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Pharmacodynamic Biomarkers and Differential Effects of TNF- and GM-CSF-Targeting Biologics in Rheumatoid Arthritis

ABSTRACT: A major unmet need in rheumatoid arthritis (RA) is the choice of treatment options for patients with an inadequate response to anti-TNF agents (anti-TNF–IR). In order to identify pharmacodynamic biomarkers and assess differential effects of TNF- and non–TNF-targeting agents on RA patients with an inadequate response to anti-TNF–IR in comparison with biologic-naïve patients, peripheral protein markers and gene expression levels in association with clinical response posttreatment in two disease strata were assessed in disease-modifying antirheumatic drug (DMARD)-IR and anti-TNF-IR patients. Serum proteomics results indicated the existence of specific pharmacodynamic markers for golimumab and mavrilimumab, regardless of prior anti-TNF treatment. In contrast, both antibodies induced early and sustained suppression of RA disease markers, including IL-6, CRP, IL2RA, and MMP1, in DMARD-IR patients. Golimumab-induced early changes rapidly returned toward baseline concentrations in anti-TNF–IR patients, whereas mavrilimumab-induced changes were maintained through Day 169. RNA sequencing demonstrated gene expression changes at Day 169 after administration of mavrilimumab but not golimumab in anti-TNF–IR patients. Additionally, receiver operating characteristic curve and regression analysis showed the association of early IL-6 change and subsequent clinical responses to golimumab in anti-TNF-IR patients. Our results revealed golimumab- and mavrilimumab-specific pharmacodynamic biomarkers, and demonstrated differential biomarker-treatment relationships in anti-TNF–IR and DMARD-IR patients respectively. Early IL-6 change after anti-TNF antibody treatment may be a potential predictive biomarker for selection of different treatment regimens in anti-TNF-IR patients.

ORGANISM(S): Homo sapiens

PROVIDER: GSE120178 | GEO | 2019/06/13

REPOSITORIES: GEO

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Project description:TNF antagonists are routinely used in severe rheumatoid arthritis (RA) patients who failed conventional DMARD therapy. According to large clinical trials, the three available drugs (adalimumab, infliximab and etanercept) display similar effects in terms of efficacy, tolerability and side effects. These studies also indicate that about 25% of RA patients treated with TNF-antagonists do not display any significant clinical improvement. The aim of this study was to investigate global molecular patterns in synovial biopsies from RA patients obtained 12 weeks after initiation of adalimumab therapy. All patients had rheumatoid arthritis (RA), according to the American College of rheumatology criteria for the diagnosis of RA. They had active disease at the time of initiation of adalimumab therapy and were resistant to conventional therapy. They all had erosive changes imaged on conventional x-rays of the hands and/or feet. All patients were treated with disease-modifying antirheumatic drugs (DMARD’s), 23 with methotrexate (median dose 15 mg/week, range 7.5 – 20 mg/week), and 2 with leflunomide (20 mg/day); 18 of them were treated with low-dose steroids (prednisolone ≤ 7.5 mg/day). Six patients had been included in double-blind clinical trials before inclusion in the present study (1 in a Golimumab versus placebo trial, 3 in a MapKinase inhibitor versus placebo trial and 2 in a TACE-inhibitor versus placebo trial). These trials were stopped at least 3 months prior to initiation of TNF-blocking therapy. All drug dosages were stable from at least 3 months prior to initiation of TNF blocking therapy until completion of the study. No steroid injections were allowed during the duration of the study. Adalimumab therapy was initiated at a dosage of 40 mg subcutaneously every other week. Disease activity at baseline and 12 weeks after initiation of therapy (T12) was evaluated using DAS(28)-CRP (3- and 4-variables) scores, and response to therapy was assessed according to the EULAR response criteria that categorize patients in responders (good- or moderate-) and non- (or poor-) responders based on changes in DAS activity between T0 and T12 and absolute DAS values at T12. Synovial biopsies were obtained by needle-arthroscopy of knee of the patients at T12. The aim of the study was to compare gene expression profiles in synovial tissue of RA patients who responded versus not responded to adalimumab therapy.

Project description:The purpose of this study was (1) to identify novel genes involved in the pathogenesis of Rheumatoid Arthritis (RA) disease, which may provide additional targets for therapeutic intervention and (2) to examine the molecular mechanisms associated with the response to anti-TNF treatment. Microarray analysis of LPS-stimulated whole blood from RA patients pre and post anti-TNF treatment was conducted. This study identified 818 transcripts, differentially expressed in RA patients pre-treatment compared to non-RA control samples. While a number of these genes were associated with RA in previous studies, validating our data, a number of novel genes with possible functions in RA disease were also identified. The number of transcripts (1051) significantly altered post anti-TNF treatment indicates the impact of anti-TNF therapy on systemic gene expression. A number of these transcripts were confirmed to be altered in a larger patient group and may represent potential genetic markers of a patientâs clinical response to anti-TNF treatment. Experiment Overall Design: Transcriptome profiling was performed on two RA patients, pre- and three months post-Enbrel therapy and two matched non-RA controls. The whole blood model described by Wang et al (2000) was used with minor modifications. Briefly, to EDTA anti-coagulated blood, LPS (30ng/ml) was added immediately after drawing, and incubated at 37oC for 4 hours, mixing at 80s. After 4 hours red blood cells were lysed and pelleted, white cells were washed once in PBS (Gibco) and frozen at â70oC for subsequent RNA extraction. Total RNA was extracted using the RNeasy kit (QIAGEN) as per manufacturerâs instructions. Samples were treated with DNA-Free (Ambion) to remove genomic DNA and checked using intron-overlapping primers prior to generating cRNA probes or cDNA (data not shown). Affymetrix array data was normalised (globally) and statistically (t-test) analysed using GeneSight software (Biodiscovery). Gene expression changes with a p value of < 0.05 and a fold change of 3 or greater were considered differentially expressed.

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Pharmacodynamic Biomarkers and Differential Effects of TNF- and GM-CSF-Targeting Biologics in Rheumatoid Arthritis

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