Tocilizumab, a monoclonal antibody that blocks interleukin-6 receptors, was found effective against severe, persistent systemic juvenile idiopathic arthritis that had been unresponsive to all previous treatments in a phase III clinical trial.

A total of 85% of the 112 study subjects achieved the primary outcome of a juvenile idiopathic arthritis (JIA) ACR 30 response, most of them after receiving only one dose of tocilizumab (Actemra). In addition, control of systemic and laboratory features of JIA was sustained throughout 1-year of follow-up using open-label therapy, "with a progressive decrease in joint involvement and clinically relevant improvement in physical function," Dr. Fabrizio De Benedetti of Ospedale Pediatrico Bambino Gesù, Rome, and his associates reported Dec. 20 in the New England Journal of Medicine.

"Almost one-third of patients had clinically inactive disease at week 52. Glucocorticoid sparing, with maintenance of disease control, was also achieved: 52% of the patients discontinued oral glucocorticoids, with the remaining patients receiving doses in the range associated with minimal toxicity," the investigators wrote.

They performed this multicenter trial in patients with "severe, persistent systemic JIA for whom no effective treatment was available, as reflected by the long duration of disease, large number of active joints, and high frequency of previous exposure to biologic agents at baseline." The ongoing 5-year study is being conducted at 43 medical centers, all members of PRINTO (the Paediatric Rheumatology International Trials Organisation) and PRCSG (the Pediatric Rheumatology Collaborative Study Group).

There were two parts to the study: a randomized double-blind placebo-controlled 12-week first phase, followed by an open-label extension in which all the subjects were eligible for active treatment for up to 5 years.

During the first phase of the study, 75 patients were randomly assigned to receive tocilizumab and 37 to receive placebo intravenously every 2 weeks. Concomitant therapy with stable doses of NSAIDs, oral glucocorticoids, and methotrexate was allowed. The study subjects were aged 2-17 years.

Study subjects were assessed every 2 weeks for the number of joints with active arthritis, the number of joints with limited range of motion, a global assessment of disease activity by a physician, the patient’s or the parent’s assessment of the patient’s overall well-being, and physical function using the Disability Index of the Childhood Health Assessment Questionnaire.

The primary outcome of this first phase was the proportion of patients who achieved a JIA American College of Rheumatology 30 response, defined as an improvement of 30% or more in three or more of the six variables of the ACR core set for JIA, plus no more than one variable worsening by more than 30%, plus the absence of fever.

At week 12, significantly more patients receiving tocilizumab met this primary outcome (85%) than patients receiving placebo (24%). Moreover, significantly more patients receiving tocilizumab achieved a JIA ACR 70 response (71% vs. 8%) or a JIA ACR 90 response (37% vs. 5%).

Systemic symptoms (fever and rash) as well as laboratory abnormalities (anemia, thrombocytosis, and hyperferritinemia) also improved significantly with tocilizumab, Dr. De Benedetti and his colleagues said (N. Engl. J. Med. 2012 Dec. 20 [doi:10.1056/NEJMoa1112802]).

Systemic JIA progressively improved in the 110 patients who continued into the extension phase of the study. At 1 year, 59% of them had a JIA ACR 90 response. Nearly half of the entire group had no actively affected joints, and 28% met the criteria for inactive disease.

A total of 82% of these patients had had moderate or severe functional impairment at baseline, but this percentage dropped to 38% at 1 year. A total of 52% of the cohort discontinued glucocorticoids altogether, and the remainder decreased their dose markedly.

"Cumulatively, 39 serious adverse events (including 18 serious infections) occurred in patients who received tocilizumab. Patients treated with tocilizumab appeared to have a 25% risk of a serious adverse event and an 11% risk of serious infection per year of treatment," the investigators wrote.

Six patients died: three who were receiving tocilizumab and three who had withdrawn from the study. Two died from pulmonary hypertension at 6 and 13 months after withdrawal, while one died from probable macrophage activation syndrome 13 months after withdrawal due to inefficacy. Of the three patients who died while taking the agent, one had suspected tension pneumothorax, one had probable streptococcal sepsis, and one died from trauma in a traffic accident.

The background mortality for patients with systemic JIA "as severe as that in our study population" is not known, the researchers noted.

Transient neutropenia occurred in 19 patients and transient increases in aminotransferase levels occurred in 21.

Data on longer-term safety are still needed, they added.

This study was sponsored and designed by Hoffmann-La Roche, which performed the data processing, data management, statistical analysis, and reporting of the results. Dr. De Benedetti and his associates reported numerous ties to industry sources.

IL-6 inhibitor tocilizumab proved effective in severe, refractory JIA