Abstract
ObjectivesOur goal was to assess for the histological and transcriptomic effects of abatacept on RA synovia, and to compare them with previously published data from four other DMARDs: tocilizumab, rituximab, methotrexate, and adalimumab.MethodsSynovial tissue was obtained using ultrasound-guided biopsy from affected joints of 14 patients, before and 16 weeks after treatment with subcutaneous abatacept 125 mg weekly. Paraffin-sections were stained and scored for CD3+, CD20+, and CD68+ cell infiltration. Transcriptional profiling was performed using GeneChip Human Genome U133 Plus 2.0 arrays (Affymetrix) and analyzed on Genespring GX (Agilent). Pathway analyses were performed on Genespring GX, Metascape, and EnrichR.ResultsGene expression analysis identified 304 transcripts modulated by abatacept in synovial tissue. Downregulated genes were significantly enriched for immune processes, strongly overlapping with our findings on other therapies. Data were pooled across these studies, revealing that genes downregulated by DMARDs are significantly enriched for both T-cell and myeloid leukocyte activation pathways. Interestingly, DMARDs seem to have coordinate effects on the two pathways, with a stronger impact in good responders to therapy as compared to moderate and non-responders.ConclusionWe provide evidence that the effects of five DMARDs on the RA synovium culminate in the same pathways. This confirms previous studies suggesting the existence of common mediators downstream of DMARDs, independent of their primary targets.
Highlights
Despite the increasing arsenal of targeted therapies used to treat rheumatoid arthritis (RA), a significant proportion of patients fail to reach clinical remission [1, 2]
By combining these data with those generated from four other DMARDs: methotrexate, tocilizumab, rituximab, and adalimumab [6,7,8], we provide compelling evidence, in a large series (50 pre-/post-treatment pairs) of synovial biopsies, for a shared set of highly inter-connected genes and pathways modulated downstream of RA therapies
Synovial biopsies were collected from fourteen methotrexateresistant RA patients, before and 16 weeks after treatment with abatacept 125 mg per week subcutaneously
Summary
Despite the increasing arsenal of targeted therapies used to treat rheumatoid arthritis (RA), a significant proportion of patients fail to reach clinical remission [1, 2]. The use of alternating cycles of different therapies after insufficient response is not uncommon Notwithstanding their disparate primary targets, cytokines/cytokine receptors (TNFa, IL6/IL6R), cell populations (CD20+ B cells), co-stimulatory molecules (CD80/ 86), or signaling proteins (Janus Kinases; JAKs), biological/ targeted synthetic disease-modifying anti-rheumatic drugs (b/ tsDMARDs) show strikingly similar levels of efficacy in largescale studies patients refractory to methotrexate [3, 4]. The probability of response to any particular DMARD decreases with the number of DMARDs previously used, regardless of class (drug-target) switch [3,4,5] These clinical observations led to the hypothesis that DMARDs have convergent effects downstream of their immediate targets (the common pathway hypothesis). This is supported by a series of studies from our group showing that different DMARDs induce similar transcriptomic changes in paired (pre- versus posttreatment) RA synovial biopsies [6,7,8]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
