Th17 Responses Evaluated in RA Patients on Inhibitors of TNFα

Overview

Preliminary data suggest that up-regulation of Interleukin -17 (IL-17) and the T-helper 17 (Th17) pathway occurs in rheumatoid arthritis (RA) patients on anti-Tumour Necrosis Factor (TNF) therapy who demonstrated an incomplete clinical response. A deeper understanding of this is required in order to determine whether IL-17 or the Th17 pathway is a valid target for intervention in this population to improve response outcome. The study objective is to observe biologic naïve RA subjects on anti-TNF therapies and take measurements of peripheral blood and synovial tissue to assess differences in the IL-17 and Th17 pathways between responders and non-responders. The aim of the study is to test if increased Th17 pathway activity is present in subjects who do not respond clinically to anti-TNF therapy. Clinical assessments, synovial bio-markers and ultrasound will be used as determinants of clinical response. The study may identify disease characteristics that determine which subjects may be more likely to respond to anti-TNF therapy, or those who may require either a different treatment option, or additional pathway inhibition in addition to TNF, in order to achieve clinical response.

The study aims to recruit 50 participants in total to this study. Potential candidate for this research include those that have active rheumatoid arthritis (RA) with the symptoms, and current medication status that qualify for anti-TNFα therapy. This is the treatment plan patients will be placed on regardless of whether or not they are taking part in the study; however, within the research environment, information will be gathered that may be able to help better understand the levels of response to anti-TNF treatment and why this differs between people. Participants will be asked to provide blood and urine samples as part of the research. Pieces of genetic material called ribonucleic acid (RNA) will be extracted from the study specific blood samples (and synovial tissue from patients that are part of the biopsy sub-study) provided by participants. This material will be analysed to reveal information about what genes are 'active' in the joint environment during anti-TNF treatment period. This information can tell us what proteins might be involved in the inflammation of affected joints and might also be able to predict what type of response patients will experience in response to different treatments. The analysis of research samples from this study will provide new information on the mechanisms for response/non-response to anti-TNF therapy. Optional Biopsy sub-study A number of participants that have consented to the main study will be invited to take part in the optional biopsy sub-study. This will involve taking a biopsy of one of the affected joints via an ultrasound guided procedure. The procedure is minimally invasive and has good safety and tolerability with participants. The procedure is performed under local anaesthetic and removes tiny pieces of inflamed tissue (synovial tissue) from the lining of the joint using a needle under the guidance of an ultrasound scanner. This sub-study will collect tissue from affected joints to help answer the research questions in this study Optional DNA genetic sampling Participants are also invited to take part in the optional DNA genetic sampling and are asked to contribute DNA samples for this study. The purpose of this optional part of the research study is to help understand how anti-TNF therapies work, and how they may cause side effects, to further understand rheumatoid arthritis, and to understand why some people respond to anti-TNF therapy while others do not. Genetic (genotyping) testing refers to patient sample being used for genetic research. This is the study of DNA and how it determines our traits. DNA research can also explain why some people respond well to their medications and others do not and can also provide reasons as to why some people develop some diseases and others do not. Samples from participants that have consented to the optional DNA genetic sampling will also be used for a type of genetic research called epigenetics. This is the study of chemical modifications of DNA that occur over time, without a change in DNA sequence. These modifications control the way cells produce proteins and respond to the environment. Epigenetics research is not a test to diagnose a person for a genetic disease or to determine whether a person may have a risk of developing a genetic disease. It is only used to understand prevailing disease and how drugs may work in different groups of people. In epigenetic testing, DNA samples from participants will be analysed to determine how this may influence response to anti-TNF therapy.