Faecal Analyses in Rheumatoid Arthritis Therapy (FART)

Faecal Analyses in Rheumatoid Arthritis Therapy: An Prospective Observational Study of the Intestinal Microbiome in Patients With Rheumatoid Arthritis Receiving Immunosuppressive Therapy

This study evaluates the intestinal microbiome and disease activity in patients with rheumatoid arthritis receiving immunosuppressive therapy. Patients will be analysed at two time points in reference to two predefined primary endpoints:

• Changes in intestinal microbiome
• Response to therapy

The investigators want to evaluate if successful treatment of rheumatoid arthritis coincide with specific changes in the gut flora.

Study Overview

• Status: Completed
• Conditions: Rheumatoid Arthritis
• Intervention / Treatment: Drug: MTX start; Drug: TNF start

Detailed Description

Methotrexate (MTX) and tumor necrosis factor (TNF) -inhibitors are two efficient medications for the treatment of rheumatoid arthritis. In a substantial number of cases however, these medications remain ineffective. At present, the scientific community has limited understanding of why some patients are resistant to these medications. The purpose of this study is to understand if the gut flora may associate with treatment response.

Recent studies have associated rheumatoid arthritis with intestinal dysbiosis. Specifically, the bacteria Prevotella copri, has been associated with this disease, an observation that has been supported also by mechanistic studies. In patients receiving methotrexate, normalization of dysbiosis has been associated with successful treatment.

This study is of observational character and integrated in the routine clinical care of patients with rheumatoid arthritis at the Rheumatology Clinic, Skane University Hospital, Lund, Sweden. Study participants are asked to deliver blood and fecal sampling at two time-points together with clinical evaluation of disease activity. With an estimated inclusion of 50 patients, at least 20 responders and 20 non-responders are expected to be included and to be compared to each other.

If successful treatment response in rheumatoid arthritis is associated with specific alterations of the gut flora, these results may guide future studies on the impact of dysbiosis and probiotics on this disease.

• Study Type: Observational
• Enrollment (Anticipated): 50

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

This study encompasses consecutive patients with rheumatoid arthritis who by their physician at the Rheumatology Clinic, Skåne University Hospital, have been prescribed any of the predefined drugs.

Patients who are willing to comply with the study protocoll are included.

The study population is consequently not a sample, but encompasses a majority of patients being prescribed theses medications at our University clinic.

Description

Inclusion Criteria:

• Rheumatoid arthritis according to the 2010 classification criteria
• About to start methotrexate or TNF-inhibitor because of active disease

Exclusion Criteria:

• Failure to understand protocol
• A history of alcohol abuse
• Concomitant inflammatory bowel disease
• Any history of diverticulitis
• A history of failure to comply with prescribed medication
• Ongoing biological therapy

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
MTX start; Patients with active rheumatoid arthritis who are either naive to methotrexate, or have not used this medicine in the last year and who are about to start therapy with methotrexate i.v. or s.c.	Drug: MTX start; Patient prescribed MTX s.c. or p.o. because of active rheumatoid arthritis; Other Names: MTX
TNF start; Patients with active rheumatoid arthritis who are either naive to TNF-inhibitors, or have not used this medicine in the last year and who are about to start therapy with any of the following (biosimilars included); infliximab, adalimumab, etanercept, certolizumab or golimumab	Drug: TNF start; Patient prescribed TNF-inhibitor because of active rheumatoid arthritis; Other Names: TNF

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Intestinal gut flora in rheumatoid arthritis	Intestinal gut flora based on DNA-based microbial analysis of fecal samples	Analysis made at study start/baseline
Change in gut flora	Change in Dysbiosis Index Score at follow up compared to baseline. The Dysbiosis Index Score measures degree of intestinal dysbiosis on a scale from 1 to 5, where 5 indicates dysbiosis. The Index has been extensively described at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5029765/	Change from baseline Dysbiosis Index Score at 6 months
Change in disease activity/treatment response at follow up	Change in Disease Activity Score 28 (DAS-28), an established index of disease activity in rheumatoid arthritis between 0-10, where 10 equals maximum activity.	Change from baseline DAS-28 at 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adherance to immunosuppressive therapy	Is the patient still prescribed the same immunosuppressant compared to baseline?	Analysis made at 6 months follow up
Change in intestinal concentration Prevotella	Alterations in intestinal concentrations of Prevotella bacteria according to polymerase chain reaction (PCR)-based analysis	Change from baseline concentration at 6 months
Change in intestinal concentration Lactobacillus	Alterations in intestinal concentrations of Lactobacillus bacteria according to PCR-based analysis	Change from baseline concentration at 6 months
Change in intestinal concentration Clostridia	Alterations in intestinal concentrations of Clostridia bacteria according to PCR-based analysis	Change from baseline concentration at 6 months

Collaborators and Investigators

• Sponsor: Region Skane
• Investigators: Principal Investigator: Kristofer Andréasson, MD PhD, Skane University Hospital

Publications and helpful links

General Publications

• Andreasson K, Alrawi Z, Persson A, Jonsson G, Marsal J. Intestinal dysbiosis is common in systemic sclerosis and associated with gastrointestinal and extraintestinal features of disease. Arthritis Res Ther. 2016 Nov 29;18(1):278. doi: 10.1186/s13075-016-1182-z.
• Zhang X, Zhang D, Jia H, Feng Q, Wang D, Liang D, Wu X, Li J, Tang L, Li Y, Lan Z, Chen B, Li Y, Zhong H, Xie H, Jie Z, Chen W, Tang S, Xu X, Wang X, Cai X, Liu S, Xia Y, Li J, Qiao X, Al-Aama JY, Chen H, Wang L, Wu QJ, Zhang F, Zheng W, Li Y, Zhang M, Luo G, Xue W, Xiao L, Li J, Chen W, Xu X, Yin Y, Yang H, Wang J, Kristiansen K, Liu L, Li T, Huang Q, Li Y, Wang J. The oral and gut microbiomes are perturbed in rheumatoid arthritis and partly normalized after treatment. Nat Med. 2015 Aug;21(8):895-905. doi: 10.1038/nm.3914. Epub 2015 Jul 27.
• Pianta A, Arvikar SL, Strle K, Drouin EE, Wang Q, Costello CE, Steere AC. Two rheumatoid arthritis-specific autoantigens correlate microbial immunity with autoimmune responses in joints. J Clin Invest. 2017 Aug 1;127(8):2946-2956. doi: 10.1172/JCI93450. Epub 2017 Jun 26.

Study record dates

Study Major Dates

• Study Start (ACTUAL): August 1, 2016
• Primary Completion (ACTUAL): November 1, 2018
• Study Completion (ACTUAL): June 1, 2019

Study Registration Dates

• First Submitted: December 11, 2018
• First Submitted That Met QC Criteria: December 11, 2018
• First Posted (ACTUAL): December 14, 2018

Study Record Updates

• Last Update Posted (ACTUAL): September 16, 2019
• Last Update Submitted That Met QC Criteria: September 13, 2019
• Last Verified: September 1, 2019

More Information

Terms related to this study

• Keywords: methotrexate; microbiome; dysbiosis; tnf-inhibitor
• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Arthritis; Arthritis, Rheumatoid
• Other Study ID Numbers: FART1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No