The Scottish Early Rheumatoid Arthritis (SERA) Study: an inception cohort and biobank

Dale, James; Paterson, Caron; Tierney, Ann; Ralston, Stuart H.; Reid, David M.; Basu, Neil; Harvie, John; McKay, Neil; Saunders, Sarah; Wilson, Hilary; Munro, Robin; Richmond, Ruth; Baxter, Derek; McMahon, Michael; McLaren, John; Kumar, Vinod; Siebert, Stefan; McInnes, Iain B.; Porter, Duncan

doi:10.1186/s12891-016-1318-y

Cited by 22 publications

(23 citation statements)

References 33 publications

(30 reference statements)

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“…The SERA study is a national prospective inception cohort of patients with new RA or undifferentiated arthritis, together with age-gender matched controls [ 50 , 51 ]. We used 67 SERA patients for the discovery/validation phases (plus 34 healthy controls) and an additional 19 patients from an independent cohort, who were enrolled in a blinded validation study (demographic and clinical characteristics are shown in Additional file 1 : Tables S2–S4).…”

Section: Methodsmentioning

confidence: 99%

Chromosome conformation signatures define predictive markers of inadequate response to methotrexate in early rheumatoid arthritis

Carini

Hunter²,

Ramadass³

et al. 2018

J Transl Med

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BackgroundThere is a pressing need in rheumatoid arthritis (RA) to identify patients who will not respond to first-line disease-modifying anti-rheumatic drugs (DMARD). We explored whether differences in genomic architecture represented by a chromosome conformation signature (CCS) in blood taken from early RA patients before methotrexate (MTX) treatment could assist in identifying non-response to DMARD and, whether there is an association between such a signature and RA specific expression quantitative trait loci (eQTL).MethodsWe looked for the presence of a CCS in blood from early RA patients commencing MTX using chromosome conformation capture by EpiSwitch™. Using blood samples from MTX responders, non-responders and healthy controls, a custom designed biomarker discovery array was refined to a 5-marker CCS that could discriminate between responders and non-responders to MTX. We cross-validated the predictive power of the CCS by generating 150 randomized groups of 59 early RA patients (30 responders and 29 non-responders) before MTX treatment. The CCS was validated using a blinded, independent cohort of 19 early RA patients (9 responders and 10 non-responders). Last, the loci of the CCS markers were mapped to RA-specific eQTL.ResultsWe identified a 5-marker CCS that could identify, at baseline, responders and non-responders to MTX. The CCS consisted of binary chromosome conformations in the genomic regions of IFNAR1, IL-21R, IL-23, CXCL13 and IL-17A. When tested on a cohort of 59 RA patients, the CCS provided a negative predictive value of 90.0% for MTX response. When tested on a blinded independent validation cohort of 19 early RA patients, the signature demonstrated a true negative response rate of 86 and a 90% sensitivity for detection of non-responders to MTX. Only conformations in responders mapped to RA-specific eQTL.ConclusionsHere we demonstrate that detection of a CCS in blood in early RA is able to predict inadequate response to MTX with a high degree of accuracy. Our results provide a proof of principle that a priori stratification of response to MTX is possible, offering a mechanism to provide alternative treatments for non-responders to MTX earlier in the course of the disease.Electronic supplementary materialThe online version of this article (10.1186/s12967-018-1387-9) contains supplementary material, which is available to authorized users.

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Section: Methodsmentioning

confidence: 99%

Chromosome conformation signatures define predictive markers of inadequate response to methotrexate in early rheumatoid arthritis

Carini

Hunter²,

Ramadass³

et al. 2018

J Transl Med

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“…Data were obtained from the Scottish Early Rheumatoid Arthritis (SERA) inception cohort, which prospectively recruited patients with new-onset RA and undifferentiated arthritis (≥1 swollen joint) between 2011 and 2015 attending rheumatology centres across Scotland. 15 Participants in SERA were treated by their usual rheumatology team as per standard clinical practice, independent of their participation in the cohort. This current study evaluated participants in SERA who fulfilled the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) 2010 criteria for RA 16 at the baseline visit.…”

Section: Methodsmentioning

confidence: 99%

“…Patients with an alternative autoimmune rheumatic diagnosis at baseline, patients whose diagnosis was revised to another rheumatic disease during follow-up or patients who had previously received any DMARD were excluded. 15 …”

Section: Methodsmentioning

confidence: 99%

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Neutropaenia in early rheumatoid arthritis: frequency, predicting factors, natural history and outcome

et al. 2018

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ObjectivesTo determine the frequency, severity and natural history of neutropaenia in early rheumatoid arthritis (RA), explore its associations with clinical features and assess its impact on clinical management.MethodsThe Scottish Early Rheumatoid Arthritis inception cohort prospectively recruited patients with newly diagnosed RA and followed them up every 6 months. Patients with RA who developed at least one episode of neutropaenia (grade 1: <2.0×10^9/L; grade 2: <1.5×10^9/L; grade 3: <1.0×10^9/L; grade 4: <0.5×10^9/L) were compared with those who did not. Comparisons were also made between patients who experienced one or more episodes of neutropaenia and between patients with different neutropaenia grades.Results77 neutropaenia episodes were recorded in 58 of 771 (7.5%) patients with RA, who were followed up for a median (range) of 18 (6–48) months. Neutropaenia occurred at a median (range) of 12 (0–120) months after RA diagnosis. The majority had mild neutropaenia (grade 1: n=42; grade 2: n=14; grade 3: n=1; grade 4: n=1). Neutropaenia was transient (single episode) in the majority (44; 75.8%) of cases but led to treatment discontinuation in 14 (24.1%) patients. Patients who developed neutropaenia were more likely to be female (p=0.01) and non-smokers (p=0.007) and had lower baseline neutrophil levels (p<0.0001). Binomial regression analysis confirmed the latter (p<0.0001, B: −0.491) as neutropaenia predictor. The rate of infections did not differ between patients who developed neutropaenia and those who did not (p=0.878).ConclusionNeutropaenia was a common finding in this cohort. It was usually mild, transient and not associated with increased infection rates. Neutropaenia occurrence was associated with non-smoking, female gender and lower baseline neutrophil levels.

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“…The use of human samples for cohorts 1, 3 and 4 was approved by the South East Scotland Bioresource NHS Ethical Review Board (Ref 15/ES/0094). Ethical permission to collect samples donated to the SERA inception (cohort 2) was approved by the West of Scotland Local Research Ethics Committee (Ref 10/S0703/4) as previously described (10). Informed consent was obtained from all study participants prior to sample collection.…”

Section: Ethical Review and Donor Selection Criteriamentioning

confidence: 99%

Rheumatoid arthritis patients express a skewed repertoire of polyclonal, hypomutated B-cell receptors

Cowan

Miles

Capitani

et al. 2019

Preprint

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Abbreviations BCR -B cell receptor DMARD -Disease modifying anti-rheumatic drug VH -variable portion of the heavy chain BCDT -B cell depletion therapy ACPA -anti citrullinated protein antibodies RF-rheumatoid factor NGS -next generation sequencing PBMC -peripheral blood mononuclear cells ERA -early rheumatoid arthritis ESRA -established RA CDR -complementarity determining region SHM -somatic hypermutation AID -activation-induced cytidine deaminase GC -germinal centre FR -framework region CS -class-switching Conflict of interest statementThe authors have declared that no conflict of interest exists. • Abstract ObjectivesThe success of B cell depletion therapy in rheumatoid arthritis (RA) therapy testifies to their importance in disease pathogenesis, but the precise B cells mediating this are unclear. For example, it is unknown if RA patients predominantly express a limited number of circulating clonally expanded populations of B cells with highly mutated B cell antigen receptors (BCRs) that would constitute a shared antigen driven response. MethodsTo address this, we have undertaken the largest study to date utilising next generation sequencing (NGS), to identify the full length of the peripheral blood BCR sequences from the antigen-binding heavy chain. Between 25,000 to 200,000 BCR sequences per patient were analysed from 127 newly diagnosed RA patients, 16 heathy controls, 16 RA patients with established disease and 8 paired blood and synovial samples. This was complemented with B cell subset analysis from an additional 64 RA patients and 22 healthy controls. ResultsRA patients expressed a significantly higher percentage of circulating poorly mutated polyclonal IgG +ve variable heavy (IgG-Vh) BCR sequences, both at the time of diagnosis and following treatment. These sequences resided predominantly within TNF-alpha secreting IgG +ve CD27 -ve B cells, that were expanded in RA peripheral blood and enriched in the rheumatoid synovium. Surprisingly, peripheral and synovial B cell repertoires of RA patients are quite distinct, sharing very few IgG sequences. ConclusionsThis is the first report to conclusively establish that a substantial component of the peripheral B cell repertoire in RA consists of polyclonal hypomutated IgG +ve BCRs that may play a critical role in driving an autoimmune mediated inflammation.

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The Scottish Early Rheumatoid Arthritis (SERA) Study: an inception cohort and biobank

Cited by 22 publications

References 33 publications

Chromosome conformation signatures define predictive markers of inadequate response to methotrexate in early rheumatoid arthritis

Chromosome conformation signatures define predictive markers of inadequate response to methotrexate in early rheumatoid arthritis

Neutropaenia in early rheumatoid arthritis: frequency, predicting factors, natural history and outcome

Rheumatoid arthritis patients express a skewed repertoire of polyclonal, hypomutated B-cell receptors

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