DOP09 Mirikizumab-induced transcriptome changes in patient biopsies at Week 12 are maintained through Week 52 in patients with Ulcerative Colitis

Abstract Background Mirikizumab (miri), an anti-IL-23p19 monoclonal antibody, demonstrated efficacy and was well-tolerated in a phase 2 randomised clinical trial in patients with moderate-to-severe ulcerative colitis (UC; NCT02589665). After 12 weeks (W) of treatment, miri was shown to down-regulate several transcripts correlated with increased UC disease activity as well as anti-TNF resistance. Here we show W52 gene expression analysis from the induction responder cohort at W12 for both miri and PBO treated patient biopsy samples to identify sustained changes in gene expression. Methods Miri-treated patients who achieved clinical response (decrease in 9-point Mayo subscore [rectal bleeding, stool frequency, endoscopy] of ≥2 points and ≥35% from baseline [BL] with either a decrease of RB subscore of ≥1 or an RB subscore of 0 or 1) or better at W12 were re-randomised to miri 200 mg administered subcutaneously (SQ) every 4 weeks or every 12 weeks through W52. Patients given placebo (PBO) in induction who achieved clinical response continued on PBO in the maintenance period. Colonic biopsies were obtained at W0, 12, and 52 from the most affected area at least 30 cm from the anal verge (miri N=31, PBO N=7). Transcript changes at W12 from BL in the PBO and miri arms were clustered into differentially expressed genes (DEGs) using the Bayesian Limma R-package. Among these DEGs, similarly expressed genes (SEGs) were identified as those which maintained their W12 expression level through W52. Results Analysis of transcript changes in W12 responders who continued to maintenance identified a profile of DEG-SEGs in responders (Fig 1A). Of these genes, 63 (70.8%) were present only in miri responders, 5 (5.6%) were present only in PBO responders, and 21 (23.6%) were present in both groups (Fig 1B, C). The magnitude of transcript changes was greater at W12, and more consistent through W52, in the group of miri responders compared to PBO responders (Fig 2). A separate cluster of DEG-SEGs correlated with to disease activity indeces (Robarts Histopathology Index [RHI], modified Mayo; both r>0.5) were shown to be sustained in the miri treated patients but not in the placebo patients. Conclusion In this limited sample of W12 PBO and miri responders, miri responders showed broader, larger, and more sustained magnitude of changes at W52 compared to PBO responders. The qualitative description of transcripts suggests a distinct molecular healing pathway associated with miri treatment, as compared to the spontaneous healing that occurred in PBO responders. A cluster of transcripts that correlated with disease activity indices was identified, demonstrating consistency across molecular, endoscopic and clinical indices of healing in UC.

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DOP65 Mirikizumab regulates genes involved in anti-TNF resistance and ulcerative colitis disease activity

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjz203.104 ◽

2020 ◽

Vol 14 (Supplement_1) ◽

pp. S103-S104

Author(s):

B Steere ◽

J Schmitz ◽

N Powell ◽

R Higgs ◽

K Gottlieb ◽

...

Keyword(s):

Gene Expression ◽

Ulcerative Colitis ◽

Disease Activity ◽

Clinical Outcomes ◽

Large Scale ◽

Association Studies ◽

Randomised Clinical Trial ◽

P Value ◽

Genome Wide Association Studies ◽

Mixed Effect

Abstract Background Mirikizumab (miri), a p19-directed IL-23 antibody, demonstrated efficacy and was well-tolerated in a phase 2 randomised clinical trial in patients with moderate-to-severe UC (NCT02589665). This abstract explores gene expression changes in colonic tissue from study patients and their association with clinical outcomes. Methods Patients were randomised 1:1:1:1 to receive intravenous placebo (PBO, N = 63), miri 50 mg (N = 63) or 200 mg (N = 62) with the possibility of exposure-based dose increases, or fixed miri 600 mg (N = 61) every 4 weeks for 12 weeks. Patient biopsies were collected at baseline (BL) and Week 12, and differential gene expression was measured using an Affymetrix HTA2.0 exon-format microarray workflow. Genes were represented by their largest groups of highly correlated exons. Weeks 0 and 12 data were compared in all treatment groups to produce differential expression values (DEVs). Mean fold changes in DEVs between PBO and each dose group were calculated in a mixed-effect model. A threshold of false discovery rate-adjusted p-value ≤ 0.05 was applied to the significance of the fold change values, and a filter of an absolute value for the fold changes of ≥0.5 log2 units was applied. Results The greatest improvement in clinical outcomes at Week 12 was observed in the 200 mg miri group1; likewise, the greatest PBO-adjusted change from BL in transcripts was observed in this group. Transcripts correlating with key UC disease activity indices at BL, including modified Mayo score (MMS), ulcerative colitis Endoscopic Index of Severity (UCEIS), Geboes score, and Robarts Histopathology Index (RHI), included MMP1, MMP3, S100A8, IL1B, and UGT2A3, with the highest correlations occurring with the histopathologic indices (Figure 1). Miri treatment modulated the expression of transcriptional modules predicted to be enriched in cell profiles identified as key drivers of UC2 (Table 1, columns 1–2) as well as genes determined to be associated with UC by genome-wide association studies (GWAS; Table 1, column 3). Moreover, miri treatment affected transcripts involved in resistance to anti-TNF treatments (Table 1, column 4). A number of the genes in these categories were among those most affected by miri treatment (Table 1, columns 5–6). Conclusion This is the first large-scale gene expression study of diseased tissue from UC patients treated with anti-IL23p19 therapy. It is the first study to show how anti-IL23p19 therapy modulates biological pathways involved in resistance to anti-TNFs. These results are consistent with the demonstrated efficacy of miri in patients in whom TNF antagonists have failed. References

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P144 Clock gene expression levels inversely correlate with disease activity in ulcerative colitis and Crohn’s disease

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjab076.271 ◽

2021 ◽

Vol 15 (Supplement_1) ◽

pp. S228-S228

Author(s):

Y Weintraub ◽

S Cohen ◽

N Chapnik ◽

A Anafy ◽

A Yerushalmy-Feler ◽

...

Keyword(s):

Gene Expression ◽

Ulcerative Colitis ◽

Crohn’S Disease ◽

Disease Activity ◽

Clock Gene ◽

Clock Genes ◽

Clinical Status ◽

Expression Levels ◽

Clock Gene Expression ◽

Gene Expression Levels

Abstract Background Pathophysiological mechanisms active in inflammatory bowel disease (IBD), such as mucosal barrier repair, innate and adaptive immune responses, intestinal motility and gut microbiome, all exhibit diurnal variations. Chronic disruption of the molecular clock augment inflammatory response. We have shown that newly diagnosed, naïve to treatment, young IBD patients showed reduced clock gene expression in both inflamed and non-inflamed intestinal tissues and in peripheral White Blood Cells (WBC). This reduction correlated with disease activity. Our aim in this study was to determine whether certain clock genes correlate with disease activity scores or inflammatory markers in Crohn’s disease (CD) vs. ulcerative colitis (UC). Methods 17 patients with CD and 13 with UC, 8–22 years old, were recruited. Patients were evaluated upon diagnosis and during medical treatment. Disease activity scores, C-reactive protein (CRP) and fecal calprotectin (Fcal) levels were measured and WBC were analysed for clock gene (CLOCK, BMAL1, CRY1, CRY2, PER1 and PER2) expression. Clock gene expression levels were correlated to disease activity scores (clinically active vs. remission), CRP levels (<5 mg/l vs. >5 mg/l) and Fcal levels (< 250 μg/mg vs. >250 μg/mg) in CD (21 samples) and UC (20 samples). Results In UC, BMAL (p<0.008), CLOCK (p<0.02), CRY1 (p<0.002), CRY2 (p<0.0009), PER1 (p<0.003) and PER2 (p<0.003) showed decreased expression when Fcal levels were > 250 μg/mg. When compared with the clinical status and CRP levels, only BMAL1 showed reduced expression (p<0.003 and p<0.001, respectively). In CD, clinical status correlated with clock gene expression: CLOCK (p<0.035), PER1 (p<0.001) and CRY1 (p<0.028) were reduced in active disease. CRP and Fcal did not correlate with clock gene expression. Conclusion Altered levels of certain clock genes were demonstrated in young CD and UC patients in exacerbation vs. remission. In UC, Fcal levels inversely correlated with all major circadian genes and partially with clinical status and CRP levels. In CD patients clock gene expression inversely correlated with clinical status.

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P682 Faecal calprotectin and C-reactive protein levels are associated with long-term clinical and endoscopic outcomes: Analysis of the OASIS open-label extension trial of etrasimod for ulcerative colitis

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjz203.810 ◽

2020 ◽

Vol 14 (Supplement_1) ◽

pp. S555-S556

Author(s):

A Yarur ◽

M Chiorean ◽

J Zhang ◽

W Reinisch ◽

S Vermeire ◽

...

Keyword(s):

Ulcerative Colitis ◽

Disease Activity ◽

Clinical Response ◽

Clinical Remission ◽

C Reactive Protein ◽

Open Label ◽

Faecal Calprotectin ◽

Reactive Protein ◽

Open Label Extension

Abstract Background Reliable biomarkers of ulcerative colitis (UC) disease activity may be useful in clinical trials and practice. Etrasimod is an oral, selective, sphingosine 1-phosphate receptor modulator with efficacy in a 12-week, phase 2, double-blind (DB), randomised, controlled trial in adult patients with moderately-to-severely active UC (OASIS; NCT02447302). Patients who completed the DB study were eligible to enrol in an open-label extension (OLE; NCT02536404) and receive etrasimod 2 mg once daily for up to an additional 34 weeks. The aim of this post-hoc analysis was to assess the correlation of sequential faecal calprotectin (FC) and C-reactive protein (CRP) levels throughout the DB study and OLE with clinical and endoscopic outcomes at end of treatment (EOT) in the OLE. Methods In the DB study, patients received etrasimod 1 mg, etrasimod 2 mg or placebo. The OLE evaluable cohort comprised patients who received etrasimod 2 mg throughout the OLE. The modified intention-to-treat (mITT) population comprised patients with non-missing assessments. EOT was the last observation for each patient, occurring at week 46 (OLE week 34) for study completers or at last visit for patients who discontinued or had missing data. Endpoints were modified Mayo Clinic score (mMCS; range 0–9; including endoscopy, rectal bleeding [RB], and stool frequency [SF]); clinical remission (endoscopic subscore ≤1 [with absence of friability], RB ≤1, and SF score ≤1 with ≥1 point decrease from DB baseline); clinical response (clinical remission or decrease in mMCS of ≥2 points and ≥30% decrease from DB baseline, with either a RB decrease of ≥1 or RB score of ≤1); and endoscopic improvement (subscore ≤1). FC and CRP were measured longitudinally to EOT. Comparisons between subgroups were assessed with a Wilcoxon rank-sum test (2-sided P values). Analysis of correlation between variables was conducted using the Spearman’s rank coefficient. Results The evaluable cohort included 105 patients, 31 of whom received etrasimod 2 mg throughout both DB and OLE periods. At EOT 70%, 35% and 45% of patients in the mITT evaluable cohort had clinical response, clinical remission and endoscopic improvement, respectively. Differences in FC and CRP levels between patients with and without clinical remission at EOT are shown in Figures 1 and 2, respectively for patients who received etrasimod 2 mg throughout both the DB and OLE periods. Correlation analyses of FC and CRP with clinical (mMCS) and endoscopic disease activity and with each other are shown in Table 1. Conclusion FC and CRP appear to correlate with clinical and endoscopic outcomes over long-term treatment with etrasimod. Additional validation is needed to determine their utility in treat-to-target management strategies.

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P688 Effect of golimumab induction therapy on histologic disease profile in patients with moderate to severe ulcerative colitis: Results from the randomised, placebo-controlled Phase 3 PURSUIT-SC trial

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjz203.816 ◽

2020 ◽

Vol 14 (Supplement_1) ◽

pp. S560-S560

Author(s):

T Johansson ◽

C Weinstein ◽

A MEEHAN ◽

A Tzontcheva ◽

P Xu ◽

...

Keyword(s):

Ulcerative Colitis ◽

Disease Activity ◽

Induction Therapy ◽

Structural Changes ◽

Present Report ◽

Anal Verge ◽

Induction Treatment ◽

Phase 3 ◽

Double Blind ◽

Screening Endoscopy

Abstract Background Histologic improvement is an emerging goal in ulcerative colitis (UC) management. We previously demonstrated in the 6-week, multicentre, randomised, placebo-controlled, double-blind Program of Ulcerative colitis Research Studies Utilising an Investigational Treatment [PURSUIT-SC] Phase 3 trial that SC induction therapy with the tumour necrosis factor-α inhibitor, golimumab (GLM), led to statistically significant and clinically meaningful improvements in the signs and symptoms of UC compared with placebo, including clinical remission, mucosal healing, and improved health-related QoL, in patients with moderate to severe active UC.1 In the present report, we explored the histologic effects of GLM induction therapy in PURSUIT-SC by examining data from a prespecified histology sub-study. Methods The Phase 3 PURSUIT-SC trial evaluated the safety and efficacy of induction therapy with GLM in 774 patients with moderate to severe UC disease activity (defined as Mayo scores of 6–12, including an endoscopic subscore of ≥ 2). Patients were randomised 1:1:1 to receive SC induction treatment with placebo at Weeks 0 and 2, GLM 200 mg at Week 0 followed by 100 mg at Week 2 (GLM 200–>100 mg), or GLM 400 mg at Week 0 followed by 200 mg at Week 2 (GLM 400–>200 mg). Rectal biopsies were collected during endoscopy at screening and Week 6 in those randomised patients who consented to participate in the histology sub-study (N=98). During the screening endoscopy, two adjacent biopsies were collected 15 to 20 cm beyond the anal verge in an area that was most representative of the inflammation observed. At Week 6, two additional biopsies were to be obtained from the same location biopsied at screening. Biopsies were graded using the Geboes Score (GS) by a single expert gastrointestinal histopathologist, who was blinded to subject, treatment and study visit. The GS comprises seven histologic grades assessing structural changes and inflammatory disease activity. Higher GS grade scores indicate more severe histologic disease. Results Evaluable biopsy data were available in 89 patients (placebo, n = 30; GLM 200–>100 mg, n = 30; GLM 400–>200 mg, n = 29). At Week 6, compared with placebo, treatment with GLM induction therapy led to a decrease in the proportion of biopsies with GS grade scores of > 1 and an increase in the proportion of biopsies with GS grade scores of ≤ 1, with the greatest improvements being observed in the GLM 400–>200 mg group (figure). Conclusion The findings of this exploratory histologic sub-study in the PURSUIT-SC trial suggest that GLM induction therapy led to an improvement in histologic disease activity compared with placebo in patients with moderate-to-severe UC. Reference

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Optimization of prediction of UC relapse and adjustment of adequate therapy in patient with ulcerative colitiss

South Russian Journal of Therapeutic Practice ◽

10.21886/2712-8156-2020-1-2-65-71 ◽

2020 ◽

Vol 1 (2) ◽

pp. 65-71

Author(s):

A. V. Tkachev ◽

K. E. Mazovka ◽

L. S. Mkrtchyan ◽

A. S. Makarenko ◽

L. T. Takidze

Keyword(s):

Mathematical Model ◽

Ulcerative Colitis ◽

Disease Activity ◽

Colon Mucosa ◽

Adequate Therapy ◽

Clinical Indices ◽

Personalized Approach ◽

Metalloproteinase 9 ◽

Selection Of ◽

Activity Indices

Objective: to improve the assessment of activity of ulcerative colitis and the ability to predict the development of relapse of the disease, as well as the selection of adequate therapy.Materials and methods: the study included 90 people: 70 patients with ulcerative colitis and 20 healthy volunteers. The disease activity was evaluated using 7 disease activity indices. The expression of matrix metalloproteinase -9 (MMP-9) in the colon mucosa was evaluated by immunohistochemistry.Results: data were obtained on the activity of MMP-9 in colonobioptates in patients with ulcerative colitis with varying degrees of disease severity, which complements our knowledge of the pathogenetic mechanisms of UC and, based on the developed mathematical model, allows predicting the development of recurrence of UC. Based on the analysis of clinical indices of UC activity, an algorithm for evaluating the effectiveness of basic therapy has been developed.Conclusion: tools are provided to improve the prognosis of UC relapse, and a personalized approach to evaluating the effectiveness of the alternatives of drug therapy is developed.

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OP09 Immunomodulatory mechanisms of faecal microbiota transplantation are associated with clinical response in ulcerative colitis: early results from STOP-Colitis

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjz203.008 ◽

2020 ◽

Vol 14 (Supplement_1) ◽

pp. S010-S010 ◽

Cited By ~ 3

Author(s):

M N Quraishi ◽

Y H Oo ◽

A Beggs ◽

D Withers ◽

A Acharjee ◽

...

Keyword(s):

Gene Expression ◽

Ulcerative Colitis ◽

Clinical Response ◽

Mononuclear Cells ◽

Effector Memory ◽

Cd4 Cells ◽

Faecal Microbiota ◽

Faecal Microbiota Transplantation ◽

Immune Balance ◽

Treg Subset

Abstract Background Studies of faecal microbiota transplantation (FMT) for treating ulcerative colitis (UC) have shown promising results. Mechanisms by which FMT modulates inflammation, however, remain unexplored. Through a prospective, open-label pilot of FMT in UC (STOP-Colitis) we conducted a sub-study to explore changes in host colonic mucosal immune cell subsets and gene expression following FMT. Methods Patients in this study received eight infusions of FMT over an 8-week period. Colon biopsies and blood were obtained at baseline and at the end of the study. Immunophenotyping of colonic lamina propria mononuclear cells (LPMC) and peripheral blood mononuclear cells (PBMC) was conducted. RNA sequencing was performed on colon biopsies for differential gene expression analysis followed by multi-omic integration. Results Seventeen patients were recruited to this sub-study; of which, 12 completed 8 weeks of FMT per protocol. Response (reduction in MAYO score) was seen in 67% (8/12) of patients. Analysis of colonic LPMC populations revealed a significant increase in regulatory T cells (Tregs, CD4+CD25+CD127lowFoxP3+; Δ 5.02%; p < 0.01), especially effector memory Treg subset (CD4+CD25+CD127-CCR7-CD45RA-; Δ 12%; p < 0.001), gut homing Tregs (CD4+CD25+CD127-CCR7-CD45RA-α4+; Δ 18.55%; p < 0.01) and IL-10 producing CD4 cells (Δ 2.16%; p = 0.04) in responders following FMT. Along with this, there was a significant reduction in mucosal Th17 cell (CD4+CD161+CCR6+; Δ −7.61%; p = 0.017), IL-17 producing CD4 cell (Δ −7.69%; p = 0.05) and CD8 cell (Δ -5.18%; p = 0.04) populations in FMT responders. Colonic mucosal gene expression and pathway analysis demonstrated that response to FMT was associated with significant downregulation of host antimicrobial defence response mainly REG and defensin family of anti-microbial peptides, pathogen-associated molecular pattern binding receptors, proteases, multiple MHC class II genes associated with antigen presentation and proinflammatory immune pathways. There was a significant upregulation of butanoate and propionate metabolic pathways in FMT responders. Analysis of PBMC revealed a significant increase in IL-10 producing CD4 cells suggesting that induction of peripheral immune tolerance is preferentially compartmentalised to the gut mucosa. Conclusion Response to FMT is associated with a significant increase in mucosal gut homing Tregs and butanoate metabolism along with a reduction in Th17 cells and multiple anti-microbial defence and proinflammatory pathways. FMT induces change in immune balance in local milieu which leads to clinical response in UC. Exploring microbial mediators in FMT which influence immunometabolism is now under investigation to underpin novel biotherapeutic approaches.

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P124 Clock gene expression levels can differentially distinguish between ulcerative colitis and Crohn’s disease

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjz203.253 ◽

2020 ◽

Vol 14 (Supplement_1) ◽

pp. S198-S200

Author(s):

Y Weintraub ◽

S Cohen ◽

N Chapnik ◽

A Yerushalmy-Feler ◽

A Ben-Tov ◽

...

Keyword(s):

Gene Expression ◽

Ulcerative Colitis ◽

Crohn’S Disease ◽

Disease Activity ◽

Clock Gene ◽

Clock Genes ◽

Clinical Status ◽

Expression Levels ◽

Clock Gene Expression ◽

Gene Expression Levels

Abstract Background Pathophysiological mechanisms active in inflammatory bowel disease (IBD), such as mucosal barrier repair, innate and adaptive immune responses, intestinal motility and gut microbiome, all exhibit diurnal variations. Chronic disruption of the molecular clock augments inflammatory response. We have shown that newly diagnosed, naïve to treatment, young IBD patients showed reduced clock gene expression in both inflamed and non-inflamed intestinal tissues and in peripheral White blood cells (WBCs). This reduction correlated with disease activity1. Our aim in the current study was to determine whether certain clock genes correlate with disease activity scores or inflammatory markers in Crohn’s disease (CD) vs. ulcerative colitis (UC). Methods Fourteen CD and 11 UC patients, 8–22 years old, were recruited. Patients were evaluated upon diagnosis and during medical treatment. Disease activity scores, C-reactive protein (CRP) and faecal calprotectin (Fcal) levels were measured and WBC were analysed for clock gene (CLOCK, BMAL1, CRY1, CRY2, PER1 and PER2) expression. Clock gene expression levels were correlated to disease activity scores (clinically active vs. remission), CRP levels (<5 mg/l vs. >5 mg/l) and Fcal levels (<250 μg/mg vs. >250 μg/mg) in CD (21 samples) and UC patients (20 samples). Results In UC, CLOCK (p < 0.025), CRY1 (p < 0.033) and PER1 (p < 0.038) showed decreased expression when Fcal levels were >>250 μg/mg. When compared with the clinical status only BMAL1 showed reduced expression (p < 0.019). CRP levels showed no correlation with clock gene expression. In CD, CRP as well as the clinical status correlated with clock gene expression. Whereas CLOCK was reduced (p < 0.019), PER2 was induced (p < 0.005) when CRP levels were >5 mg/dl. Furthermore, CLOCK (p < 0.0005), PER1 (0.017) and PER2 (0.044) were reduced in CD patients with an active disease. However, Fcal did not correlate with clock gene expression. Conclusion Altered levels of certain clock genes were demonstrated in young CD and UC patients in relapse vs. remission and correlated with Fcal in UC patients and clinical status as well as CRP levels in CD patients. Reference

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Pretreatment synovial transcriptional profile is associated with early and late clinical response in rheumatoid arthritis patients treated with rituximab

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2011-201115 ◽

2012 ◽

Vol 71 (11) ◽

pp. 1888-1894 ◽

Cited By ~ 28

Author(s):

Vanessa E Hogan ◽

Cécile T J Holweg ◽

David F Choy ◽

Sarah K Kummerfeld ◽

Jason A Hackney ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Gene Expression ◽

T Cell ◽

Disease Activity ◽

Clinical Response ◽

Clinical Laboratory ◽

Gene Expression Signature ◽

Poor Response ◽

Interferon Α ◽

Gene Score

ObjectivePersonalised healthcare is contingent on the identification of biomarkers that represent disease relevant pathways and predict drug response. The authors aimed to develop a gene expression signature in synovial tissue that could enrich clinical response of rheumatoid arthritis (RA) patients to rituximab.MethodsThe authors studied synovial gene expression using high-throughput quantitative real-time-PCR in 20 RA patients who underwent arthroscopy before and after treatment with rituximab. Several objective approaches were used to explore patterns in the data and to find genes associated with changes in disease activity due to treatment.ResultsThis analysis revealed two patient populations associated with distinct clinical, laboratory and histological features and, importantly, showed enrichment for response (60% non-responders vs 90% responders). A composite baseline gene score (GS) correlated with change in disease activity score (ΔDAS) between baseline and month 3 (r=0.74, p=0.0002), but also with ΔDAS at later time-points (month 9, r=0.54, p=0.016; month 15, r=0.45, p=0.06; month 21, r=0.72, p=0.003). Notably, the GS significantly correlated with baseline erythrocyte sedimentation rate (r=0.69, p=0.0008), but not with other DAS components. The GS genes represented T cell, macrophage, remodelling and interferon-α biology. Responders demonstrated higher expression of macrophage and T cell genes, while non-responders showed higher expression of interferon-α and remodelling genes.ConclusionsThis study reveals a baseline synovial GS that correlates with early and late clinical responses to rituximab. The GS biology suggests that T cells and macrophages are important for response to B cell depleting therapy, while expression of remodelling and interferon-α genes correlates with poor response.

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