Tocilizumab inhibits progression of joint damage in rheumatoid arthritis irrespective of its anti-inflammatory effects: disassociation of the link between inflammation and destruction

Abstract

Background: Treatment with tumour necrosis factor inhibitors (TNF-i) plus methotrexate (MTX), but not MTX monotherapy alone, inhibits joint damage progression even at higher levels of disease activity. Such disassociation of disease activity and structural damage has not been shown for biological agents other than TNF-i.

Objectives: To evaluate whether interleukin 6 (IL-6) inhibition with tocilizumab (TCZ) interferes with joint destruction beyond its effects on disease activity.

Methods: A random 90% sample of data from the (The Tocilizumab Safety and the Prevention of Structural Joint Damage Study) LITHE trial on active rheumatoid arthritis (RA) despite MTX was used, which compared addition of placebo (n=117) with addition of TCZ (n=414) every 4 weeks. Baseline and 1-year values of clinical and serological variables were correlated with changes to 1 year of the total Genant-modified Sharp score (TGSS) using a Spearman test, and the progression of TGSS, erosion and joint space narrowing (JSN) scores in groups with low and high disease activity were compared for placebo and TCZ (Kruskal-Wallis).

Results: Baseline variables were similar among the groups. Change of TGSS was lower in patients receiving TCZ than placebo (TCZ: 0.29 ± 0.96; placebo: 0.90 ± 1.92; p=0.0007). In patients receiving placebo, the correlation with TGSS change was significant for baseline scores of the simplified disease activity index (SDAI; r=0.18, p=0.047) and swollen joint count 28 (r=0.22, p=0.019), with similar trends for C-reactive protein. Similar correlations were seen for SDAI, clinical disease activity index, disease activity score 28 at 1 year with x-ray change during that year (r=0.26-0.28, p=0.002-0.006). In contrast, none of the baseline or 1-year variables showed significant correlation with x-ray changes in patients receiving TCZ+MTX, suggesting a disassociation of the link between disease activity and damage by TCZ. Finally, for patients in remission or with low disease activity, progression of TGSS, erosion and JSN was similar among treatment groups (TGSS: placebo, 0.4±1.1; TCZ, 0.2 ± 0.7; p=NS), while for patients with moderate or high disease activity placebo-treated patients progression was significantly greater (TGSS: 1.2 ± 2.2 vs 0.4 ± 1.2; p=0.0009).

Conclusions: IL-6 inhibition with TCZ plus MTX retards joint damage progression independently of its impact on disease activity. Similar effects have hitherto been reported only for TNF-i. This indicates that the effects of IL-6 inhibition on progression of joint damage in RA are among the most profound currently attainable.

Figure 1

Mean change from baseline to 1 year of the total Genant-modified Sharp score (TGSS) among patients in low disease activity states (low disease activity or remission) and high disease activity states (moderate or high disease activity) after exposure to placebo (plus methotrexate (MTX)), tocilizumab (TCZ) at 4 mg/kg and/or 8 mg/kg (plus MTX). The differences in TGSS between low and high disease activity status were significant for placebo (p=0.0009), but generally low and not significant for the TCZ-treated group, irrespective of the dose and disease activity status.

Figure 2

Change from baseline to 1 year of radiographic score in (A) patients with normal C-reactive protein (CRP; ≤0.3 mg/dl) at 1 year and (B) patients with raised CRP (>0.3 mg/dl) at 1 year treated with either placebo or tocilizumab (TCZ) at 4 mg/kg or 8 mg/kg.