Rheumatoid arthritis (RA) is a chronic disease that causes pain, stiffness, swelling, and limitation in the motion and function of multiple joints. Though joints are the principal body parts affected by RA, inflammation can develop in other organs as well. An estimated 1.3 million Americans have RA, and the disease typically affects women twice as often as men.
Response to TNF-alpha inhibitor drugs varies widely among RA patients. Researchers at the Mayo Clinic, the Feinstein Institute, the University of Alabama and other institutions looked at whether circulating type-I interferon (IFN) levels may predict treatment response to TNF-alpha inhibitors and other biologic drugs in RA. More accurate prediction of who is likely to respond to therapy may help rheumatologists create more effective treatment strategies for RA patients, the researchers noted as the impetus for their study.
Using blood samples from available registries, the researchers studied an initial group of 32 RA patients and validated the findings in an independent group of 80 RA patients. All the patients had blood samples available prior to starting treatment with a TNF-alpha inhibitor. Type-I IFN measurements were made in the blood samples, and compared with subsequent response to treatment with TNF-alpha inhibitors. “We were hoping that a pre-treatment blood test might predict the response to TNF-alpha inhibitor therapy. As a result, this blood test could be used to assist the decision-making process about which drug to use in a particular RA patient,” said Timothy B. Niewold, MD, FACR of the Mayo Clinic in Rochester, Minn., and a lead author on the study.
The researchers found that an increased ratio of IFN-β/IFN-α >1.3 in the patients’ pre-treatment serum sample was associated with lack of response. Similarly, higher IFN-β/IFN-α ratio was positively correlated with higher Disease Activity Scores at the same point in treatment with the TNF-alpha inhibitor. These findings were consistent in the initial exploratory patient group and the second larger validation group.
In the validation group, no patient with an IFN-β/IFN-α ratio >1.3 achieved a good response by EULAR criteria at 12 weeks of treatment. There was no impact of anti-CCP antibody titer or mechanism of action of the TNF-alpha inhibitor (monoclonal antibody versus receptor decoy) on the relationship between type-I IFN ratio and response to TNF-alpha inhibitors.
The study’s authors concluded that pre-treatment serum interferon levels predict response to TNF-alpha inhibitor therapy in RA. This study suggests that a pre-treatment blood test result could predict a particular patient’s response to TNF-alpha inhibitors, and thus guide the decision about choice of therapy in RA. The authors conclude that this information may help rheumatologists make more effective treatment decisions for their RA patients.
“It is clear that different RA patients respond to different therapies, and yet we do not understand the biological differences between patients that cause this variable response, or have methods for predicting which treatment will best suit a particular patient. This study makes progress in this area, and we hope that it will help us to deliver more effective and personalized care for patients with RA,” said Dr. Niewold.
Funding sources for this study included the Rheumatology Research Foundation and the National Institutes of Health.
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Paper Number: 2927
Baseline Serum Interferon Beta/Alpha Ratio Predicts Response to Tumor Necrosis Factor Alpha Inhibition in Rheumatoid Arthritis
Priyanka Vashisht1, Jessica M. Dorschner2, Mark A. Jensen2, Beverly Chrabot3, Theresa Wampler Muskardin2, Marlena Kern4, Tetrad Investigators5, ABCoN Consortium6, S. Louis Bridges Jr.7, P.K. Gregersen8 and Timothy B. Niewold2, 1University of Nebraska Medical Center, Omaha, NE, 2Mayo Clinic, Rochester, MN, 3University of Chicago, Chicago, IL, 4Feinstein Institute for Medical Research, Manhasset, NY, 5AL, 6NY, 7University of Alabama at Birmingham, Birmingham, AL, 8The Feinstein Institute for Medical Research, Manhasset, NY
Background/Purpose Response to tumor necrosis factor alpha (TNF-α) inhibition is variable in rheumatoid arthritis (RA). Previous studies have suggested that circulating type I interferon (IFN) levels may predict treatment response to TNF-α inhibitors and other biological agents in RA. Prediction of likely responders prior to initiating therapy would represent a major advance in biological treatment strategies for RA.
Methods We studied a test set of 32 RA patients from the ABCoN registry and a validation set of 80 RA patients from the TETRAD registry. All subjects had serum available prior to treatment with a TNF-α inhibitor. In the test set, only those with a good response or no response at 14 weeks by EULAR criteria were included. In the validation set, subjects were included from the EULAR good, moderate, and non-response categories defined at 12 weeks post-treatment. Pre-treatment total serum type I IFN activity as well as IFN-α vs. IFN-β activity were measured using a functional reporter cell assay.
Results In the test set, an increased ratio of IFN-β/IFN-α >1.3 in the pre-treatment serum sample was associated with lack of response by EULAR criteria at 14 weeks (p=0.009), and a receiver-operator curve supported a ratio of 1.3 as the optimal cut-off. Similarly, higher IFN-β/IFN-α ratio was positively correlated with higher DAS score at 14 weeks in the test set (Spearman’s rho= 0.57, p=0.0075). In the validation set, subjects with an IFN-β/IFN-α ratio >1.3 were significantly more likely to have non-response by EULAR criteria at 12 weeks (p=0.0035), and no patient with this ratio or greater achieved a good response. In meta-analysis, IFN-β/IFN-α ratio >1.3 was a strong discriminator of good response vs. non-response at 12-14 weeks (OR = 18.0, p=7.4x10-5), and also a significant predictor of non-response vs. either moderate or good response at 12-14 weeks (OR = 4.34, p=0.0014). Anti-CCP antibody titer and mechanism of action (mAb vs etanercept) of TNF-α inhibitor did not influence this relationship.
Conclusion Increased pre-treatment serum IFN-β/IFN-α ratio was strongly associated with non-response to TNF-α inhibition by EULAR criteria at 12-14 weeks. This blood test may be useful in making treatment decisions using TNF-α inhibitors in RA and other diseases.
Disclosures:P. Vashisht, None.J. M. Dorschner, None.M. A. Jensen, None.B. Chrabot, None.T. Wampler Muskardin, None.M. Kern, None.T. Investigators, None.A. Consortium, None.S. L. Bridges Jr., None.P. K. Gregersen, None.T. B. Niewold, Janssen Pharmaceutica Product, L.P., EMD Serono, 2, Biogen Idec, EMD Serono, 5
Meeting Link: American College of Rheumatology Annual Meeting
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