1416: Bioactive Lipid Profiling Can Identify Dynamic Biomarkers in Response to Biologic Therapy Result of the CorEvitas CERTAIN Comparative Effectiveness Study

Roxana Coras¹, Mona Alotaibi², Dimitrios Pappas³, Joel Kremer⁴, Jeffrey Curtis⁵, Arthur Kavanaugh⁶, Ted Mikuls⁷, Geoffrey Thiele⁸, mohit jain² and Monica Guma⁹, ¹University of California San Diego, San Diego, CA, ²Department of Medicine, School of Medicine, University of California San Diego, San Diego, CA, ³CorEvitas, LLC, Waltham, MA, ⁴The Corrona Research Foundation, Delray Beach, FL, ⁵University of Alabama at Birmingham, Hoover, AL, ⁶University of California San Diego, La Jolla, CA, ⁷Division of Rheumatology, University of Nebraska Medical Center, Omaha, NE, ⁸University of Nebraska Medical Center, Omaha, NE, ⁹UCSD, La Jolla, CA

Background/Purpose: Bioactive lipids comprise distinct classes of bioactive molecules with functions that are critical for joint disease, including regulation of not only inflammation but also cartilage and bone damage. Because many of the key polyunsaturated fatty acids (PUFA) pathway enzymes can act in parallel or in concert to produce multiple lipid products, a comprehensive systems biology approach is required to investigate the relevance of oxylipin signaling in clinical context.

Methods: Bioactive lipids were measured in plasma from two cohorts of RA patients from the CorEvitas (formerly known as Corrona) CERTAIN registry (1) at baseline prior and 6 months after TNF inhibitors (all biologic naïve, N=102) or anti-IL6 (all previously exposed to biologics, N=114). Response to treatment was categorized by minimal clinically important difference (MCID) in Clinical Disease Activity Index (CDAI) (2) at 6 months after treatment initiation. Patients had to have a 6 month follow up visit and plasma available at both the baseline and the f/u time points. Liquid chromatography (LC) system coupled with high resolution QExactive orbitrap mass spectrometer (LC/MS) was used for bioactive lipids profiling. Around 300 spectral features were identified as potential oxylipins by searching against an in-house MS/MS library. We analyzed samples pre- and post biologic therapy to determine the temporal change of oxylipins in response to therapy, and compared in responders (R) versus non-responders (NR) using nonparametric tests.

Results: 102 patients (average age 54, standard deviation [SD] 12.6, 82% female [83], average BMI 29.7, SD 6.7, average CDAI 27.1, SD 13.7) starting anti-TNF therapy and 114 patients (average age 57, SD 13, 90% female [102], average BMI 30.5, SD 7.4, average CDAI 28.7, SD 13.8) starting tocilizumab were analyzed. RA patients were classified as anti-TNF responders (R, n = 74) and non-responders (NR, n = 28), or anti-IL6 R (n=73) and NR (n=41). Levels of twenty-five bioactive lipids changed after anti-TNF therapy. Among them, the levels of the anti-inflammatory lipoxin A4 (LXA4) were only increased in R. The levels of other oxylipins including TXB2, HXB3, and 8,5-diHETE were also increased in R. Levels of twenty-three bioactive lipids changed after anti-IL6 therapy. Among them, the levels of the oxylipin 9,10 EpOME, only increased in R. The levels of other oxylipins including resolving 1 and Maresin 2 decreased in R. Figure 1 shows changes in some oxylipins after anti-TNF or anti-IL6 treatment. Of note, metabolites changed differently in both therapeutic groups.

Conclusion: Bioactive lipids may help understand the underlying biological pathways. Analysis of circulating bioactive lipid patterns and pathway changes using LC/MS has the potential to identify metabolic pathways that relate to response to different biological therapies. Understanding the underlying biological pathways certainly can give some rationale to support an assay or give some direction to develop new treatments.
Figure 1. Line plots showing change in oxylipin levels in anti-TNF. responders versus anti-IL6 responders at 6 months of biologic therapy categorized by MCID in CDAI

Disclosures: R. Coras, None; M. Alotaibi, None; D. Pappas, CorEvitas, Novartis, Sanofi, Genentech, Roche, AbbVie; J. Kremer, CorEvitas; J. Curtis, AbbVie/Abbott, Amgen, ArthritisPower, Aqtual, Bendcare, Bristol-Myers Squibb(BMS), CorEvitas, FASTER, GlaxoSmithKlein(GSK), IlluminationHealth, Janssen, Labcorp, Eli Lilly, Myriad, Novartis, Pfizer, Sanofi, Scipher, Setpoint, UCB, United Rheumatology; A. Kavanaugh, AbbVie, Amgen, Pfizer, Bristol-Myers Squibb(BMS), Centocor-Janssen, UCB, AstraZeneca, Roche; T. Mikuls, Gilead Sciences, Bristol-Myers Squibb, Horizon, Sanofi, Pfizer Inc; G. Thiele, None; m. jain, Sapient; M. Guma, Pfizer, Novartis, Gilead, Sonoma Bio, Genentech.