Protein Degradation Markers in Measuring Response to Tocilizumab Treatment

The LITHE study was conducted to identify responders to treatment with tocilizumab.

Tocilizumab (TCZ) is a humanized anti-human IL-6 receptor antibody of the IgG1 subclass. TCZ is made by grafting the complement-determining regions of a mouse anti-human IL-6 receptor monoclonal antibody onto human IgG1. Tocilizumab competes for both the membrane-bound and soluble forms of the human IL-6 receptor, thereby inhibiting the binding of the native cytokine to its receptor and interfering with the cytokine’s effects.  To investigate whether the measurement of blood-based protein degradation markers could be applied as a diagnostic tool to select patients with a higher likelihood of response to TCZ treatment, Bay-Jensen and colleagues measured serum levels of various biomarkers in patients enrolled in the Tocilizumab Safety and the Prevention of Structural Joint Damage (LITHE) study.

The LITHE study is a phase 3, multicenter, randomized, 3-arm, placebo-controlled, parallel-group trial in patients with moderately to severely active RA and inadequate response to methotrexate. The study consisted of a 1-year, double-blind, placebo-controlled treatment phase followed by a second year of open-label therapy and an optional 3-year open-label extension phase.  A total of 740 patients with RA meeting the inclusion criteria were treated with placebo, or TCZ 4 mg/kg or 8 mg/kg. Serum biomarkers—including osteocalcin (OC), C-reactive protein (CRP), citrullinated and MMP-degraded vimentin (VICM),  MMP-degraded type 1 collagen (C1M), MMP-degraded type 2 collagen(C2M), MMP-degraded type 3 collagen (C3M), and  the C-terminal telopetide of type 1 collagen (CTX-1)—were then measured.

The investigators found that 4 biomarkers of joint tissue matrix turnover—C1M, C2M, C3M, and CTX/OC-I—measured at either baseline or at 4 weeks posttreatment were predictive of early clinical response. Specifically, patients were 6.8-fold (P=.003) more likely to have an early response to TCZ if they had low C2M and high bone turnover as indicated by CTX-I/OC.  No biomarker at baseline distinguished early responders from nonresponders except for bone turnover marker CTX-I/OC (AUC 0.66, P=.0005). Changes in C1M (AUC 0.67, P=.0072), C2M (AUC 0.72, P=.0002), C3M (AUC 0.63, P=.018) and the combination of biomarkers (AUC 0.81, P=.0025) were most predictive of response.

Summary and Clinical Applicability 

Not all patients with RA respond to the same extent to various classes of RA medications, and clinical decisions to treat with a specific medication could benefit from the identification of patients who would be early responders to the initiation of that specific treatment.  This study showed that patients with elevated baseline serum markers for destabilized bone turnover were predictive of response to TCZ.  With future studies validating these findings, clinicians may be better able to stratify patients into groups that are more likely to be responders to TCZ treatment based on serum biomarker testing.


Bay-Jensen AC, Platt A, Siebuhr AS, Christiansen C, Byrjalsen I, Karsdal MA. Early changes in blood-based joint tissue destruction biomarkers are predictive of response to tocilizumab in the LITHE study. Arthritis Res Ther. 2016;18(1):13. doi: 10.1186/s13075-015-0913-x. [Epub ahead of print]