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Tocilizumab in early progressive rheumatoid arthritis: FUNCTION, a randomized controlled trial

Clinical Research 10 min 254

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Created On: 10/10/2019

Tocilizumab in early progressive rheumatoid arthritis: FUNCTION, a randomized controlled trial

In rheumatoid arthritis (RA), timely treatment may provide long-term clinical benefits and radiographic outcomes.

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Key take away

The results of the present study add to the body of evidence showing the efficacy of Tocilizumab as therapy for patients with rheumatoid arthritis across several populations, including patients who respond inadequately to disease-modifying antirheumatic drugs or to anti-TNF agents.

Background

In rheumatoid arthritis (RA), timely treatment may provide long-term clinical benefits and radiographic outcomes. In order to achieve remission or low disease activity in people with severe RA and poor prognostic features, early intensive treatment is the most supported recommendation. The treatment includes the use of traditional disease-modifying antirheumatic drugs (DMARDs) in combination or early initiation of a biological DMARD. Interleukin-6 (IL-6) plays an essential role in pathogenesis of RA. It has been found to be associated with the development of systemic symptoms and local inflammation, pannus formation and bone resorption resulting in joint damage. Raised IL-6 levels are found to be associated with RA disease activity. Tocilizumab (TCZ) is a humanized monoclonal antibody that binds to IL-6 receptor-α and inhibits IL-6–mediated pro-inflammatory signaling. It has demonstrated efficacy and safety in the treatment of patients with RA. Four phase III trials have demonstrated the clinical benefit of combining TCZ with DMARDs in patients with RA with inadequate responses to DMARDs. Three trials have demonstrated the efficacy and safety of TCZ monotherapy in patients with RA.

Rationale behind research:

No study has previously evaluated the efficacy of inhibiting IL-6 signaling in a population consisting exclusively of methotrexate (MTX)-naïve patients with early RA.

Therefore, the present study was conducted to evaluate clinical and radiographic efficacy and safety of TCZ, in combination with MTX and as monotherapy, in early RA

Objective:

To evaluate clinical and radiographic efficacy and safety of TCZ, in combination with MTX and as monotherapy, in early RA

Method

Study outcomes

Primary Outcomes: Proportion of patients achieving remission (DAS28-ESR<2.6) at week 24.
Secondary Outcomes: Assessment of ACR response criteria, radiographic efficacy by the van der Heijde–modified total Sharp score (mTSS), quality of life using the Short Form-36 (SF-36) physical and mental component scores (PCS and MCS) and physical function assessment by the Health Assessment Questionnaire–Disability Index (HAQ-DI) score.

Time Points: Week 24 and 52

Result

Outcomes:

Statistically significant more patients achieved DAS28-ESR remission at weeks 24 and 52 with 8 mg/kg TCZ+MTX than with placebo + MTX (45% vs 15% and 49% vs 20%. Significantly more 8 mg/kg TCZ+placebo than placebo+MTX patients achieved DAS28-ESR remission at week 24 (39% vs 15%).
Significantly greater response rates were also observed for 8 mg/kg TCZ+MTX versus placebo+MTX for ACR20/50/70 responses at weeks 24 and 52. DAS28-ESR remission and ACR response rates indicated improvement in RA signs and symptoms in the 8 mg/kg TCZ +placebo and 4 mg/kg TCZ+MTX groups at weeks 24 and 52.
Compared with placebo +MTX, inhibition of joint damage was significantly greater with 8 mg/kg TCZ+MTX. Up to 83% of patients in all TCZ-treated groups showed no radiographic progression from baseline at weeks 24 and 52, whereas 73% in the placebo + MTX group showed no change.
Significantly greater improvements in mean HAQ-DI scores from baseline to week 52 were observed for 8 mg/kg TCZ +MTX than for placebo+MTX (mean, −0.81 vs −0.64; from placebo+MTX, −0.17 (−0.28 to −0.06). Both 8 mg/kg TCZ+placebo and 4 mg/kg TCZ+MTX showed improvements in HAQ-DI scores from baseline to week 52 (mean (difference from placebo+MTX; 95% CI), −0.67 (−0.03 to −0.15; 0.08) and −0.75 (−0.11 to −0.22; 0.00), respectively) at least equal to those of placebo +MTX (−0.64).
Serious adverse events were similar among treatment groups. Adverse events resulting in premature withdrawal occurred in 20% of patients in the 8 mg/kg TCZ+MTX group.

Conclusion

The present results suggest that TCZ is effective in combination with MTX and as monotherapy for the treatment of patients with early RA. Several other biological agents have proven efficacy in the early RA population. Because of differences in study design, comparisons across trials are difficult. Nevertheless, TCZ appears to demonstrate benefits in patients with early RA (in regard to DAS28 remission, ACR responses and radiographic endpoints), compared with patients treated with MTX alone, that are generally consistent with those observed in previous studies of biological therapies in similar populations.

Although a number of head-to-head comparison studies of different biological agents have recently been published, these have generally been performed in patients who have more established RA and who have responded inadequately to previous DMARDs. It would be of interest to conduct such studies in more treatment-naive patients with early RA. Overall, the results of this study support the effectiveness and clinical benefit of TCZ in MTX-naive patients with early progressive RA. These results add to the body of evidence showing the efficacy of TCZ as therapy for patients with RA across several populations, including patients who respond inadequately to DMARDs or to anti-TNF agents and patients who receive TCZ monotherapy because MTX is contraindicated or cannot be tolerated.

Limitations

The blinded nature precluded dose modification of intravenous TCZ/placebo, MTX dose was limited to 20 mg/week and laboratory abnormalities were managed, according to protocol, by interruption or discontinuation of intravenous dosing. These conditions may not reflect actual clinical practice. Furthermore, it is unclear whether these results are generalizable to patients with early RA that is less severe.