Open label phase II trial of single, ascending doses of MRA in Caucasian children with severe systemic juvenile idiopathic arthritis: proof of principle of the efficacy of IL-6 receptor blockade in this type of arthritis and demonstration of prolonged clinical improvement

Juvenile idiopathic arthritis (JIA) is a heterogeneous group of persistent arthritides of unknown origin occurring before 16 years of age [1]. One subset, systemic JIA (sJIA), is defined by the additional presence of debilitating fever, evanescent rash, hepatosplenomegaly, lymphadenopathy and serositis. Severe complications include osteoporosis, growth retardation, systemic amyloidosis and macrophage activation syndrome and are observed more frequently in patients with long-standing disease than in other JIA subsets. Patients with sJIA have a range of other prominent features, including marked elevation of erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), leucocytosis with high neutrophil counts and thrombocytosis [2]. Ferritin concentrations are high and correlate with systemic disease activity [2, 3]. Anaemia is microcytic and characterised by a marked defect in iron supply for erythropoiesis [4]. Virtually all children with sJIA are negative for antinuclear antibodies and rheumatoid factor [2, 4]. The mean duration of active disease is five to six years in Caucasians, with disabling polyarthritis becoming prominent in up to 50% of patients, while the systemic features usually regress within three to four years [5]. Twenty three percent of these patients have poor outcomes as adults [6].

The polyarthritis of sJIA is often extraordinarily resistant to treatment. Steroids are used to control systemic symptoms, but do not alter long-term prognosis and are associated with severe side effects such as osteoporosis and growth failure, to which patients with sJIA appear particularly susceptible. Methotrexate, effective in other forms of paediatric polyarthritis, appears less effective in sJIA [7]. Etanercept has been shown to have limited efficacy, with a possible increased risk of macrophage activation syndrome [8, 9]. There is no strong evidence of definite improvements with the use of cyclosporine, azathioprine, or cyclophosphamide [2]. Chlorambucil has been used to treat amyloidosis with an improvement in survival by inducing remission [2, 10]: but, as with cyclophosphamide, there are concerns over its long-term use due to side effects [10]. Pilot data on anakinra suggest blocking IL-1 can be effective [11, 12], but further placebo controlled/comparative trials are necessary. Moreover, as anakinra is a daily subcutaneous injection, which is well known to cause some discomfort and pain, it may not be widely tolerated by children. There is, therefore, a need for a more effective treatment for sJIA, based on an understanding of the underlying pathophysiology of the disease process that may alleviate the systemic features of sJIA, as well as prevent progression of joint damage.

There is a strong body of evidence that IL-6 production is particularly high in sJIA and that this is genetically determined by a variant of the gene encoding IL-6 in a significant proportion of patients [13, 14]. In addition to the increase in serum IL-6, it has been found that there is a significant increase in soluble IL-6 receptor (sIL-6R) concentrations [15]. The large quantities of serum IL-6 present in IL-6/sIL-6R complexes have been found to be of particular biological relevance in vivo [16]. IL-6 levels correlate with disease activity, fever pattern and platelet counts, indicating an important role for IL-6 in the pathogenesis of sJIA [17‐19]. Components of the IL-6 signalling pathway are, therefore, rational targets for the treatment of sJIA.

MRA (tocilizumab) is a humanized anti-human IL-6 receptor antibody of kappa-IgG₁ subclass, developed collaboratively by Osaka University and Chugai Pharmaceutical Company Ltd (Japan). MRA is humanized by the grafting of complementarity determining regions of a mouse anti-human IL-6 receptor monoclonal antibody onto human IgG₁ by recombinant DNA technology. It has been shown to compete for both the membrane-bound and soluble forms of human IL-6 receptor, thus inhibiting the binding of IL-6 to its receptor and its pro-inflammatory activity [20]. As IL-6 is postulated to play a pivotal role in the pathogenesis and disease activity of sJIA, MRA is being developed in this indication. An anti-IL-6 receptor monoclonal antibody, such as MRA, may have an important role to play, not only in relieving the patient of the systemic features of the disease, but also in preventing the progression of joint damage and reducing extra-articular complications of the disease.

The primary objectives of this trial were to determine the safety and tolerability of single, ascending doses of MRA in children with sJIA and to determine the pharmacokinetic profile of a range of single intravenous doses of MRA in children with sJIA, as recommended by the Medicines and Healthcare products Regulatory Agency, UK. The secondary objectives were to evaluate the efficacy of the range of single intravenous doses and to explore the potential for an antigenic response.

Eighteen children (white, Middle East and Asian Caucasians), diagnosed with sJIA and having active disease for at least three months while receiving greater than 0.2 mg/kg/day of prednisolone or its equivalent, were enrolled from the UK and France. Diagnosis was defined using the International League of Associations for Rheumatology criteria [1]. Ethics committee approval and written informed consent were obtained. All patients had at least one active systemic feature, one active joint and the doses of nonsteroidal anti-inflammatory drugs and steroids were unchanged for at least two weeks before the infusion of MRA. Concurrent methotrexate therapy was allowed to a maximum of 20 mg/m² weekly, stabilized for at least four weeks prior to administration of the study medication. Patients receiving other disease-modifying anti-rheumatic drugs went through a washout period (at least five half-lives of the drug) before inclusion. Children with a history of macrophage activation syndrome were excluded.

Patients were divided equally within two age ranges (2 to 5 and 6 to 18 years) to receive 2, 4 or 8 mg/kg of MRA by intravenous infusion. A safety review was conducted before progression to the next dose range. Clinical assessments were carried out before infusion, at 48 h post-infusion and weekly thereafter. The duration of follow up for the 2, 4 and 8 mg/kg groups was 4, 6 and 8 weeks, respectively. Clinical assessment was performed using the JIA core set criteria (parent global visual analogue scale (VAS), physician's global VAS, number of active joints, number of joints with limited range, the childhood health assessment questionnaire (CHAQ) and ESR) and the definition of improvement as defined by international consensus (3 or more core set criteria improved by 30% and no more than 1 core set criterion worsened by 30%) [21]. Improvements of 50% and 70% were defined as above, substituting 30 with 50 and 70, respectively. Systemic features were recorded, as previously described [7]. The Systemic Feature Score included an assessment of fever, rash, cervical lymphadenopathy, axillary lymphadenopathy, inguinal lymphadenopathy, hepatomegaly, splenomegaly and clinical evidence of serositis (pericarditis, pleuritis or peritonitis). In addition to any occurrence of fever at the assessment visit, the parents/caregivers were asked about the presence of fever in the 24 h period preceding the assessment visit as part of the Systemic Feature Score. The overall Systemic Feature Score could range from 0 to 8 and is the sum of the eight individual features, which were scored as either absent (0 points) or present (1 point).

Laboratory measurements included full blood count, liver (gamma-glutamyl transpeptodase (GGT), aspartate aminotransferace (AST), alanine aminotransferase (ALT), bilirubin) and kidney (urea, serum creatinine, albumin) function tests, serum CRP and ESR. These were performed in the accredited routine laboratories of the participating hospitals. Levels of serum MRA, IL-6, sIL-6R and anti-MRA antibodies were screened during the follow up period by contract laboratories of the sponsor. The sponsor of the trial was Chugai Pharma Europe Ltd. Due to the exploratory nature of the study, no formal sample size calculations were performed. The sample size was based on clinical judgment and practical considerations. No formal statistical analysis of any data was performed.

Single dosing with MRA in these 18 European Caucasian children does not appear to cause any drug related serious infections during the infusion and follow-up period. A report of multiple dosing in a group of Japanese children with a similar disease did not reveal serious infections as a significant side effect over one year [22].

An increased incidence of infection, including serious life threatening infections, has been observed with other monoclonal antibodies active against components of the immune system. In this study, infections were generally mild in intensity and the incidence of infections did not increase at the higher dose levels. Only the herpes simplex mouth ulcer during a disease flare three weeks post infusion was considered to be possibly related to MRA, although herpes simplex mouth ulcer has been reported previously during a disease flare of this patient. Of the nine infections reported, six were associated with a lymphocyte count below the lower limit of normal; however, lymphopenia was present in the majority of patients following dosing and nine patients with low lymphocyte counts did not have a corresponding infection. Further studies will need to address the longer term safety of MRA in a larger patient population, as this pilot study was to prove the safety of the therapy in a single dose setting.

MRA appears to be dramatically effective clinically in children with sJIA following a single infusion. Eleven patients achieved a clinical improvement – a 30% improvement in the composite score for disease activity in JIA (as defined by Giannini et al. [21]) – with maximum effect seen at one week for all the dose ranges. Eight and three patients, respectively, achieved 50% and 70% improvements in the composite score of disease activity mostly in the higher dose groups. The maximum duration of benefit was within four to eight weeks after dosing with all efficacy endpoints. The serum levels of the biological markers of the acute phase response (CRP and ESR) also showed dramatic decrease from baseline; many decreased 10-fold and, in a few patients, the serum CRP normalised. The prolonged effect of a single dose supports the hypothesis that IL-6 is a key cytokine in the upregulation of genes crucial in the inflammation processes of sJIA. This effect is in sharp contrast to the experience with single infusions of 30 mg/kg of intravenous methyl prednisolone that, given previously in these children, all resulted in transient and smaller clinical and laboratory improvements, lasting a maximum of 48 h before return to baseline. Response to MRA also compares well with anti-tumour necrosis factor therapy. Two infusions of 10 mg/kg of infliximab one week apart in a 16 year old sJIA patient led to some beneficial effect on the fever for only five days and no change in the joint symptoms [23]. Subsequent surveys of response rates to anti-tumour necrosis factor therapy have also shown that, at the most, there is significant improvement in only 30% [8, 9]. Blockade of IL-6 signalling within inflammatory and immune cells could lead to secondary changes that may account for the prolonged well-being experienced by many patients in this small open trial. Another possible explanation of this prolonged clinical improvement in symptoms is that MRA may remain longer in the extravascular compartment; this possibility will need to be explored. Further controlled studies will need to be done, with multiple dosing, to assess the short and longer term efficacy and safety of MRA.

A recent report by Yokota et al. [22] using clinical and laboratory parameters similar to this study showed a similar and marked response in Japanese patients with sJIA to multiple dosing with MRA. The disease known as sJIA in Japan is very similar to that reported in Caucasians, but not enough is known about the phenotypes and genotypes to make a direct extrapolation of drug response. So this study provides further evidence in Caucasians that IL-6 is a key cytokine in this disease and blockade of its signalling by a monoclonal antibody produces dramatic and prolonged clinical and laboratory improvements.

MRA given as a single intravenous infusion to severe sJIA patients was tolerated over the 2 to 8 mg/kg dose range studied. There was no evidence of dose-limiting toxicity and no dose-limiting safety issues were observed at any of the dose levels administered during the study.

Evidence of efficacy was observed at all dose levels studied, both in clinical and biological markers. The efficacy response appeared to be more limited at the lowest dose level (2 mg/kg). The overall clinical response appeared to continue after MRA was undetectable in serum and gradually decreased over a four to six week period following the infusion of MRA. These promising results with MRA in sJIA, a disease with an unmet medical need, will be further developed in phase III trials.