Relationship Between Baseline and Early Changes in C‐Reactive Protein and Interleukin‐6 Levels and Clinical Response to Tocilizumab in Rheumatoid Arthritis

Abstract

ObjectiveTo clarify the relevance of measuring interleukin‐6 (IL‐6) and C‐reactive protein (CRP) levels in order to predict clinical response to tocilizumab (TCZ) in rheumatoid arthritis patients.MethodsIn a pooled, post hoc analysis of 5 pivotal trials of TCZ, we examined the distributions of baseline serum concentrations of IL‐6 and CRP, stratified by randomized treatment group, and week 24 Disease Activity Score in 28 joints (DAS28) status (DAS28 <2.6 versus DAS28 ≥2.6). Relationships between early biomarker changes and later changes in DAS28 scores were evaluated using Spearman's correlations and scatterplots. Finally, percentage changes from baseline in IL‐6 and CRP levels were evaluated.ResultsDistributions of baseline IL‐6 and CRP levels were similar for patients who achieved DAS28 scores <2.6 within 6 months of TCZ initiation and those who did not. Correlations between early changes in these 2 biomarkers and change in DAS28 scores were low (rho < 0.3 for all). Mean percentage increases from baseline in IL‐6 concentrations were observed in all treatment groups (highest in the 8 mg/kg dose group); mean percentage decreases in CRP concentrations were greater at week 2 and at all visits for the 8 mg/kg dose group.ConclusionBaseline serum concentrations of IL‐6 and CRP may not be predictive of clinical outcomes after TCZ treatment. Data demonstrate the efficacy of TCZ in patients across a broad range of baseline serum IL‐6 and CRP concentrations. Similarly, changes in these biomarkers after TCZ dosing are expected and may or may not correspond to changes in other clinical signs and symptoms. These results complement previous reports describing the complex interactions among biomarker changes, other therapeutic mechanisms of action, and clinical outcomes.

A novel scoring system based on common laboratory tests predicts the efficacy of TNF-inhibitor and IL-6 targeted therapy in patients with rheumatoid arthritis: a retrospective, multicenter observational study

“…However, several studies have failed to identify the dominant cytokine in a specific individual with RA [ 21 ]. In this study, we found that the relative mRNA levels of IL-6 and TNF-α were inversely correlated in blood samples from 45 newly diagnosed RA patients.…”

“…While Plt, Hb, AST, and ALT were correlated with TCZ efficacy, it was an interesting finding that C-reactive protein (CRP) was not correlated with the efficacy of TCZ, and this tendency was similar in the additional 228 patients (data not shown). Recently, it was reported that baseline serum concentration of CRP might not be predictive of clinical outcomes after TCZ treatment [ 21 ]. Although the reasons for this phenomenon are unclear, such acute inflammatory markers might not be suitable for prediction because of their dispersion.…”

Erratum: JAK inhibition as a therapeutic strategy for immune and inflammatory diseases

“…Since then, its effectiveness has been borne out in long-term extension studies tracking disease activity in >4000 patients 2,4142–44 . This is particularly true for disease activity measures that incorporate the CRP 45 , which may reflect blockade of IL-6 signaling 8,46 . Tofacitinib has also been effective in improving patient-reported outcomes 36,4748 and other disease measures that do not incorporate CRP 45 .…”

Reply

“…Calprotectin and CRP are different proteins, and thus the unit used to express their concentrations does not make them less or more comparable, as they are different means of inflammation. In rheumatology, biomarker research is a growing field, with many comparative studies focusing on the accuracy of CRP versus new biomarkers using different units (1,2). In fact, the pivotal studies that demonstrated that calprotectin more accurate-ly stratifies disease activity than CRP levels in juvenile idiopathic arthritis (3) and inflammatory bowel disease (4) used the same units we did.…”