Ian Bruce

Treat-to-target in systemic lupus erythematosus: recommendations from an international task force

Publisher: BMJ

Date: 16-04-2014

DOI: 10.1136/ANNRHEUMDIS-2013-205139

Abstract: The principle of treating-to-target has been successfully applied to many diseases outside rheumatology and more recently to rheumatoid arthritis. Identifying appropriate therapeutic targets and pursuing these systematically has led to improved care for patients with these diseases and useful guidance for healthcare providers and administrators. Thus, an initiative to evaluate possible therapeutic targets and develop treat-to-target guidance was believed to be highly appropriate in the management of systemic lupus erythematosus (SLE) patients as well. Specialists in rheumatology, nephrology, dermatology, internal medicine and clinical immunology, and a patient representative, contributed to this initiative. The majority convened on three occasions in 2012-2013. Twelve topics of critical importance were identified and a systematic literature review was performed. The results were condensed and reformulated as recommendations, discussed, modified and voted upon. The finalised bullet points were analysed for degree of agreement among the task force. The Oxford Centre level of evidence (LoE, corresponding to the research questions) and grade of recommendation (GoR) were determined for each recommendation. The 12 systematic literature searches and their summaries led to 11 recommendations. Prominent features of these recommendations are targeting remission, preventing damage and improving quality of life. LoE and GoR of the recommendations were variable but agreement was >0.9 in each case. An extensive research agenda was identified, and four overarching principles were also agreed upon. Treat-to-target-in-SLE (T2T/SLE) recommendations were developed by a large task force of multispecialty experts and a patient representative. It is anticipated that 'treating-to-target' can and will be applicable to the care of patients with SLE.

High frequency of antidrug antibodies and association of random drug levels with efficacy in certolizumab pegol-treated patients with rheumatoid arthritis: results from the BRAGGSS cohort

Publisher: BMJ

Date: 31-05-2016

DOI: 10.1136/ANNRHEUMDIS-2015-208849

Abstract: To evaluate (i) the association between random certolizumab drug levels, antidrug antibodies (ADAbs) and treatment response in patients with rheumatoid arthritis (RA) (ii) longitudinal factors associated with ADAbs and certolizumab drug levels. This prospective cohort included 115 patients with RA treated with certolizumab. Serum s les were collected at 3, 6 and 12 months following treatment initiation. Drug levels and ADAbs were measured using ELISA and radioimmunoassay, respectively, at 3, 6 and 12 months. Disease Activity Score in 28 joints (DAS28) were measured at each visit and 12 months European League Against Rheumatism (EULAR) response was calculated. Patient self-reported adherence was collected longitudinally. Ordinal logistic regression and generalised estimating equation were used to test the association: (i) between drug levels, from serum s led and treatment response (ii) between ADAbs and drug levels (iii) patient-centred factors and drug levels. ADAbs were detected in 37% (42/112 patients by 12 months). The presence of ADAbs were significantly associated with lower drug levels over 12 months (β=−0.037, 95% CI −0.055 to 0.018, p .0001) but not independently with 12 months EULAR response (β=0.0013 (95% CI −0.0032 to 0.00061), p=0.18). Drug level was associated with 12 months EULAR response (β=0.032 (95% CI 0.0011 to 0.063), p=0.042). In the multivariate model, ADAb level and adherence were significantly associated with drug concentrations. This is the first study to demonstrate that higher certolizumab drug levels are associated with better 12 months EULAR response. ADAbs in certolizumab-treated patients with RA were detected at higher levels than previous studies and help determine the aetiology of a low drug level.

Novel Loci Associated with Increased Risk of Sudden Cardiac Death in the Context of Coronary Artery Disease

Publisher: Public Library of Science (PLoS)

Date: 04-04-2013

DOI: 10.1371/JOURNAL.PONE.0059905

A framework for remission in SLE: consensus findings from a large international task force on definitions of remission in SLE (DORIS)

Publisher: BMJ

Date: 24-11-2016

DOI: 10.1136/ANNRHEUMDIS-2016-209519

Abstract: Treat-to-target recommendations have identified ‘remission’ as a target in systemic lupus erythematosus (SLE), but recognise that there is no universally accepted definition for this. Therefore, we initiated a process to achieve consensus on potential definitions for remission in SLE. An international task force of 60 specialists and patient representatives participated in preparatory exercises, a face-to-face meeting and follow-up electronic voting. The level for agreement was set at 90%. The task force agreed on eight key statements regarding remission in SLE and three principles to guide the further development of remission definitions: 1. Definitions of remission will be worded as follows: remission in SLE is a durable state characterised by …………………. (reference to symptoms, signs, routine labs). 2. For defining remission, a validated index must be used, for ex le, clinical systemic lupus erythematosus disease activity index (SLEDAI)=0, British Isles lupus assessment group (BILAG) 2004 D/E only, clinical European consensus lupus outcome measure (ECLAM)=0 with routine laboratory assessments included, and supplemented with physician's global assessment. 3. Distinction is made between remission off and on therapy: remission off therapy requires the patient to be on no other treatment for SLE than maintenance antimalarials and remission on therapy allows patients to be on stable maintenance antimalarials, low-dose corticosteroids (prednisone ≤5 mg/day), maintenance immunosuppressives and/or maintenance biologics. The task force also agreed that the most appropriate outcomes (dependent variables) for testing the prognostic value (construct validity) of potential remission definitions are: death, damage, flares and measures of health-related quality of life. The work of this international task force provides a framework for testing different definitions of remission against long-term outcomes.

2021 DORIS definition of remission in SLE: final recommendations from an international task force

Publisher: BMJ

Date: 11-2021

DOI: 10.1136/LUPUS-2021-000538

Abstract: To achieve consensus on a definition of remission in SLE (DORIS). Remission is the stated goal for both patient and caregiver, but consensus on a definition of remission has been lacking. Previously, an international task force consisting of patient representatives and medical specialists published a framework for such a definition, without reaching a final recommendation. Several systematic literature reviews were performed and specific research questions examined in suitably chosen data sets. The findings were discussed, reformulated as recommendations and voted on. Based on data from the literature and several SLE-specific data sets, a set of recommendations was endorsed. Ultimately, the DORIS Task Force recommended a single definition of remission in SLE, based on clinical systemic lupus erythematosus disease activitiy index (SLEDAI)=0, Evaluator’s Global Assessment .5 (0–3), prednisolone 5 mg/day or less, and stable antimalarials, immunosuppressives, and biologics. The 2021 DORIS definition of remission in SLE is recommended for use in clinical care, education, and research including clinical trials and observational studies.

Genome-wide association study identifies eight loci associated with blood pressure

Publisher: Springer Science and Business Media LLC

Date: 10-05-2009

DOI: 10.1038/NG.361

Correction: Corrigendum: Dense genotyping of immune-related susceptibility loci reveals new insights into the genetics of psoriatic arthritis

Publisher: Springer Science and Business Media LLC

Date: 06-07-2015

DOI: 10.1038/NCOMMS8741

Dense genotyping of immune-related susceptibility loci reveals new insights into the genetics of psoriatic arthritis

Publisher: Springer Science and Business Media LLC

Date: 05-02-2015

DOI: 10.1038/NCOMMS7046

Abstract: Psoriatic arthritis (PsA) is a chronic inflammatory arthritis associated with psoriasis and, despite the larger estimated heritability for PsA, the majority of genetic susceptibility loci identified to date are shared with psoriasis. Here, we present results from a case–control association study on 1,962 PsA patients and 8,923 controls using the Immunochip genotyping array. We identify eight loci passing genome-wide significance, secondary independent effects at three loci and a distinct PsA-specific variant at the IL23R locus. We report two novel loci and evidence of a novel PsA-specific association at chromosome 5q31. Imputation of classical HLA alleles, amino acids and SNPs across the MHC region highlights three independent associations to class I genes. Finally, we find an enrichment of associated variants to markers of open chromatin in CD8 + memory primary T cells. This study identifies key insights into the genetics of PsA that could begin to explain fundamental differences between psoriasis and PsA.

Irish society for rheumatology

Publisher: Springer Science and Business Media LLC

Date: 04-1994

DOI: 10.1007/BF02967228

PTPN22 is associated with susceptibility to psoriatic arthritis but not psoriasis: evidence for a further PsA-specific risk locus

Publisher: BMJ

Date: 28-04-2015

DOI: 10.1136/ANNRHEUMDIS-2014-207187

A Method to Exploit the Structure of Genetic Ancestry Space to Enhance Case-Control Studies

Publisher: Elsevier BV

Date: 05-2016

DOI: 10.1016/J.AJHG.2016.02.025

Association between age at disease onset of anti-neutrophil cytoplasmic antibody–associated vasculitis and clinical presentation and short-term outcomes

Publisher: Oxford University Press (OUP)

Date: 23-05-2020

DOI: 10.1093/RHEUMATOLOGY/KEAA215

Abstract: ANCA-associated vasculitis (AAV) can affect all age groups. We aimed to show that differences in disease presentation and 6 month outcome between younger- and older-onset patients are still incompletely understood. We included patients enrolled in the Diagnostic and Classification Criteria for Primary Systemic Vasculitis (DCVAS) study between October 2010 and January 2017 with a diagnosis of AAV. We ided the population according to age at diagnosis: & years or ≥65 years. We adjusted associations for the type of AAV and the type of ANCA (anti-MPO, anti-PR3 or negative). A total of 1338 patients with AAV were included: 66% had disease onset at & years of age [female 50% mean age 48.4 years (s.d. 12.6)] and 34% had disease onset at ≥65 years [female 54% mean age 73.6 years (s.d. 6)]. ANCA (MPO) positivity was more frequent in the older group (48% vs 27% P = 0.001). Younger patients had higher rates of musculoskeletal, cutaneous and ENT manifestations compared with older patients. Systemic, neurologic,cardiovascular involvement and worsening renal function were more frequent in the older-onset group. Damage accrual, measured with the Vasculitis Damage Index (VDI), was significantly higher in older patients, 12% of whom had a 6 month VDI ≥5, compared with 7% of younger patients (P = 0.01). Older age was an independent risk factor for early death within 6 months from diagnosis [hazard ratio 2.06 (95% CI 1.07, 3.97) P = 0.03]. Within 6 months of diagnosis of AAV, patients & years of age display a different pattern of organ involvement and an increased risk of significant damage and mortality compared with younger patients.

Comparative performances of machine learning methods for classifying Crohn Disease patients using genome-wide genotyping data

Publisher: Springer Science and Business Media LLC

Date: 17-07-2019

DOI: 10.1038/S41598-019-46649-Z

Abstract: Crohn Disease (CD) is a complex genetic disorder for which more than 140 genes have been identified using genome wide association studies (GWAS). However, the genetic architecture of the trait remains largely unknown. The recent development of machine learning (ML) approaches incited us to apply them to classify healthy and diseased people according to their genomic information. The Immunochip dataset containing 18,227 CD patients and 34,050 healthy controls enrolled and genotyped by the international Inflammatory Bowel Disease genetic consortium (IIBDGC) has been re-analyzed using a set of ML methods: penalized logistic regression (LR), gradient boosted trees (GBT) and artificial neural networks (NN). The main score used to compare the methods was the Area Under the ROC Curve (AUC) statistics. The impact of quality control (QC), imputing and coding methods on LR results showed that QC methods and imputation of missing genotypes may artificially increase the scores. At the opposite, neither the patient/control ratio nor marker preselection or coding strategies significantly affected the results. LR methods, including Lasso, Ridge and ElasticNet provided similar results with a maximum AUC of 0.80. GBT methods like XGBoost, LightGBM and CatBoost, together with dense NN with one or more hidden layers, provided similar AUC values, suggesting limited epistatic effects in the genetic architecture of the trait. ML methods detected near all the genetic variants previously identified by GWAS among the best predictors plus additional predictors with lower effects. The robustness and complementarity of the different methods are also studied. Compared to LR, non-linear models such as GBT or NN may provide robust complementary approaches to identify and classify genetic markers.

Impact of glucocorticoids on the incidence of lupus-related major organ damage: a systematic literature review and meta-regression analysis of longitudinal observational studies

Publisher: BMJ

Date: 12-2021

DOI: 10.1136/LUPUS-2021-000590

Abstract: In systemic lupus erythematosus (SLE), disease activity and glucocorticoid (GC) exposure are known to contribute to irreversible organ damage. We aimed to examine the association between GC exposure and organ damage occurrence. We conducted a literature search (PubMed (Medline), Embase and Cochrane January 1966–October 2021). We identified original longitudinal observational studies reporting GC exposure as the proportion of users and/or GC use with dose information as well as the occurrence of new major organ damage as defined in the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index. Meta-regression analyses were performed. Reviews, case-reports and studies with years of follow-up, patients, different outcomes and special populations were excluded. We selected 49 articles including 16 224 patients, 14 755 (90.9%) female with a mean age and disease duration of 35.1 years and of 37.1 months. The mean follow-up time was 104.9 months. For in idual damage items, the average daily GC dose was associated with the occurrence of overall cardiovascular events and with osteoporosis with fractures. A higher average cumulative dose adjusted (or not)/number of follow-up years and a higher proportion of patients on GC were associated with the occurrence of osteonecrosis. We confirm associations of GC use with three specific damage items. In treating patients with SLE, our aim should be to maximise the efficacy of GC and to minimise their harms.

Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls

Publisher: Springer Science and Business Media LLC

Date: 07-06-2007

DOI: 10.1038/NATURE05911

Increasing incidence of adult idiopathic inflammatory myopathies in the City of Salford, UK: a 10-year epidemiological study

Publisher: Oxford University Press (OUP)

Date: 2018

DOI: 10.1093/RAP/RKY035

Host–microbe interactions have shaped the genetic architecture of inflammatory bowel disease

Publisher: Springer Science and Business Media LLC

Date: 31-10-2012

DOI: 10.1038/NATURE11582

Sustained glucocorticoid tapering in the phase 3 trials of anifrolumab: a post hoc analysis of the TULIP-1 and TULIP-2 trials

Publisher: Oxford University Press (OUP)

Date: 26-08-2023

DOI: 10.1093/RHEUMATOLOGY/KEAC491

Abstract: Glucocorticoid sparing is a key priority for SLE management. We evaluated the effects of sustained glucocorticoid tapering in patients with SLE. This was a post hoc analysis of the randomized, placebo-controlled, 52-week phase 3 Treatment of Uncontrolled Lupus via the Interferon Pathway (TULIP)-1 and TULIP-2 trials of anifrolumab (300 mg i.v. once every 4 weeks for 48 weeks) plus standard therapy in patients with moderate to severe SLE. In a cohort of patients receiving glucocorticoids (prednisone or equivalent) 10 mg or more per day at baseline, we assessed changes in glucocorticoid dosage, patient-reported outcomes (PROs) and safety. Outcome measures were compared between sustained glucocorticoid taper responders (7.5 mg or less per day by week 40 sustained through week 52) and non-responders, regardless of treatment group, and between patients receiving anifrolumab or placebo. Among the 726 patients in the TULIP trials, 375 patients received glucocorticoids 10 mg or more per day at baseline, and of these, 155 (41%) patients were sustained glucocorticoid taper responders. Compared with non-responders (n = 220), sustained glucocorticoid taper responders reduced their mean cumulative glucocorticoid dose by 32%, improved PRO scores, reduced blood pressure and experienced fewer serious adverse events. Sustained glucocorticoid tapering was achieved by 51% (96/190) of patients receiving anifrolumab vs 32% (59/185) receiving placebo. Compared with placebo, more anifrolumab-treated patients achieved both sustained glucocorticoid taper and reduced overall disease activity [38% (72/190) vs 23% (43/185)]. Sustained glucocorticoid tapering is associated with clinical benefits. Anifrolumab treatment has potential to reduce disease activity and glucocorticoid exposure, a key goal of SLE management. ClinicalTrials.gov identifier: NCT02446912 and NCT02446899.

Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls

Publisher: Springer Science and Business Media LLC

Date: 04-2010

DOI: 10.1038/NATURE08979

Concordance and discordance in SLE clinical trial outcome measures: analysis of three anifrolumab phase 2/3 trials

Publisher: BMJ

Date: 17-05-2022

DOI: 10.1136/ANNRHEUMDIS-2021-221847

Abstract: In the anifrolumab systemic lupus erythematosus (SLE) trial programme, there was one trial (TULIP-1) in which BILAG-based Composite Lupus Assessment (BICLA) responses favoured anifrolumab over placebo, but the SLE Responder Index (SRI(4)) treatment difference was not significant. We investigated the degree of concordance between BICLA and SRI(4) across anifrolumab trials in order to better understand drivers of discrepant SLE trial results. TULIP-1, TULIP-2 (both phase 3) and MUSE (phase 2b) were randomised, 52-week trials of intravenous anifrolumab (300 mg every 4 weeks, 48 weeks TULIP-1/TULIP-2: n=180 MUSE: n=99) or placebo (TULIP-1: n=184, TULIP-2: n=182 MUSE: n=102). Week 52 BICLA and SRI(4) outcomes were assessed for each patient. Most patients (78%–85%) had concordant BICLA and SRI(4) outcomes (Cohen’s Kappa 0.6–0.7, nominal p .001). Dual BICLA/SRI(4) response rates favoured anifrolumab over placebo in TULIP-1, TULIP-2 and MUSE (all nominal p≤0.004). A discordant TULIP-1 BICLA non-responder/SRI(4) responder subgroup was identified (40/364, 11% of TULIP-1 population), comprising more patients receiving placebo (n=28) than anifrolumab (n=12). In this subgroup, placebo-treated patients had lower baseline disease activity, joint counts and glucocorticoid tapering rates, and more placebo-treated patients had arthritis response than anifrolumab-treated patients. Across trials, most patients had concordant BICLA/SRI(4) outcomes and dual BICLA/SRI(4) responses favoured anifrolumab. A BICLA non-responder/SRI(4) responder subgroup was identified where imbalances of key factors driving the BICLA/SRI(4) discordance (disease activity, glucocorticoid taper) disproportionately favoured the TULIP-1 placebo group. Careful attention to baseline disease activity and monitoring glucocorticoid taper variation will be essential in future SLE trials. NCT02446912 and NCT02446899 .

Health Innovation Manchester

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University Of Manchester

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University Of Manchester

Location: United Kingdom of Great Britain and Northern Ireland

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Manchester University NHS Foundation Trust

Location: United Kingdom of Great Britain and Northern Ireland

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