failure of cyclophosphamide and tacrolimus trials, has been reported .
Cryoglobulinemic vasculitis
Cryoglobulinemic vasculitis is a systemic vasculitis affecting small vessels, with the presence of immune complexes whose physical properties are such that they precipitate in the cold. Most cases are related to hepatitis C virus (HCV) infection but may also occur secondary to autoimmune disorders such as systemic lupus erythematosus (SLE), primary Sjogren’s syndrome or RA.
Current treatment is focussed on therapy of the underlying disease, such as with antiviral agents or immunosuppressive drugs, with rituximab effective in resistant cases.
Several studies showed elevated levels of serum IL-6 in HCV and non-HCV mixed cryoglobulinemia . Moreover, B-cell proliferation was enhanced in vitro by adding HCV core protein, which was blocked by adding an IL-6R antibody.
A single case of cryoglobulinemic vasculitis secondary to RA, with moderate CRP elevation, has been reported to have responded well to IL-6 blockade after three infusions of tocilizumab .
Behcet’s syndrome
Behcet’s syndrome is a systemic vasculitis more common to peoples of the eastern Mediterranean basin and Japan and much less common elsewhere, accompanied by oral and genital aphthae and involving several organs (e.g., mucocutanous, eyes, central nervous system (CNS), joints, intestine and vascular thromboses), with only few drugs having been shown – on an any level of evidence, controlled trials or otherwise – to be effective. IL-6 has been found to be elevated in the blood of Behcet’s patients with active disease compared to those in remission or healthy individuals . High IL-6 levels were also measured in the CSF of Behcet patients with aseptic meningitis and parenchymal neuro-Behcet .
Two separate case reports of the efficacy of tocilizumab in complicated Behcet’s have recently been reported .
Relapsing polychondritis
Relapsing polychondritis (RP) is a rare disease, characterised by recurrent inflammation and destruction particularly of fibrous-type cartilage as found in the auricle of the ear, trachea, nose and similar tissues. Although the pathogenesis remains unclear, autoimmune reactions to antigens present in cartilages, such as type II collagen and matrilin, are thought to evoke symptoms. In acute flares, especially with major airway involvement, intensive treatment with corticosteroids, immunosuppressive drugs and biologic modifiers such as anti-TNFα and IL-1 receptor antagonist have been used. Two cases of RP treated with tocilizumab have been published: both exhibited critical airway involvement, refractory to steroid and immunosupressive drugs. Because of a high CRP level, these patients were expected to respond to tocilizumab, and after 9 months of monthly infusions they achieved remission with and steroid tapering .
Polymyositis
Polymyositis (PM), an inflammatory myopathy exhibiting proximal muscle weakness, elevated creatinine phosphokinase (CPK) blood levels and mononuclear cell infiltrate of degenerating/regenerating muscle cells on muscle biopsy, is usually treated by corticosteroids, immunosuppressive drugs or intravenous immunoglobulins, with rituximab recently added as a therapeutic option. IL-6 seems to be implicated in the pathogenesis of PM via several lines of evidence. First, IL-6 production has been found in excess in the peripheral blood and in the involved muscle in this condition . Second, cytotoxic T cells are thought to be involved in muscle fibre damage of PM patients and IL6 reportedly functions as a killer helper factor in the induction of cytotoxic T cells .
Narazaki et al. recently published the cases of two PM patients refractory to steroid and immunosuppressive therapy . These two patients rapidly responded to tocilizumab. After 2 months of treatment, they recovered strength and normalised CPK.
Related posts:
Mixed connective tissue disease: An overview of clinical manifestations, diagnosis and treatment
Undifferentiated CTD: A wide spectrum of autoimmune diseases
Idiopathic inflammatory myopathies
Spondyloarthropathies
Neurologic and other systemic manifestations in FMF: Published and own experience
Psoriatic arthritis
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
