Biomarkers May Predict Clinical Response to Inflix

Newswise — Infliximab, an antibody directed against tumor necrosis factor, has been shown to produce improvement in the signs and symptoms of ankylosing spondylitis and psoriatic arthritis. In research presented this week at the American College of Rheumatology Annual Scientific Meeting in Washington, DC, early changes in certain blood proteins, or biomarkers, were found to be predictive of later clinical response to the drug in these two diseases.

Ankylosing spondylitis and psoriatic arthritis are inflammatory diseases that produce swelling, pain and long-term joint and bone deterioration. These disease processes dramatically affect the body's production of various proteins and other factors associated with inflammation and bone turnover. It is estimated that ankylosing spondylitis affects 129 out of every 100,000 people in the United States; and psoriatic arthritis affects an estimated 1 million of the approximately 7.5 million Americans who are living with psoriasis.

To determine the effect of anti-TNF therapy on inflammation and bone turnover, researchers compared clinical and biomarker responses in patients with ankylosing spondylitis or psoriatic arthritis receiving 5 mg/kg of infliximab (Remicade) with responses to placebo. Blood samples taken from 261 patients from the ASSERT trial (a trial assessing the safety and efficacy of infliximab in ankylosing spondylitis) and 107 patients from the IMPACT II trial (a trial assessing the safety and efficacy of infliximab in psoriatic arthritis) were collected to measure a number of biomarkers in order to provide an objective measurement and evaluation of biological processes. The biomarkers evaluated were associated with inflammation including interleukin-6 (IL-6), vascular endothelial growth factor (VEGF), C-reactive protein (CRP) and bone formation (bone alkaline phosphatase and osteocalcin).

When compared with placebo, infliximab therapy significantly reduced IL-6 and VEGF levels within two weeks in patients with both diseases. The early reduction (by week two) in IL-6 was related to an improvement in clinical response measures (ASAS 20 for ankylosing spondylitis and ACR 20 for psoriatic arthritis) at 14 or 24 weeks after initiation of treatment with infliximab. Decreases in CRP observed at weeks 14 or 24 were also associated with improvement in clinical response to treatment with infliximab. Baseline VEGF values were significantly associated with clinical response measures in patients receiving placebo treatment.

"This study demonstrates that modulation of certain serum markers are associated with improvement in clinical response in both ankylosing spondylitis and psoriatic arthritis, and may lead to earlier identification of patients that will benefit from treatment with infliximab," explains Sudha Visvanathan, PhD, Assistant Director, Clinical Pharmacology and Experimental Medicine, Centocor Research and Development, Inc., Malvern, Pennsylvania. "The results of our study also suggest that IL-6 may be a good, early indicator of improvement in response to infliximab treatment for potentially debilitating and progressive diseases like ankylosing spondylitis and psoriatic arthritis."

The American College of Rheumatology is the professional organization for rheumatologists and health professionals who share a dedication to healing, preventing disability and curing arthritis and related rheumatic and musculoskeletal diseases. For more information on the ACR's annual meeting, see http://www.rheumatology.org/annual.

Presentation Number: 2016

Comparison of the Effect of Infliximab on Inflammation and Bone Formation Biomarkers and Associations With Clinical Response in Ankylosing Spondylitis and Psoriatic Arthritis

S. Visvanathan1, C. Marano1, J. Braun2, A. Kavanaugh3, S. Yan1, T. Gathany1, J. Han1, B. Zhou1, D. Baker1, C. Wagner1. 1Centocor R & D, Inc., Malvern, PA; 2Rheumazentrum-Ruhrgebiet, Herne, Germany; 3UCSD, La Jolla, CA

Background: The disease processes that occur in ankylosing spondylitis (AS) and psoriatic arthritis (PsA) involve many cytokines that lead to changes in markers of inflammation and bone formation. Blockade of TNF? with infliximab (IFX) modulates several of these markers. Patterns of biomarker changes resulting from IFX therapy could be predictive of clinical benefit in patients with AS and PsA.

Objectives: 1) To compare changes in biomarkers associated with inflammation and bone formation in patients with AS and PsA treated with IFX vs placebo and 2) To explore any association between changes in these biomarkers and clinical response in AS and PsA IFX-treated patients vs placebo.

Methods: IL-6, VEGF, osteocalcin, bone alkaline phosphatase (BAP) and C-reactive protein (CRP) were measured in 261 patients from the ASSERT trial and 107 patients from the IMPACT II trial treated with 5 mg/kg IFX or placebo. Statistical analyses (analysis of variance on the van der Waerden normal scores of the biomarkers and multiple logistic regression analysis of the clinical responses) were performed without correction for multiple comparisons. The ASAS20 (for AS) response at wk 24 or ACR20 (for PsA) response at wk 14 were used in multiple logistic regression analyses including all biomarkers.

Results: IFX therapy resulted in significant reductions in IL-6 (p<0.001 for AS and PsA) and VEGF (p=0.002 for PsA; p<0.001 for AS) at wk 2 compared with placebo. Significant decreases in IL-6 (p<0.001 for PsA and AS) and VEGF (p<0.001 for AS only) were also observed at wk 14/24 for IFX- treated patients compared with placebo. A significant increase in BAP at wk 2 (p=0.013) was observed in AS but not PsA patients after treatment with IFX compared to placebo. Multiple logistic regression analyses showed that a reduction from baseline to wk 2 in IL-6 alone was significantly associated with an ACR20/ASAS20 response in the combined PsA and AS IFX group (b=-0.013, p=0.0005 ). Further, a decrease from baseline to wk 14/24 in CRP (b = -0.016, p < 0.0001) was significantly associated with ACR20/ASAS20 response in the combined PsA and AS IFX groups. In contrast, only baseline levels of VEGF (b=-0.002, p=0.025) were significantly associated with clinical response in the combined PsA and AS placebo groups. The changes in osteocalcin were not significant compared with placebo.

Conclusion: Treatment with IFX resulted in significant, early reductions from baseline in IL-6 and VEGF compared with placebo in both AS and PsA patients. An early decrease in IL-6 and a later decrease in CRP was significantly associated with clinical response at wk 14/24 across the combined AS and PsA IFX group. These results suggest that IL-6 may be a good biomarker of early clinical response to treatment with IFX in AS and PsA.

Disclosure Block: S. Visvanathan, Centocor, 3; C. Marano, Centocor, 3; J. Braun, Centocor, 2; A. Kavanaugh, Centocor, 2; S. Yan, Centocor, 3; T. Gathany, Centocor, 3; J. Han, Centocor, 3; B. Zhou, Centocor, 3; D. Baker, Centocor, 3; C. Wagner, Centocor, 3.