ReviewInhibition of IL6 in rheumatoid arthritis and juvenile idiopathic arthritis
Introduction
Rheumatoid Arthritis (RA) is a chronic, systemic and progressive autoimmune disease. Untreated, RA causes significant deformity, dysfunction and destruction of affected joints, as well as accelerated mortality and substantial morbidity. RA most commonly arises in the population between the 4th and 6th decades of life. However, as there is at present no cure for this condition affected patients bear the disease into their elderly years. Autoimmune arthritis also affects patients at the other end of life. Juvenile idiopathic arthritis (JIA) affects children up to approximately 16 years of age, and often persists throughout life. The profound destructive potential of RA and JIA can be observed even in the earliest stage of the disease. This emphasizes the need for the discovery of effective treatments to suppress inflammation and to prevent further damage. The most commonly used drugs to treat RA are the so-called disease modifying antirheumatic drugs (DMARDs), predominantly methotrexate (MTX), which is the most frequently prescribed DMARD. For a minority of patients, treatment with DMARDs may be sufficient. Inhibitors of the key inflammatory cytokine tumor necrosis factor (TNF) have brought significant relief for a number of patients, and have elevated the goals of treatment, such that remission is now considered to be the ultimate aim of therapy. Especially considering these new lofty goals, a number of patients do not respond adequately to available treatments. Thus there is still a need for further analysis of the underlying immunopathology of RA and JIA in order to detect new possible targets for the therapy. Recent studies have suggested that the cytokine interleukin-6 (IL-6) may play an important role in both RA and JIA. There is keen interest towards development of biological agents that antagonize the effect of this cytokine.
Section snippets
Tocilizumab
To date, most of the data regarding the potential effect of IL-6 inhibition in RA and JIA comes from studies of tocilizumab. Tocilizumab is a humanized monoclonal antibody specific for the IL-6 receptor (IL-6R). Although relatively few cell types constitutively express the IL-6R, soluble forms of IL-6R can bind to its signaling partner, gp-130, which is widely expressed. Thus, by this trans-signaling, IL-6 is able to activate a wide variety of cell types by binding to IL-6R tocilizumab prevents
Clinical trials of tocilizumab in rheumatoid arthritis
In a study called OPTION (Tocilizumab Pivotal Trial in Methotrexate Inadequate Responders), the combination of tocilizumab with MTX was explored (Table 1). In this study 623 RA patients with moderate to severe disease despite concomitant MTX were randomized to receive tocilizumab i.v. at doses of 4 mg/kg or 8 mg/kg or placebo [4]. Enrolled patients had a mean disease duration of 7.6 years, a mean DAS28 score of 6.8 and mean swollen and tender joint counts of 20 and 32, respectively. A minority of
Clinical trials in juvenile idiopathic arthritis
In randomized, double-blind, placebo-controlled, withdrawal phase III trial by Yokota and colleagues, 56 children (aged 2–19 years) with disease refractory to conventional treatment were given three doses of tocilizumab 8 mg/kg every 2 weeks during a 6 week open label lead in phase [11] (Table 2). Notably, the patients involved in this study had average disease duration of 4.47 years, CRP level at 5.7 mg/dl and active arthritis in 7 joints on average. This 6 week open label lead in phase was followed
Conclusions
Data from clinical studies suggest that IL-6 might be a good target for immune modulating therapy in several autoimmune systemic inflammatory diseases, including RA and JIA [13], [14], [15]. An inhibitor of IL-6, tocilizumab, has proven effective in these conditions, and is under study in others. In RA, IL-6 inhibition with tocilizumab has resulted in improved signs and symptoms of diseases, improved functional ability and quality of life; treatment also inhibited progression of radiographic
References (15)
- et al.
Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trial
Lancet
(2008) - et al.
Efficacy and safety of tocilizumab in patients with systemic-onset juvenile idiopathic arthritis: a randomized, double blind, placebo-controlled, withdrawal phase III trial
Lancet
(Mar 22 2008) - et al.
Therapy of rheumatoid arthritis by blocking Il-6 signal transduction with humanized anti Il-6 receptor antibody
Springer Semin. Immunopathol.
(1998) - et al.
Toxicity, pharmacokinetics and dose finding study of repetitive treatment with the humanized anti-interleukin-6 receptor antibody MRA in rheumatoid arthritis
J. Rheumatol.
(2003) - et al.
Drugs
(2009) - et al.
il-6 receptor inhibition with tocilizumab reduces disease activity in patients with rheumatoid arthritis with inadequate response to disease-modifying antirheumatic drugs
Arthritis Rheum.
(2008) - et al.
Study of active controlled monotherapy used for rheumatoid arthritis, and IL-6 inhibitor (SAMURAI): evidence of clinical and radiographic benefit from an x-ray reader-blinded randomized controlled trial of tocilizumab
Ann. Rheum. Dis.
(2007)