Multicenter Study

OPEN, RANDOMIZED STUDY OF RHEUMATOID ARTHRITIS PATIENTS WHO SWITCHED FROM ETANERCEPT TO INFLIXIMAB COMPARED WITH THOSE WHO REMAINED ON ETANERCEPT: CHANGES IN SERUM INFLAMMATORY, BONE, AND CARTILAGE MARKERS CORRELATED WITH EFFICACY

Objectives: To evaluate changes in serum markers of inflammation and bone and cartilage metabolism in a randomized, open-label, exploratory study designed to evaluate whether switching from etanercept (ETA) + MTX to infliximab (IFX) + MTX provided therapeutic benefit in rheumatoid arthritis (RA) patients (pts) who failed ETA.

Methods: The study population consisted of pts with RA who despite receiving a stable dose of ETA + MTX for > two months prior to study entry were not improved. Pts were randomized to either continue ETA or receive IFX (3mg/kg) instead. Serum biomarkers tested included ICAM-1, MMP-3, IL-8, VEGF, COL 2/3-4C long neoepitope (COL 2-3/4C), CTX-I, and osteocalcin. The percent change from baseline for serum markers were compared between the two groups. Correlations were calculated for change from baseline for each biomarker and ACR 20, ACR 50, DAS 28 and vdHSS at week 16.

Results:

At 16 weeks, 61% of IFX-treated pts achieved an ACR 20 response compared with 29% of ETA-treated pts. At week 14, the median changes in vdHSS were 0.0 (IQR: –0.5, 0.5) for IFX and 0.3 (IQR: –0.3, 0.8) for ETA. There were larger reductions from baseline in ICAM-1 (11.1% vs 1.1%), but similar reductions in VEGF (19.8% vs 20%) and MMP-3 (5.7% vs 5.2%) in the IFX group compared to the ETA group at week 16. Spearman rank correlation analyses were conducted to determine if there were significant correlations between percent reduction from baseline in markers and clinical parameters (Table 1). High baseline MMP-3 levels were associated with increases in vdHSS (r=0.72874, p=0.0072) in the IFX group and high baseline levels of CTX-1 and COL 2-3/4C correlated with improvement in the vdHSS in the ETA group (CTX-1: r= -0.67563, p=0.0159; COL 2-3/4C: r=-0.67417, p=0.0162).

Marker at week 14	Treatment	Efficacy parameter at week 16	R Value	P Value
IL-8	IFX	ACR20	-0.66108	0.0268
IL-8	IFX	ACR50	-0.59833	0.0518
IL-8	ETA	ACR20	-0.31119	0.3248
IL-8	ETA	ACR50	*	*
Osteocalcin	IFX	vdHSS	-0.78161	0.0045
Osteocalcin	ETA	DAS28	0.69930	0.0114

*no patients achieved ACR50

Conclusion: Improvement in clinical efficacy was significantly correlated with change from baseline in IL-8 and osteocalcin in the IFX and ETA groups. High baseline levels of MMP-3 were correlated with an increase in vdHSS in the IFX group whereas high baseline levels of CTX-1 and COL 2-3/4C correlated with improvement in vdHSS in the ETA group.

This study was carried out in several research centers:

J. Rojas1, S. Visvanathan 1 , M. Weisman 2 , O. Troum 3 , V. Bray 4 , D. Wallace 5 , N. Gaylis 6 , J. Ritter 7 , D. Yocum 8 , R. Hegedus 9 , K.E. Gilmer 9 , D.E. Furst 10

1Clinical Pharmacology and Experimental Medicine, Centocor Research and Development, Inc., Malvern, 2Division of Rheumatology, Cedars-Sinai Medical Center, 3Keck School of Medicine, University of Southern California, Los Angeles, 4Rheumatology, Denver Arthritis Clinic, Denver, 5Rheumatology, Wallace Rheumatic Study Center, Los Angeles, 6Rheumatology, Infusion and Immunotherapy Center of South Florida, Aventura, 7Rheumatology, Center for Arthritis and Rheumatology, S. Miami, 8Rheumatology, University of Arizona Health Sciences Center, Tucson, 9Medical Affairs, Centocor, Inc., Malvern, 10Rheumatology, University of California-Los Angeles, Los Angeles, United States