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

Abstract

BackgroundTreatment 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.ObjectivesTo evaluate whether interleukin 6 (IL-6) inhibition with tocilizumab (TCZ) interferes with joint destruction beyond its effects on disease activity.MethodsA random 90% sample of data from the (The Tocilizumab Safety and the Prevention of Structural Joint Damage Study) LITHEtrial 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).ResultsBaseline 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).ConclusionsIL-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.

Cytokines as Therapeutic Targets in Rheumatoid Arthritis and Other Inflammatory Diseases

“…In addition to clinical efficacy, several studies have demonstrated the ability of tocilizumab to reduce radiographic progression (Nishimoto et al, 2007;Kremer et al, 2011;Dougados et al, 2013). Radiographic progression is reduced with tocilizumab even in the presence of persistent synovitis or high disease activity (Smolen et al, 2012), a feature also described with anti-TNF agents and rituximab (Landewe et al, 2006;Emery et al, 2009;Smolen et al, 2009;Aletaha et al, 2013).…”

Evaluation of Serum Interleukin‐6 Level as a Surrogate Marker of Synovial Inflammation and as a Factor of Structural Progression in Early Rheumatoid Arthritis: Results From a French National Multicenter Cohort

“…Ultrasound (US) and magnetic resonance imaging (MRI) evaluations are more sensitive techniques to identify synovitis than clinical examination and are better than conventional radiography to detect bone erosion (3). The exact position of US in RA management has been recently clarified (4).…”

Sarilumab Plus Methotrexate in Patients With Active Rheumatoid Arthritis and Inadequate Response to Methotrexate: Results of a Phase III Study

“…Elevated levels of IL-6 have been reported in the serum and synovial fluid of patients with RA and have been found to correlate with inflammation and disease activity (8)(9)(10). A humanized inhibitor of IL-6 activity (11,12) has been shown to be effective in RA, administered either as monotherapy or in combination with methotrexate (MTX) and other nonbiologic DMARDs (13)(14)(15)(16)(17)(18). Sarilumab is a fully human anti-IL-6Ra monoclonal antibody that binds membranebound and soluble human IL-6R with high affinity, thereby blocking IL-6-mediated cis-and trans-signaling, with no evidence of complement-dependent or antibodydependent cell-mediated cytotoxicity (19).…”