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=7.4×10^-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.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/baseline-serum-interferon-betaalpha-ratio-predicts-response-to-tumor-necrosis-factor-alpha-inhibition-in-rheumatoid-arthritis/