CD11c as a Transcriptional Biomarker to Predict Response to Anti-TNF Monotherapy With Adalimumab in Patients With Rheumatoid Arthritis

Abstract

We performed transcription profiling using monocytes to identify predictive markers of response to anti-tumor necrosis factor (anti-TNF) therapy in patients with rheumatoid arthritis (RA). Several potential predictors of response were identified, including CD11c. Validation in samples from independent cohorts (total of n = 27 patients) using reverse transcription-PCR confirmed increased expression of CD11c in responders to adalimumab (100% sensitivity; 91.7% specificity, power 99.6%; alpha = 0.01). Pretherapy CD11c levels significantly correlated with the response criteria as defined by the American College of Rheumatology (ACR) (r = 0.656, P < 0.0001). However, CD11c was neither predictive of response to methotrexate (MTX) alone (n = 34) nor to MTX in combination with adalimumab (n = 16). Clinical responders revealed a reset to a normal expression pattern of resident/inflammatory monocyte markers, which was absent in nonresponders. Therefore, an analysis of key cell types identifies potentially predictive biomarkers that may help to restrict the use of adalimumab to therapy responders. Larger studies, including studies of monotherapy with other drugs, are now needed to confirm and validate the specificity of CD11c for anti-TNF biologics.

Anti-TNF Therapy, from Rationale to Standard of Care: What Lessons Has It Taught Us?

“…Why some patients never respond is intriguing, and efforts have been made using biomarker studies to identify response to therapy, but none have been validated. A study based on a genome-wide association scan suggests a complex multigenetic basis for response or resistance to therapy (34)(35)(36). Secondary nonresponsiveness after a successful initial response does appear, in part, to be related to the immunogenicity of the therapeutic Ab (37).…”

Investigating CD11c expression as a potential genomic biomarker of response to TNF inhibitor biologics in whole blood rheumatoid arthritis samples

“…A strength of this study was the large sample size tested relative to previous treatment response gene expression profiling studies and the use of samples from extreme ends of the response spectrum, which resulted in greater power to detect the same effect size as previously reported in the study of adalimumab-treated patients [12]. For example, in the original study, after initial identification of CD11c expression associating with treatment response in 7 patients by microarray analysis, validation was conducted in 27 patients from an independent cohort by RT-PCR [12].…”

“…For example, in the original study, after initial identification of CD11c expression associating with treatment response in 7 patients by microarray analysis, validation was conducted in 27 patients from an independent cohort by RT-PCR [12]. By contrast, the current study of 75 RA samples is, to the best of our knowledge, one of the largest and most well-powered treatment response studies of gene expression conducted to date in RA.…”

“…Indeed, expression of CD11c (ITGAX), an integrin molecule involved in cell adhesion and chemotaxis [11] has shown evidence for association with response to treatment with a TNF inhibitor drug (TNFi) in RA patients. It was reported that increased expression of CD11c prior to treatment significantly correlates with good response to adalimumab monotherapy (p value <0.0001); with sensitivity of 100 % and specificity of 91.7 % [12].…”

ADAMTS Revenge on Eve?

“…Since biomarkers to predict response are available not only from the autoantibody profile (as part of the immunome), but may also be encoded in the genes (the genome) or provided by the composition of mRNA expression (the transcriptome), proteins, and metabolites (proteome and metabolome), the field for future research is wide open. For example, transcription profiling on monocytes revealed that increased expression of CD11c at baseline is associated with response to adalimumab monotherapy in patients with RA 5 . In this issue of The Journal Tsuzaka, et al identify mRNA expression levels of ADAMTS-5 as a novel predictive marker for response to a TNF-blocking agent 6 .…”