Rheumatoid Arthritis - IL6-directed Therapies
Several studies have been presented at prior ACR meetings using the drug tocilizumab, a monoclonal antibody that binds to the IL-6 receptor, inhibiting the activity of the pleiotropic proinflammatory cytokine IL6. Two recent studies, AMBITION using tocilizumab as monotherapy and RADIATE in TNF failures recently published (Emery P, Keystone E, Tony HP, Cantagrel A, van Vollenhoven R, Sanchez A, Alecock E, Lee J, Kremer J. IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals: results from a 24-week multicentre randomised placebo-controlled trial. Ann Rheum Dis. 2008 Nov;67(11):1516-23.), were reviewed from the EULAR 2008 meeting.
At ACR 2008, one new study was presented as a late-breaking abstract that evaluated the effect of tociluzimab in preventing structural damage. A prior study from Japan in patients on low doses of methotrexate has also reported a beneficial effect of tocilizumab in slowing radiographic progression (1).
Abstract LB14: Tocilizumab Inhibits Structural Joint Damage in Rheumatoid Arthritis Patients with an Inadequate Response to Methotrexate: The LITHE Study
Authors:
JM Kremer, RM Fleischmann, A-M Halland, J Brzezicki, T Woodworth, E Fisheleva, E Alecock, R Burgos-Vargas
Purpose:
The efficacy of tocilizumab (TCZ) plus methotrexate (MTX) in preventing structural joint damage in MTX-inadequate responders (IR) patients and improving patient function was investigated in a planned 12-month analysis of a 2-year study.
Methods:
This was a Phase 3, randomized, double-blind, placebo-controlled trial. MTX-IR patients with moderate-to-severe active RA received MTX once weekly (10-25 mg oral or parenterally) plus TCZ 4 or 8 mg/kg, or placebo (control) IV every 4 weeks for 1 year. A switch to blinded rescue treatment was available at Weeks 16 and 28, if required. Primary endpoints included changes from baseline in Genant-modified Sharp score (linear extrapolation) and the area under the curve (AUC) in the Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 52.
Results:
The analysis population (ITT) included 1190 randomized patients (TCZ 8 mg/kg n=398, TCZ 4 mg/kg n=399, control n=393). Mean joint erosion, joint space narrowing, and total Genant-modified Sharp scores showed significant inhibition of radiographic progression from baseline in both TCZ groups compared with control (Table). The mean change from baseline in HAQ-DI significantly decreased in TCZ-treated patients compared with control. DAS28 remission rates were significantly higher in the TCZ 8 mg/kg group (47%) compared with control (8%), and low disease activity rates were significantly higher with TCZ 8 mg/kg (64%) and 4 mg/kg (45%) groups compared with control (19%). The safety profile was consistent with previous studies and did not change from 6 to 12 months. The most common serious adverse events were serious infections (TCZ 8 mg/kg 3.0%, TCZ 4 mg/kg 2.5%, control 1.5%). Medically significant infusion events were reported in the TCZ 4 mg/kg group only (4 anaphylactic reaction, 2 hypersensitivity).
|
TCZ 8 mg/kg + MTX |
TCZ 4 mg/kg + MTX |
Control + MTX |
Total Genant-modified Sharp Score--Baseline, mean (SD) |
29.1 (28.5) |
29.5 (28.7) |
28.8 (32.4) |
Total Genant-modified Sharp score-- Change from baseline, mean (SD), |
0.3 (1.3)* |
0.3 (1.5)* |
1.1 (3.0) |
Erosion Score Change from baseline, mean (SD) |
0.2 (0.9)* |
0.2 (0.9)* |
0.7 (1.9) |
Joint Space Narrowing Score Change from baseline, mean (SD) |
0.1 (0.6)** |
0.1 (0.7)** |
0.4 (1.7) |
No progression in total Genant-modified Sharp Score |
85% |
81% |
67% |
No progression erosion |
87% |
83% |
70% |
No progression JSN |
91% |
91% |
85% |
*p < 0.0001, **p < 0.01 vs control |
|||
Conclusion:
TCZ therapy significantly inhibited the progression of structural joint damage, improved function (HAQ-DI), and the signs and symptoms of RA significantly more than control, with an acceptable safety profile. More patients treated with TCZ + MTX achieved DAS28 remission compared to MTX alone.
Editorial Comment:
This study demonstrates that IL6 inhibition using tocilizumab in combination with methotrexate inhibits structural progression better than methotrexate alone, with effects seen on both joint space narrowing and erosions. As with other studies evaluating radiographic progression with other biological agents, most patients (even those treated with methotrexate alone) did not show progression over the course of the study, albeit fewer in those treated with both doses of TCZ in combination with MTX. One would anticipate future analyses to evaluate coupling/uncoupling between radiographic and clinical endpoints with this mechanism of action. While these group level results are important in establishing IL6 inhibition as a MOA associated with disease-modification, we remain without good markers to help us determine who among our patients with RA are at highest risk for progression at an individual patient level.
Editor: Clifton Bingham, III, M.D.
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