Tailoring therapy to individual patient’s needs: intensive management of early rheumatoid arthritis using either clinical, laboratory or musculoskeletal ultrasound assessment of disease activity

Dale, James Edward (2014) Tailoring therapy to individual patient’s needs: intensive management of early rheumatoid arthritis using either clinical, laboratory or musculoskeletal ultrasound assessment of disease activity. PhD thesis, University of Glasgow.

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Background: Outcomes in the management of early rheumatoid arthritis (RA) have been significantly improved through the use of composite disease activity measures (such as the DAS28) and aggressive DMARD escalation until a lower disease activity target has been achieved. Imaging studies suggest that the DAS28 may be insensitive to low levels of subclinical active disease that is associated with an increased risk of flare and progressive joint damage. Further, in some cases, elevations of the DAS28 may not necessarily be related to on going active synovitis. In both instances, relying upon the DAS28 assessment alone may lead to patients being considered for an inappropriate treatment decision since, patients with active subclinical disease may not be considered for further DMARD escalation whilst patients with non-inflammatory causes of DAS28 elevation may be offered additional DMARD therapy that is either ineffective or potentially toxic. There is emerging evidence that musculoskeletal ultrasound (MSUS), gene expression profiles and inflammatory protein microarrays might provide useful additional disease activity information that allows clinicians to reach a treatment decision that is targeted at an individual patient’s specific needs. Objectives: 1. To determine whether using MSUS assessment of global disease activity in addition to the DAS28 produces significantly better short-medium term clinical and radiological outcomes 2. To determine whether grouping early RA patients by either RA phenotype or disease activity level is associated with evidence of differential gene expression between the comparator groups 3. To determine the degree of correlation and agreement between the Multi-Biomarker Disease Activity (MBDA) test, the DAS28 and a MSUS disease activity assessment Methods 111 patients with either clinical diagnoses of early RA (symptom duration < 1 year) or anti-CCP antibody positive inflammatory arthritis were recruited to the Targeting Synovitis in Early Rheumatoid Arthritis (TaSER) study. Clinical consultations occurred monthly for 18 months and all participants were treated using the same step-up DMARD-biologic escalation protocol. Participants were randomised to either a DAS28 or MSUS assessment group. In the DAS28 group, DMARD therapy was escalated until DAS28 low disease activity (LDAS – DAS28 <3.2) had been achieved. In the MSUS group, MSUS assessment was indicated for instances of DAS28 LDAS or DAS28 moderate disease activity (3.2≤ DAS28 <5.1) with minimal clinical synovitis (28SJC ≤1). During MSUS assessment, the bilateral radiocarpal, index and middle MCP, index and middle PIP and 2nd and 5th MTP joints were examined for the presence of gray scale synovial hypertrophy and Power Doppler (PD) signal. Active disease was defined as the presence of grade 1 or higher PD signal in 2 or more joints. DMARD therapy was not changed if there had been significant escalation within the preceding 3 months. Intra-articular and intra-muscular corticosteroid injections were administered generously during periods of active disease. Blinded clinical outcomes were collected at baseline and every 3 months until study completion. Plain x-rays of hands and feet and MRI of the dominant wrist and hand were performed at baseline and study completion and will be graded by 2 independent radiologists who are blinded to participant’s randomisation group. Primary outcomes comprised: 1. mean change in DAS44 from baseline and 18 months, 2. mean change in MRI RAMRIS erosion score between baseline and 18 months. Secondary outcome measures included: between group comparisons of the DAS44 and ACR-EULAR remission rates, EULAR response criteria, HAQ, EURO-QoL 5D, CRP, ESR, 10cm pain visual analogue score, mean change in plain x-ray Sharp score (van der Heijde modification) and mean change in MRI RAMRIS synovitis and bone marrow oedema scores. 79 Participants donated additional blood samples for nested biomarker analysis at baseline, follow-up months 3 and 18. Baseline and 3 month PAXgene RNA samples were analysed with the assistance of the Systems Biology Group, Institute of Cardiovascular and Medical Sciences, University of Glasgow using an Illumina HumanHT-12v4 Beadchip microarray. Baseline, 3 month and 18 month serum samples were analysed by Crescendo Biosciences using their in house MBDA microarray. Additional whole blood, serum and plasma samples remain available for future polyomic analyses. For the gene expression analysis, participants were segregated into comparator groups based upon baseline and 3 month RA phenotypic and disease activity data. Comparator groups were intended to represent common clinical scenarios. Between group comparisons of gene expression were conducted in the R software package using the Linear Models for Microarray Data (Limma) plug-in. An adjusted p value <0.05 was considered to represent evidence of differential gene expression. For the MBDA analysis, the degree of correlation (Spearman’s rank correlation) between DAS28 and MBDA score was calculated at each time point and for all time points pooled together. The percentage agreement between MBDA, DAS28 and MSUS disease activity state categorisations was also calculated. Results: 111 participants were recruited and 101 (91%) completed follow-up. 95 (86%) participants fulfilled 1987 ACR RA classification criteria and 107 (96%) fulfilled 2010 ACR-EULAR RA classification criteria. The presenting features appeared typical of an early RA cohort and, excepting gender, there were no statistical differences in baseline characteristics between the groups 414 MSUS assessments were performed, 369 MSUS assessments coincided with DAS28 LDAS, of which 92 (25%) identified active synovitis. 271 MSUS assessments coincided with DAS28 remission, of which 66 (24%) identified active synovitis. 45 MSUS assessments coincided with DAS28 moderate disease activity of which 15 (33%) identified active synovitis. Overall 71% of paired DAS28 and MSUS assessments agreed on the disease activity state. MSUS-driven DMARD escalation was not associated with significant improvements in clinical outcomes. Both groups experienced a similar mean change in DAS44 between baseline and 18 months (DAS28 -2.51 vs MSUS -2.76, p 0.39). There were no statistically significant between group differences in the ACR core set variables at any of the time points, nor their mean change from baseline. Over the follow-up period, the MSUS assessment group demonstrated incremental increases in the proportion of participants with EULAR good responses and DAS44 remission and a significantly higher rate of DAS44 remission at study completion (DAS28 44% vs MSUS 65%, p=0.045). The impact of MSUS-driven DMARD escalation on radiological outcomes, medium-long term outcomes and adverse event rates remains to be determined. At baseline, gender (61 genes), RhF status (5 genes) and current smoking (1 gene) were associated with evidence of differential gene expression. The expression patterns of 19 genes changed following commencement of DMARD monotherapy. However, it was not possible to demonstrate evidence of differential gene expression in relation to disease activity level or phenotypic extremes at either time point. Up-regulation of 3 genes at baseline was associated with requiring DMARD escalation at 3 months. Otherwise, baseline gene expression was not predictive of 3 month disease activity state nor disease course over 12 months. Mean baseline interferon response gene score was not predictive of response to step-up DMARD therapy. The MBDA test score correlated positively with DAS28 at a single time point (rs=0.58, p<0.0001) and the change correlated positively with corresponding changes in DAS28 (rs=0.56, p<0.0001). The MBDA test categorised a higher proportion of participants with moderate and high disease activity than the DAS28; however, a notable proportion of high (58%) and moderate (59%) MBDA assessments were not associated with MSUS evidence of synovitis. Conclusions: MSUS and MBDA assessments of global disease activity identified active disease more frequently than corresponding DAS28 assessments. Compared to DAS28 driven therapy, MSUS driven step-up DMARD escalation was not associated with significantly better clinical outcomes but was associated with a higher rate of DAS44 remission at study completion. At present, there is no evidence to support the routine of MSUS to assess global RA disease activity; however, this position may change once the radiological and medium-long term outcomes are available. Peripheral blood gene expression analysis does not appear to contribute clinically useful additional information to the assessment of early RA. The MBDA test may provide an additional measure of disease activity; however, issues relating to specificity and its impact on clinical outcomes remain to be clarified.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: Rheumatoid arthritis, DMARD, Treat-to-Target, Disease Activity Assessment, Musculoskeletal Ultrasound, Transcriptomics,
Subjects: R Medicine > R Medicine (General)
R Medicine > RC Internal medicine
R Medicine > RM Therapeutics. Pharmacology
Colleges/Schools: College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation > Immunology
Funder's Name: UNSPECIFIED
Supervisor's Name: McInnes, Professor Iain and Porter, Dr Duncan
Date of Award: 2014
Depositing User: Dr James Dale
Unique ID: glathesis:2014-4991
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 07 Apr 2014 14:26
Last Modified: 17 Mar 2017 10:00
URI: http://theses.gla.ac.uk/id/eprint/4991

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