Background Biomarkers that could predict or track disease progression among patients (pts) with rheumatoid arthritis (RA) are of great interest.
Objectives To evaluate several biomarkers for association with radiographic and clinical outcomes in early RA pts treated with adalimumab (ADA)+methotrexate (MTX) vs. MTX alone.
Methods OPTIMA was a phase 4, double-blind, randomized, controlled trial in MTX-naïve pts with early RA (<1 yr). Pts were treated for 26 weeks (wks) with ADA (40 mg every other wk)+MTX or placebo (PBO)+MTX. Radiographic progression (RP) was defined as change in modified total Sharp score (ΔmTSS) >0.5 units/yr; rapid RP (RRP) as ΔmTSS ≥3 units/yr. Immunologic biomarkers measured include CRP, soluble E-selectin (sE-sel), soluble intercellular adhesion molecule-1 (sICAM), soluble vascular cell adhesion molecule-1 (sVCAM), anti-CCP antibodies (ACPA), and rheumatoid factor (RF); metabolic biomarkers include albumin, glucagon, insulin, and leptin; cardiovascular (CV) markers include apolipoprotein A-1 (ApoA1), apolipoprotein B (ApoB), total cholesterol, HDL, LDL, and triglycerides. Association of baseline (BL) biomarkers with radiographic outcomes was evaluated using univariate analyses. A mixed-effects model was used to compare biomarker changes in clinical responders (pts achieving DAS28(CRP) <3.2 at wks 22 and 26) vs. non-responders in each treatment group; BL DAS28(CRP) and biomarker levels were adjusted as covariates. Significance was assigned where P<.05. Corrections were made for multiple comparisons.
Results 515 pts were randomized to ADA+MTX and 517 to PBO+MTX; after 26 wks, rates of RP and RRP were 25%/7% among ADA+MTX pts vs. 38%/20% among PBO+MTX pts, respectively. Regardless of treatment, pts who had poor radiographic outcomes had significantly higher BL CRP levels and lower BL mean leptin. Elevated ACPA and RF levels at BL were also associated with poor radiographic outcomes, but only for PBO+MTX pts. At wk 26, 44% of pts on ADA+MTX were clinical responders vs. 24% of pts on PBO+MTX. Eventual responders had significantly lower BL body mass index, regardless of treatment received. In the ADA+MTX group, responders had significantly larger increases in albumin, ApoA1, cholesterol and HDL, and significantly larger decreases in CRP, ET-1, sE-sel, sICAM, RF, and insulin compared to non-responders. Similarly, within the PBO+MTX group, responders had significantly larger increases in cholesterol and HDL, with significantly larger decreases in CRP, sE-sel, sVCAM, and RF. When comparing ADA+MTX responders to PBO+MTX responders, pts on ADA+MTX had significantly larger increases in albumin and ApoA1, and significantly larger decreases in CRP, lipoprotein, RF, sE-sel, and sICAM.
Conclusions Overall, treatment of early RA in OPTIMA was associated with a decrease in inflammatory markers and an improvement in markers of metabolic function and CV risk. These changes were more pronounced in pts receiving ADA+MTX compared to PBO+MTX, even when analyzing only clinical responders in each group. Moreover, several immunologic biomarkers, high CRP, ACPA and RF, identified early RA pts destined for poor radiographic outcomes, and thus, pts for whom more aggressive initial therapy may be considered. The data also suggest that leptin may be an important prognostic biomarker in RA.
Acknowledgements AbbVie Inc funded the study (NCT00420927). AbbVie was responsible for the study design, research, analysis, data collection, interpretation of data, and writing, reviewing, and approving of the publication. The authors wish to thank Bohdan P. Harvey, of AbbVie Bioresearch Center, for his contribution in formulating the statistical analysis plan as well as data interpretation. Medical writing support was provided by Kathleen V. Kastenholz, PharmD, MS, of AbbVie.
Disclosure of Interest N. Mozaffarian Shareholder of: AbbVie, Employee of: AbbVie Inc, J. Smolen Grant/research support from: AbbVie, Amgen, Astra-Zeneca, BMS, Celgene Centocor-Janssen, Glaxo, Lilly, Pfizer (Wyeth), MSD (Schering-Plough), Novo-Nordisk, Roche, Sandoz, UCB, Consultant for: AbbVie, Amgen, Astra-Zeneca, BMS, Celgene Centocor-Janssen, Glaxo, Lilly, Pfizer (Wyeth), MSD (Schering-Plough), Novo-Nordisk, Roche, Sandoz, UCB, Speakers bureau: AbbVie, Amgen, Astra-Zeneca, BMS, Celgene Centocor-Janssen, Glaxo, Lilly, Pfizer (Wyeth), MSD (Schering-Plough), Novo-Nordisk, Roche, Sandoz, UCB, V. Devanarayan Shareholder of: AbbVie, Employee of: AbbVie Bioresearch Center, F. Hong Shareholder of: AbbVie, Employee of: AbbVie Bioresearch Center, A. Kavanaugh Grant/research support from: AbbVie, Amgen, Astra-Zeneca, BMS, Celgene, Centocor-Janssen, Pfizer, Roche, UCB, Consultant for: AbbVie, Amgen, Astra-Zeneca, BMS, Celgene, Centocor-Janssen, Pfizer, Roche, UCB
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