Serological identification of fast progressors of structural damage with rheumatoid arthritis

Abstract

Introduction: Rheumatoid arthritis (RA) patients with structural progression are in most need of immediate treatment to maintain tissue integrity. The serum protein fingerprint, type I collagen degradation mediated by matrix metalloproteinases (MMP)-cleavage (C1M), is a biomarker of tissue destruction. We investigated whether baseline serum C1M levels could identify structural progressors and if the biomarker levels changed during anti-inflammatory treatment with tocilizumab (TCZ).

Methods: The LITHE-biomarker study (NCT00106535, n = 585) was a one-year phase III, double-blind, placebo (PBO)-controlled, parallel group study of TCZ 4 or 8 mg/kg every four weeks, in RA patients on stable doses of methotrexate (MTX). Spearman's ranked correlation was used to assess the correlation between baseline C1M levels and structural progression at baseline and at weeks 24 and 52. Multivariate regression was performed for delta structural progression. Change in C1M levels were studied as a function of time and treatment.

Results: At baseline, C1M was significantly correlated to C-reactive protein (P <0.0001), visual analog scale pain (P <0.0001), disease activity score28-erythrocyte sedimentation rate (DAS28-ESR) (P <0.0001), joint space narrowing (JSN) (P = 0.0056) and modified total Sharp score (mTSS) (P = 0.0006). Baseline C1M was significantly correlated with delta-JSN at Week 24 (R² = 0.09, P = 0.0001) and at Week 52 (R² = 0.27, P <0.0001), and with delta-mTSS at 24 weeks (R² = 0.006, P = 0.0015) and strongly at 52 weeks (R² = 0.013, P <0.0001) in the PBO group. C1M levels were dose-dependently reduced in the TCZ + MTX group.

Conclusions: Baseline C1M levels correlated with worsening joint structure over one year. Serum C1M levels may enable identification of those RA patients that are in most need of aggressive treatment

Trial registration: ClinicalTrials.gov: NCT00106535.

Figure 1

Biochemical markers of type I collagen. PINP, Pro-collagen type I N-terminal pro-peptide; C1M, MMP-degraded type I collagen. The C1M peptide is located at amino acid position 755 to 764 in the mature collagen strands. ICTP, Pyridinoline cross-linked carboxyterminal telopeptide of type I collagen. CTX-I, cross-linked c-telo-peptide of type I collagen at amino acid position 1207 to 1214.

Figure 2

Study design of the PBO + MTX group (n = 199) in the LITHE biomarker study. Patients with <20% improvement (escape patients) at Week 16 were given 4 mg/kg TCZ + MTX every four weeks from Week 16. At Week 28 PBO + MTX patients who had received 4 mg/kg TCZ + MTX were evaluated and patients with <20% were given 8 mg/kg TCZ + MTX every four weeks. Responders to TCZ (>20% improvement) remained on 4 mg/kg TCZ + MTX for the rest of the study. If patients who went on to 8 mg/kg TCZ + MTX did not respond after three doses, they were excluded from the remainder of the study, but were included in the Week 24 analysis. Dashed line: First rescue therapy. Dotted line: Second stage rescue therapy. MTX, methotrexate; PBO, placebo; TCZ, tocilizumab

Figure 3

C1M levels in PBO + MTX or TCZ + MTX treated patients. A: Percentage change in C1M levels from baseline in all patients (including patients, who received TCZ). TCZ4, TCZ 4 mg/kg. TCZ8, TCZ 8 mg/kg. B: C1M levels in the subpopulations of the PBO group. Non-escape Week 16 n = 86, escape Week 16 n = 81. Non-escape Week 24 n = 79, escape Week 24 n = 78, non-escape Week 52 n = 66, escape Week 52 n = 56. Values are depicted as mean + SEM. Two-way ANOVA test was used to test for differences. Significant levels: *: P <0.05, **: P <0.01, ****: P <0.0001. C1M, Type I collagen degraded by MMPs; MTX, methotrexate; PBO, placebo; TCZ, tocilizumab

Figure 4

Change in radiographic measures in big/small change in C1M. Change in radiographic measures (JSN and mTSS) after 52 weeks in patients receiving TCZ with more or less than 35% change in C1M from baseline to 16 weeks. Values are depicted as mean ± 95% CI. Students' t-test was used to test for differences. Significant levels: *: P <0.05. C1M, Type I collagen degraded by MMPs; JSN, joint space narrowing; MMPs, matrix metalloproteinases; mTSS, modified total Sharp score; TCZ, tocilizumab