Publications by authors named "Kimme Hyrich"

185 Publications

Do people with rheumatoid arthritis maintain their physical activity level at treatment onset over the first year of methotrexate therapy?

Rheumatology (Oxford) 2021 Feb 19. Epub 2021 Feb 19.

Centre for Epidemiology Versus Arthritis, Centre for Musculoskeletal Research, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.

Objectives: To describe how many people with rheumatoid arthritis (RA) reduce their baseline physical activity (PA) level over the first year of methotrexate (MTX) treatment, and which factors predict this.

Methods: Data came from the Rheumatoid Arthritis Medication Study (RAMS), a prospective cohort of people with early RA starting MTX. Participants reported demographics and completed questionnaires at baseline, six and 12 months, including reporting the number of days per week they performed ≥20 min of PA; coded as none, low (1-3 days) or high (4-7 days). The PA levels of participants over 12 months are described. Predictors of stopping PA were assessed using multivariable logistic regression.

Results: In total, 1468 participants were included (median [interquartile range] age: 60 [50, 69] years; 957 [65.2%] women). At baseline, the PA levels of the people with RA were: none = 408 (27.8%), low = 518 (35.3%), high = 542 (36.9%). 80% of participants maintained some PA or began PA between assessments (baseline to 6-months = 79.3%, 6-months to 12-months = 80.7%). 24.1% of participants reduced PA and 11.3% of participants stopped performing PA between baseline and 6-months (6-months to 12 months: 22.6% and 10.2% respectively). Baseline smoking, higher disability and greater socioeconomic deprivation were associated with stopping PA.

Conclusion: Many people with early RA were not performing PA when starting MTX, or stopped performing PA over the first year of treatment. These people may require interventions to stay active. These interventions need to be mindful of socioeconomic barriers to PA participation.
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http://dx.doi.org/10.1093/rheumatology/keab060DOI Listing
February 2021

Patient-reported wellbeing and clinical disease measures over time captured by multivariate trajectories of disease activity in individuals with juvenile idiopathic arthritis in the UK: a multicentre prospective longitudinal study.

Lancet Rheumatol 2021 Feb 4;3(2):e111-e121. Epub 2020 Dec 4.

Centre for Health Informatics, Manchester Academic Health Sciences Centre, University of Manchester, Manchester, UK.

Background: Juvenile idiopathic arthritis (JIA) is a heterogeneous disease, the signs and symptoms of which can be summarised with use of composite disease activity measures, including the clinical Juvenile Arthritis Disease Activity Score (cJADAS). However, clusters of children and young people might experience different global patterns in their signs and symptoms of disease, which might run in parallel or diverge over time. We aimed to identify such clusters in the 3 years after a diagnosis of JIA. The identification of these clusters would allow for a greater understanding of disease progression in JIA, including how physician-reported and patient-reported outcomes relate to each other over the JIA disease course.

Methods: In this multicentre prospective longitudinal study, we included children and young people recruited before Jan 1, 2015, to the Childhood Arthritis Prospective Study (CAPS), a UK multicentre inception cohort. Participants without a cJADAS score were excluded. To assess groups of children and young people with similar disease patterns in active joint count, physician's global assessment, and patient or parental global evaluation, we used latent profile analysis at initial presentation to paediatric rheumatology and multivariate group-based trajectory models for the following 3 years. Optimal models were selected on the basis of a combination of model fit, clinical plausibility, and model parsimony.

Finding: Between Jan 1, 2001, and Dec 31, 2014, 1423 children and young people with JIA were recruited to CAPS, 239 of whom were excluded, resulting in a final study population of 1184 children and young people. We identified five clusters at baseline and six trajectory groups using longitudinal follow-up data. Disease course was not well predicted from clusters at baseline; however, in both cross-sectional and longitudinal analyses, substantial proportions of children and young people had high patient or parent global scores despite low or improving joint counts and physician global scores. Participants in these groups were older, and a higher proportion of them had enthesitis-related JIA and lower socioeconomic status, compared with those in other groups.

Interpretation: Almost one in four children and young people with JIA in our study reported persistent, high patient or parent global scores despite having low or improving active joint counts and physician's global scores. Distinct patient subgroups defined by disease manifestation or trajectories of progression could help to better personalise health-care services and treatment plans for individuals with JIA.

Funding: Medical Research Council, Versus Arthritis, Great Ormond Street Hospital Children's Charity, Olivia's Vision, and National Institute for Health Research.
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http://dx.doi.org/10.1016/S2665-9913(20)30269-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843954PMC
February 2021

Factors associated with COVID-19-related death in people with rheumatic diseases: results from the COVID-19 Global Rheumatology Alliance physician-reported registry.

Ann Rheum Dis 2021 Jan 27. Epub 2021 Jan 27.

National Institute for Health Research (NIHR) University College London Hospitals Biomedical Research Centre, University College London Hospitals National Health Service (NHS) Trust, London, UK

Objectives: To determine factors associated with COVID-19-related death in people with rheumatic diseases.

Methods: Physician-reported registry of adults with rheumatic disease and confirmed or presumptive COVID-19 (from 24 March to 1 July 2020). The primary outcome was COVID-19-related death. Age, sex, smoking status, comorbidities, rheumatic disease diagnosis, disease activity and medications were included as covariates in multivariable logistic regression models. Analyses were further stratified according to rheumatic disease category.

Results: Of 3729 patients (mean age 57 years, 68% female), 390 (10.5%) died. Independent factors associated with COVID-19-related death were age (66-75 years: OR 3.00, 95% CI 2.13 to 4.22; >75 years: 6.18, 4.47 to 8.53; both vs ≤65 years), male sex (1.46, 1.11 to 1.91), hypertension combined with cardiovascular disease (1.89, 1.31 to 2.73), chronic lung disease (1.68, 1.26 to 2.25) and prednisolone-equivalent dosage >10 mg/day (1.69, 1.18 to 2.41; vs no glucocorticoid intake). Moderate/high disease activity (vs remission/low disease activity) was associated with higher odds of death (1.87, 1.27 to 2.77). Rituximab (4.04, 2.32 to 7.03), sulfasalazine (3.60, 1.66 to 7.78), immunosuppressants (azathioprine, cyclophosphamide, ciclosporin, mycophenolate or tacrolimus: 2.22, 1.43 to 3.46) and not receiving any disease-modifying anti-rheumatic drug (DMARD) (2.11, 1.48 to 3.01) were associated with higher odds of death, compared with methotrexate monotherapy. Other synthetic/biological DMARDs were not associated with COVID-19-related death.

Conclusion: Among people with rheumatic disease, COVID-19-related death was associated with known general factors (older age, male sex and specific comorbidities) and disease-specific factors (disease activity and specific medications). The association with moderate/high disease activity highlights the importance of adequate disease control with DMARDs, preferably without increasing glucocorticoid dosages. Caution may be required with rituximab, sulfasalazine and some immunosuppressants.
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http://dx.doi.org/10.1136/annrheumdis-2020-219498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843211PMC
January 2021

Rheumatic disease and COVID-19: epidemiology and outcomes.

Nat Rev Rheumatol 2021 02;17(2):71-72

Centre for Rheumatology & Department of Neuromuscular Diseases, University College London, London, UK.

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http://dx.doi.org/10.1038/s41584-020-00562-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7747184PMC
February 2021

Changes in the illness perceptions of patients with rheumatoid arthritis over the first year of methotrexate therapy.

Rheumatology (Oxford) 2020 Nov 14. Epub 2020 Nov 14.

Centre for Epidemiology Versus Arthritis, Centre for Musculoskeletal Research, Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester.

Objectives: To describe the illness perceptions of patients with RA over the first year of MTX treatment, and the association between illness perceptions and outcomes.

Methods: Data came from the Rheumatoid Arthritis Medication Study (RAMS), a UK multicentre cohort study of RA patients starting MTX for the first time. Patients were assessed at baseline, and at 6 and 12 months. Patients completed the Brief Illness Perception Questionnaire (B-IPQ) at each assessment, as well as other patient-reported outcomes (PROs). The inflammation score (2-component DAS28) was calculated. Subgroups of patients with similar trajectories across the eight (B-IPQ) items were identified using a latent class growth model. Predictors of group membership were identified using multinomial logistic regression. Associations between subgroups and PROs over follow-up were assessed using linear mixed models.

Results: Three subgroups were identified in the analysis population (N = 1087): Positive illness perceptions (N = 322), Negative illness perceptions (N = 534) and Improvers (N = 231) who switched from negative to positive illness perceptions over follow-up. Baseline disability was associated with group membership [Positive vs Negative: relative risk ratio (RRR) 0.37, 95% CI: 0.25, 0.54; Improvers vs Negative: RRR 0.60, 95% CI: 0.43, 0.83], as were other PROs (pain, fatigue, anxiety, depression). The Negative group had worse disability, pain and fatigue over follow-up compared with the other groups, controlling for inflammation.

Conclusion: Negative illness perceptions are associated with poor PROs over time. The Improvers subgroup illustrated that illness perceptions can change in RA. Illness perceptions represent a potential therapeutic target that should be assessed using randomized trials.
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http://dx.doi.org/10.1093/rheumatology/keaa615DOI Listing
November 2020

Pharmacogenetics of TNF inhibitor response in rheumatoid arthritis utilizing the two-component disease activity score.

Pharmacogenomics 2020 11 30;21(16):1151-1156. Epub 2020 Oct 30.

NIHR Manchester Biomedical Research Center, Central Manchester NHS Foundation Trust, Manchester Academic Health Science Center, Manchester, M13 9WL, UK.

TNF inhibitor drugs are a treatment option for rheumatoid arthritis, but response is not universal. Response is typically measured using the composite 4-component (4C) disease activity score 28 (DAS28) which contains more subjective measures. This study used a validated 2-component (2C) DAS28 score to determine whether SNPs associated with response were replicated in the UK population. A literature review identified TNF inhibitor response SNPs. Linear regression was conducted to replicate associations with 4C or 2C-DAS28 response. Eighteen independent SNPs were analyzed in 1828 patients. One and four associations with 4C and 2C-DAS28 response respectively were identified (p ≤ 0.05). Further genetic associations were replicated using the 2C-DAS28 which may reflect the objective nature of 2C-AS28.
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http://dx.doi.org/10.2217/pgs-2020-0043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7649675PMC
November 2020

EULAR definition of difficult-to-treat rheumatoid arthritis.

Ann Rheum Dis 2021 01 1;80(1):31-35. Epub 2020 Oct 1.

Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.

Background: Despite treatment according to the current management recommendations, a significant proportion of patients with rheumatoid arthritis (RA) remain symptomatic. These patients can be considered to have 'difficult-to-treat RA'. However, uniform terminology and an appropriate definition are lacking.

Objective: The Task Force in charge of the Development of EULAR recommendations for the comprehensive management of difficult-to-treat rheumatoid arthritis" aims to create recommendations for this underserved patient group. Herein, we present the definition of difficult-to-treat RA, as the first step.

Methods: The Steering Committee drafted a definition with suggested terminology based on an international survey among rheumatologists. This was discussed and amended by the Task Force, including rheumatologists, nurses, health professionals and patients, at a face-to-face meeting until sufficient agreement was reached (assessed through voting).

Results: The following three criteria were agreed by all Task Force members as mandatory elements of the definition of difficult-to-treat RA: (1) Treatment according to European League Against Rheumatism (EULAR) recommendation and failure of ≥2 biological disease-modifying antirheumatic drugs (DMARDs)/targeted synthetic DMARDs (with different mechanisms of action) after failing conventional synthetic DMARD therapy (unless contraindicated); (2) presence of at least one of the following: at least moderate disease activity; signs and/or symptoms suggestive of active disease; inability to taper glucocorticoid treatment; rapid radiographic progression; RA symptoms that are causing a reduction in quality of life; and (3) the management of signs and/or symptoms is perceived as problematic by the rheumatologist and/or the patient.

Conclusions: The proposed EULAR definition for difficult-to-treat RA can be used in clinical practice, clinical trials and can form a basis for future research.
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http://dx.doi.org/10.1136/annrheumdis-2020-217344DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7788062PMC
January 2021

Harnessing repeated measurements of predictor variables for clinical risk prediction: a review of existing methods.

Diagn Progn Res 2020 9;4. Epub 2020 Jul 9.

Centre for Epidemiology Versus Arthritis, Centre for Musculoskeletal Research, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.

Background: Clinical prediction models (CPMs) predict the risk of health outcomes for individual patients. The majority of existing CPMs only harness cross-sectional patient information. Incorporating repeated measurements, such as those stored in electronic health records, into CPMs may provide an opportunity to enhance their performance. However, the number and complexity of methodological approaches available could make it difficult for researchers to explore this opportunity. Our objective was to review the literature and summarise existing approaches for harnessing repeated measurements of predictor variables in CPMs, primarily to make this field more accessible for applied researchers.

Methods: MEDLINE, Embase and Web of Science were searched for articles reporting the development of a multivariable CPM for individual-level prediction of future binary or time-to-event outcomes and modelling repeated measurements of at least one predictor. Information was extracted on the following: the methodology used, its specific aim, reported advantages and limitations, and software available to apply the method.

Results: The search revealed 217 relevant articles. Seven methodological frameworks were identified: time-dependent covariate modelling, generalised estimating equations, landmark analysis, two-stage modelling, joint-modelling, trajectory classification and machine learning. Each of these frameworks satisfies at least one of three aims: to better represent the predictor-outcome relationship over time, to infer a covariate value at a pre-specified time and to account for the effect of covariate change.

Conclusions: The applicability of identified methods depends on the motivation for including longitudinal information and the method's compatibility with the clinical context and available patient data, for both model development and risk estimation in practice.
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http://dx.doi.org/10.1186/s41512-020-00078-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7346415PMC
July 2020

Response to: 'Glucocorticoid-induced relapse of COVID-19 in a patient with sarcoidosis' by Györfi .

Ann Rheum Dis 2020 Jun 30. Epub 2020 Jun 30.

Faculty of Medicine, The University of Queensland, Herston, Queensland, Australia

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http://dx.doi.org/10.1136/annrheumdis-2020-218328DOI Listing
June 2020

Translating research into clinical practice: quality improvement to halve non-adherence to methotrexate.

Rheumatology (Oxford) 2021 Jan;60(1):125-131

Kellgren Centre for Rheumatology, NIHR Manchester Biomedical Research Centre, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester.

Objective: MTX remains the cornerstone for therapy for RA, yet research shows that non-adherence is significant and correlates with response to therapy. This study aimed to halve self-reported non-adherence to MTX at the Kellgren Centre for Rheumatology.

Methods: An anonymous self-report adherence questionnaire was developed and data collected for 3 months prior to the introduction of interventions, and then regularly for the subsequent 2.5 years. A series of interventions were implemented, including motivational interviewing training, consistent information about MTX and development of a summary bookmark. Information on clinic times was collected for consultations with and without motivational interviewing. Surveys were conducted to ascertain consistency of messages about MTX. A biochemical assay was used to test MTX serum levels in patients at two time points: before and 2.8 years following introduction of the changes. Remission rates at 6 and 12 months post-MTX initiation were retrieved from patient notes and cost savings estimated by comparing actual numbers of new biologic starters compared with expected numbers based on the numbers of consultants employed at the two time points.

Results: Between June and August 2016, self-reported non-adherence to MTX was 24.7%. Following introduction of the interventions, self-reported non-adherence rates reduced to an average of 7.4% between April 2018 and August 2019. Clinic times were not significantly increased when motivational interviewing was employed. Consistency of messages by staff across three key areas (benefits of MTX, alcohol guidance and importance of adherence) improved from 64% in September 2016 to 94% in January 2018. Biochemical non-adherence reduced from 56% (September 2016) to 17% (June 2019), whilst remission rates 6 months post-initiation of MTX improved from 13% in 2014/15 to 37% in 2017/18, resulting is estimated cost savings of £30 000 per year.

Conclusion: Non-adherence to MTX can be improved using simple measures including focussing on the adherence and the benefits of treatment, and providing consistent information across departments.
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http://dx.doi.org/10.1093/rheumatology/keaa214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785311PMC
January 2021

Latent Class Trajectory Modeling of 2-Component Disease Activity Score in 28 Joints Identifies Multiple Rheumatoid Arthritis Phenotypes of Response to Biologic Disease-Modifying Antirheumatic Drugs.

Arthritis Rheumatol 2020 10 6;72(10):1632-1642. Epub 2020 Sep 6.

Versus Arthritis Centre for Genetics and Genomics, University of Manchester, NIHR Manchester Biomedical Research Centre, Manchester University NHS Foundation Trust, and Manchester Academic Health Science Centre, Manchester, UK.

Objective: To determine whether using a reweighted disease activity score that better reflects joint synovitis, i.e., the 2-component Disease Activity Score in 28 joints (DAS28) (based on swollen joint count and C-reactive protein level), produces more clinically relevant treatment outcome trajectories compared to the standard 4-component DAS28.

Methods: Latent class mixed modeling of response to biologic treatment was applied to 2,991 rheumatoid arthritis (RA) patients in whom treatment with a biologic disease-modifying antirheumatic drug was being initiated within the Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate cohort, using both 4-component and 2-component DAS28 scores as outcome measures. Patient groups with similar trajectories were compared in terms of pretreatment baseline characteristics (including disability and comorbidities) and follow-up characteristics (including antidrug antibody events, adherence to treatments, and blood drug levels). We compared the trajectories obtained using the 4- and 2-component scores to determine which characteristics were better captured by each.

Results: Using the 4-component DAS28, we identified 3 trajectory groups, which is consistent with previous findings. We showed that the 4-component DAS28 captures information relating to depression. Using the 2-component DAS28, 7 trajectory groups were identified; among them, distinct groups of nonresponders had a higher incidence of respiratory comorbidities and a higher proportion of antidrug antibody events. We also identified a group of patients for whom the 2-component DAS28 scores remained relatively low; this group included a high percentage of patients who were nonadherent to treatment. This highlights the utility of both the 4- and 2-component DAS28 for monitoring different components of disease activity.

Conclusion: Here we show that the 2-component modified DAS28 defines important biologic and clinical phenotypes associated with treatment outcome in RA and characterizes important underlying response mechanisms to biologic drugs.
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http://dx.doi.org/10.1002/art.41379DOI Listing
October 2020

Characteristics associated with hospitalisation for COVID-19 in people with rheumatic disease: data from the COVID-19 Global Rheumatology Alliance physician-reported registry.

Ann Rheum Dis 2020 07 29;79(7):859-866. Epub 2020 May 29.

Faculty of Medicine, The University of Queensland, Herston, Queensland, Australia

Objectives: COVID-19 outcomes in people with rheumatic diseases remain poorly understood. The aim was to examine demographic and clinical factors associated with COVID-19 hospitalisation status in people with rheumatic disease.

Methods: Case series of individuals with rheumatic disease and COVID-19 from the COVID-19 Global Rheumatology Alliance registry: 24 March 2020 to 20 April 2020. Multivariable logistic regression was used to estimate ORs and 95% CIs of hospitalisation. Age, sex, smoking status, rheumatic disease diagnosis, comorbidities and rheumatic disease medications taken immediately prior to infection were analysed.

Results: A total of 600 cases from 40 countries were included. Nearly half of the cases were hospitalised (277, 46%) and 55 (9%) died. In multivariable-adjusted models, prednisone dose ≥10 mg/day was associated with higher odds of hospitalisation (OR 2.05, 95% CI 1.06 to 3.96). Use of conventional disease-modifying antirheumatic drug (DMARD) alone or in combination with biologics/Janus Kinase inhibitors was not associated with hospitalisation (OR 1.23, 95% CI 0.70 to 2.17 and OR 0.74, 95% CI 0.37 to 1.46, respectively). Non-steroidal anti-inflammatory drug (NSAID) use was not associated with hospitalisation status (OR 0.64, 95% CI 0.39 to 1.06). Tumour necrosis factor inhibitor (anti-TNF) use was associated with a reduced odds of hospitalisation (OR 0.40, 95% CI 0.19 to 0.81), while no association with antimalarial use (OR 0.94, 95% CI 0.57 to 1.57) was observed.

Conclusions: We found that glucocorticoid exposure of ≥10 mg/day is associated with a higher odds of hospitalisation and anti-TNF with a decreased odds of hospitalisation in patients with rheumatic disease. Neither exposure to DMARDs nor NSAIDs were associated with increased odds of hospitalisation.
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http://dx.doi.org/10.1136/annrheumdis-2020-217871DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7299648PMC
July 2020

Understanding Refractory Rheumatoid Arthritis: Implications for a Therapeutic Approach.

Drugs 2020 Jun;80(9):849-857

Centre for Epidemiology Versus Arthritis, Centre for Musculoskeletal Research, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK.

Refractory rheumatoid arthritis (RA) has emerged as an area of unmet need in a landscape of generally well-controlled disease. Whilst most patients are adequately treated on methotrexate and other first-line disease-modifying anti-rheumatic drugs (DMARDs), a proportion requires biologic (b) and targeted synthetic (ts) DMARDs, with a further subsection failing multiple agents. Recent observational studies have adopted working definitions of refractory RA based on number of failed DMARDs, with prevalence estimates of 6-21% depending on threshold and study population. Risk factors include treatment delay, baseline disease activity and function, female gender, smoking, obesity and lower socioeconomic status. Practical and conceptual challenges in defining refractory RA arise from limitations of disease activity scores used to assess response, with attendant misclassification risk of co-existent non-inflammatory pathology, and failure to capture additional outcomes, such as fatigue, that have variable treatment response. Time is an important factor in defining refractory disease; registry studies show that growing treatment options have resulted in rapid b/tsDMARD cycling and earlier refractory status, and refractory RA is itself a dynamic concept, evolving with each new therapeutic class. Whilst the biology underpinning refractory RA remains largely unknown, a general overview of biomarker studies and clinical trials old and new offers insights into prediction of response and treatment failure. Whilst the future holds promise, current data are insufficient to personalise or meaningfully sequence b/tsDMARDs. Therefore, avoidance of a refractory course is best achieved by following proven management paradigms (e.g. early diagnosis and treat-to-target), addressing modifiable risk factors, and considering enrolment in novel trials.
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http://dx.doi.org/10.1007/s40265-020-01309-9DOI Listing
June 2020

A Common Functional Ability Score for Young People with Juvenile Idiopathic Arthritis.

Arthritis Care Res (Hoboken) 2020 Apr 14. Epub 2020 Apr 14.

Centre for Epidemiology Versus Arthritis, Division of Musculoskeletal and Dermatological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester Academic Health Sciences Centre, Manchester, UK.

Objectives: As young people enter adulthood, the interchangeable use of child and adult outcome measures may inaccurately capture changes over time. This study aimed to use item response theory (IRT) to model a continuous score for functional ability that can be used no matter which questionnaire is completed.

Methods: Adolescents (11-17 yrs) in the UK Childhood Arthritis Prospective Study self-completed an adolescent-Childhood Health Assessment Questionnaire (A-CHAQ) and a Health Assessment Questionnaire (HAQ). Their parents completed the proxy-CHAQ (P-CHAQ). Those with at least two simultaneously completed questionnaires at initial presentation or one year were included. Psychometric properties of item responses within each questionnaire were tested using Mokken analyses to assess the applicability of IRT modelling. A previously developed IRT model from the Pharmachild-NL registry was validated in CAPS participants. Agreement and correlations between IRT-scaled functional ability scores were tested using intra-class correlations and Wilcoxon signed-ranked tests.

Results: In 303 adolescents, median age at diagnosis was 13 years and 61% were female. CHAQ scores consistently exceeded HAQ scores. Mokken analyses demonstrated high scalability, monotonicity and that each questionnaire yielded reliable scores. There was little difference in item response characteristics between adolescents enrolled to CAPS and Pharmachild (maximum item residual 0.08). Significant differences were no longer evident between IRT-scaled HAQ and CHAQ scores.

Conclusion: IRT modelling allows the direct comparison of function scores regardless of different questionnaires being completed by different people over time. This facilitates ongoing assessment of function as adolescents transfer from paediatric clinics to adult services.
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http://dx.doi.org/10.1002/acr.24204DOI Listing
April 2020

Frequency of biologic switching and the outcomes of switching in children and young people with juvenile idiopathic arthritis: a national cohort study.

Lancet Rheumatol 2020 Apr 9;2(4):e217-e226. Epub 2020 Mar 9.

Centre for Epidemiology Versus Arthritis, The University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.

Background: Information is scarce about biological disease-modifying antirheumatic drug (DMARD) switching patterns in children and young people (aged ≤16 years) with juvenile idiopathic arthritis in an era of many biologic therapies. The best choice of biologic to use if the first biological DMARD is not beneficial also remains unclear. We aimed to quantify and characterise biologic switching patterns in children and young people with juvenile idiopathic arthritis, and to compare the effectiveness of using a second tumour necrosis factor inhibitor (TNFi) versus non-TNF is following failure of a first TNFi biologic in routine clinical practice.

Methods: Our study population comprised patients with juvenile idiopathic arthritis who were enrolled in two parallel UK cohort studies (the British Society for Paediatric and Adolescent Rheumatology Etanercept Cohort Study [BSPAR-ETN] and the Biologics for Children with Rheumatic Diseases [BCRD] study) between Jan 1, 2004, and April 11, 2019. Data on disease characteristics and DMARD therapy were collected at the time of initiation of a first biologic, at 6 months, at 1 year, and annually thereafter. Biologic switching patterns were described in all patients who started their first biologic from Jan 1, 2010, onwards. Among patients who started treatment with their first biologic from Jan 1, 2004, onwards, had polyarticular course juvenile idiopathic arthritis (extended oligoarthritis or polyarthritis [positive or negative for rheumatoid factor]), and who had started a second biologic, we assessed changes in outcome variables at 6 months compared with baseline and compared the proportion of patients who achieved an American College of Rheumatology Pediatric (ACR Pedi) 90 response and minimal disease activity at 6 months on the basis of the class of the second biologic (a second TNFi non-TNFi biologic). Changes in outcome variables at 6 months were compared using linear regression or logistic regression, adjusted for propensity quintiles to account for confounding by indication. We used multiple imputation to account for missing data.

Findings: Between Jan 1, 2004, and April 11, 2019, 2361 patients were enrolled on initiation of biologic therapy. From Jan 1, 2010, onwards, 1152 patients started their first biologic, most of whom started treatment with TNFis (1050 [91%]). The median follow-up was 2·2 years (IQR 1·1-3·8). During this time, 270 (23%) of 1152 patients started a second biologic, 61 (5%) started a third biologic, and 11 (1%) started a fourth biologic. Among 240 patients with polyarticular-course juvenile idiopathic arthritis, 194 (81%) started a second TNFi and 46 (19%) started a non-TNFi after an initial TNFi had failed. Choice of second treatment (second TNFi non-TNFi biologic) did not affect the proportion of patients who achieved an ACR Pedi 90 response (adjusted odds ratio [OR] 2·5, 95% CI 0·8-7·9; p=0·11) or minimal disease activity (adjusted OR 1·6, 95% CI 0·6-3·8; p=0·33).

Interpretation: For many children and young people with juvenile idiopathic arthritis, treatment with a first or second biologic is not beneficial. We found no evidence that switching to a second non-TNFi biologic was more beneficial than a second TNFi.

Funding: Versus Arthritis and The British Society for Rheumatology.
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http://dx.doi.org/10.1016/S2665-9913(20)30025-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7134528PMC
April 2020

Predictors of presenteeism, absenteeism and job loss in patients commencing methotrexate or biologic therapy for rheumatoid arthritis.

Rheumatology (Oxford) 2020 10;59(10):2908-2919

Centre for Epidemiology Versus Arthritis, Centre for Musculoskeletal Research, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester.

Objectives: Work is an important health outcome. This study aimed to identify predictors of work loss, absenteeism and presenteeism over 1 year in RA patients commencing treatment with MTX or biologics.

Methods: Patients aged 18-65 years in full/part-time employment from two UK prospective cohorts were included: MTX-starters = Rheumatoid Arthritis Medication Study; and biologic-starters = Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate. Presenteeism and absenteeism were assessed using the RA-specific Work Productivity Survey at baseline, and 6 and 12 months. Potential predictors including baseline age, gender, clinical measures (e.g. disability, pain, fatigue), psychological distress, occupation and EULAR response from baseline to 6 months were investigated.

Results: A total of 51/463 MTX-starters and 30/260 biologic-starters left work over 12 months. Higher baseline psychological distress in MTX-starters [odds ratio (OR) 1.1 (95% CI: 1.0, 1.1)] and higher disability in biologic-starters [OR 3.5 (95% CI: 1.4, 8.6)] predicted work loss. Some 16.1% of patients reported sick-leave, which was predicted by disability [OR (95% CI): MTX-starters: 1.5 (0.9, 2.3); biologic-starters: 2.4 (1.1, 5.2)]. Median presenteeism scores were very low (minimal interference) in both cohorts. Higher fatigue for MTX starters [incidence rate ratio 1.2 (95% CI: 1.0, 1.4)] and higher disability in biologic-starters (incidence rate ratio 1.4 (95% CI: 1.1, 1.7)] predicted presenteeism. Good EULAR response was associated with lower absenteeism and presenteeism in both cohorts.

Conclusion: Patients with RA still face significant limitations regarding their ability to work. Disability and EULAR response were the main predictors of work outcomes, emphasizing the need to control the disease and the importance of function in enabling work participation.
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http://dx.doi.org/10.1093/rheumatology/keaa027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7516097PMC
October 2020

What can rheumatology expect from real-world data?

Rheumatology (Oxford) 2020 01;59(1):12-13

German Rheumatism Research Centre, Epidemiology Unit, Berlin, Germany.

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http://dx.doi.org/10.1093/rheumatology/kez366DOI Listing
January 2020

Real world data in rheumatology.

Authors:
Kimme L Hyrich

Semin Arthritis Rheum 2019 12;49(3S):S22-S24

Centre for Epidemiology Versus Arthritis, Division of Musculoskeletal and Dermatological Sciences, Faculty of Biology Medicine and Health, The University of Manchester, Manchester Academic Health Science Centre, Oxford Road, Manchester M13 9PT, UK; National Institute of Health Research Manchester Biomedical Research Centre, Manchester University NHS Foundation Trust, Manchester, UK. Electronic address:

Real world data plays an important role in rheumatology, allowing us to gain deeper insights into disease progression and treatment outcomes, including safety. It takes us beyond the conclusions of a clinical trial and allows us to "test" outcomes in an uncontrolled, real-life environment. However, in order to generate trustworthy conclusions it is important that the provenance of and methodological considerations for handling real-world data are considered. This is increasingly true in this new era of big data, where not only the methods of handing such large datasets are critical, but also the ethics surrounding their collection and use. This overview summarises the key role real-world data has played in rheumatology, highlights key methodological challenges in analysing real-world data, and presents challenges for the future in order to continue to generate reliable scientific output using real-world data.
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http://dx.doi.org/10.1016/j.semarthrit.2019.09.021DOI Listing
December 2019

Long-term outcomes of patients who rate symptoms of rheumatoid arthritis as 'satisfactory'.

Rheumatology (Oxford) 2020 08;59(8):1853-1861

Centre for Epidemiology Versus Arthritis, Centre for Musculoskeletal Research, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre.

Objectives: To describe outcomes of patients with early RA in a patient acceptable symptom state (PASS) at treatment initiation and to identify clusters of symptoms associated with poor outcomes.

Methods: Data came from the Rheumatoid Arthritis Medication Study, a UK multicentre cohort study of RA patients starting MTX. The HAQ, DAS28 and other patient-reported outcome measures (PROMs) were collected at baseline, and at 6 and 12 months. Patients answering yes to the question 'Is your current condition satisfactory, when you take your general functioning and your current pain into consideration?' were defined as PASS; patients answering no were defined as N-PASS. Symptom clusters in the baseline PASS group were identified using K-medians cluster analysis. Outcomes of baseline PASS vs N-PASS patients and each cluster are compared using random effects models.

Results: Of 1127 patients, 572 (50.8%) reported being in PASS at baseline. Over one year, baseline PASS patients had lower DAS28 (mean difference = -0.71, 95% CI -0.83, -0.59) and HAQ scores (mean difference = -0.48, 95% CI -0.56, -0.41) compared with N-PASS patients. Within the baseline PASS group, we identified six symptom clusters. Clusters characterized by high disease activity and high PROMs, or moderate disease activity and high PROMs, had the worst outcomes compared with the other clusters.

Conclusion: Despite reporting their condition as 'satisfactory', early RA patients with high PROM scores are less likely to respond to therapy. This group may require increased vigilance to optimize outcomes.
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http://dx.doi.org/10.1093/rheumatology/kez497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7382599PMC
August 2020

Cervical screening uptake and rates of cervical dysplasia in the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis.

Rheumatology (Oxford) 2020 03;59(3):559-567

Arthritis Research UK Centre for Epidemiology, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.

Objectives: To compare cervical screening attendance and cytology (high- and low-grade cervical dysplasia [HGCD and LGCD]) between women with RA and the English general population and between biologic DMARD (bDMARD)-naïve and exposed women.

Methods: The British Society for Rheumatology Biologics Register for RA (BSRBR-RA), a national prospective study of RA treatment outcomes, was linked to the National Health Service Cervical Screening Programme, providing data for 12 785 women to compare with national screening data. Rates of HGCD/LGCD were compared with rates of negative smears using risk difference calculations between BSRBR-RA and national statistics. Within the BSRBR-RA, coverage was compared between those with low and high physical disability scores, while coverage and cytology results were compared between bDMARD-naïve and -exposed RA patients.

Results: The mean 5 year screening coverage was significantly higher in BSRBR-RA (83%) compared with the general population (79%), but lower in women with high disability (78%) compared with lesser disability (85%). Risk differences for HGCD were lower in the BSRBR-RA compared with national statistics, whereas risk differences for LGCD were higher. There was no statistically significant difference in the rates of HGCD or LGCD between bDMARD-exposed and -naïve women.

Conclusion: This first-ever British analysis of cervical screening rates in RA has shown that women with RA have higher screening rates than the general population. Disability negatively impacts attendance, but treatment type does not. Women with RA did not have an increased risk of HGCD compared with national statistics, which was also not influenced by bDMARD exposure.
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http://dx.doi.org/10.1093/rheumatology/kez277DOI Listing
March 2020

Early response to anti-TNF predicts long-term outcomes including sustained remission: an analysis of the BSRBR-RA.

Rheumatology (Oxford) 2020 07;59(7):1709-1714

Department of Mathematics, University of Exeter, Exeter.

Objective: To identify different trajectories of disease activity in patients with RA following initiation of a first anti-TNF.

Methods: Patients with RA starting their first anti-TNF between 2001 and 2013 were selected from the British Society for Rheumatology Biologics Register for RA. Six-monthly DAS28-ESR scores were used to identify trajectories of disease activity using latent class modelling. Data were included for six follow-ups after registration (approximately 3 years). Subgroup analysis examined changes in disease activity profiles over time.

Results: A total of 14 436 patients with RA starting their first anti-TNF were enrolled between 2001 and 2013 (13 115 between 2001 and 2008, 1321 between 2010 and 2013). The mean number of DAS28-ESR scores was 3.5/patient (s.d. 2.1), with a mean of 184.9 days (s.d. 69.9) between scores. The DAS28-ESR nadir was achieved within 250 days of commencing anti-TNF, although apparent trajectory divergence emerged by first 6-monthly follow-up at 180 days. Four distinct response trajectories comprised the most stable model. Most patients fitted into 'modest' (7986 patients; 55.3%) or 'substantial' (4676 patients; 32.4%) response trajectories. Of the remainder, 1254 (8.7%) and 520 (3.6%) fitted 'maximal' and 'minimal' response trajectories, respectively. There was a significant (P < 0.01) increase in proportion achieving 'maximal' response between 2001-2008 and 2010-2013.

Conclusion: This is the largest study to identify long-term response trajectories with anti-TNF. By 6 months, longer-term trajectory profiles of DAS28 could already be identified, with many patients identified earlier. The majority of patients had persistent moderate response, equivalent to maintained DAS28-ESR moderate disease activity. The maximal response trajectory (equivalent to sustained DAS2-ESR remission) was only achieved by approximately one-third of patients.
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http://dx.doi.org/10.1093/rheumatology/kez518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7310091PMC
July 2020

The risk of uveitis in patients with JIA receiving etanercept: the challenges of analysing real-world data.

Rheumatology (Oxford) 2020 06;59(6):1391-1397

Arthritis Research UK Centre for Epidemiology, Centre for Musculoskeletal Research, The University of Manchester, Manchester Academic Health Science Centre, Manchester.

Objectives: To describe and compare the occurrence of newly diagnosed uveitis in children with JIA receiving MTX, etanercept, adalimumab and infliximab.

Methods: This on-drug analysis included patients within UK JIA registries (British Society for Paediatric and Adolescent Rheumatology Etanercept Cohort Study and Biologics for Children with Rheumatic Diseases) with non-systemic disease, registered at MTX or biologic start with no history of uveitis. Follow-up began from date of first treatment, continuing until first uveitis, discontinuation of registered drug, most recent follow-up up or death, whichever came first. Hazard ratios comparing risk of uveitis between drugs were calculated using propensity-adjusted Cox regression.

Results: A total of 2294 patients were included (943 MTX, 304 adalimumab/infliximab, 1047 etanercept). There were 44 reported cases of uveitis (27 MTX, 16 etanercept, 1 adalimumab). Unadjusted hazard ratio showed a reduced risk of uveitis in biologic cohorts compared with MTX. After adjusting for propensity deciles, there was no significant difference in the risk of uveitis between patients receiving etanercept or MTX [hazard ratio 0.5 (0.2-1.1)]. Fully adjusted comparisons were not possible for adalimumab/infliximab as there were too few events.

Conclusions: In this first paper to compare the rate of new onset uveitis across the three main anti-TNF therapies used in JIA, a new diagnosis of uveitis is less common among patients starting biologics compared with MTX, although this did not reach statistical significance. The suggested protective effect of etanercept is likely explained by confounding, whereby patients in the MTX cohort are younger and earlier in disease, and therefore at greater risk of developing uveitis compared with etanercept patients.
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http://dx.doi.org/10.1093/rheumatology/kez449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7244776PMC
June 2020

Differential DNA methylation correlates with response to methotrexate in rheumatoid arthritis.

Rheumatology (Oxford) 2020 06;59(6):1364-1371

University College Dublin School of Medicine and Medical Science, University College Dublin, Dublin, Ireland.

Objectives: Identifying blood-based biomarkers that predict treatment response in RA is a clinical priority. We investigated differential DNA methylation as a candidate biomarker of response for the first-line drug used in RA, MTX.

Methods: DNA methylation was measured in DNA samples from individuals recruited to the Rheumatoid Arthritis Medication Study. Differentially methylated positions were compared between whole blood samples collected at baseline and at 4 weeks from patients who, by 6 months, had a good (n = 34) or poor response (n = 34) to MTX using linear modelling, adjusting for gender, age, cell composition, baseline 28-joint disease activity score (DAS28) and smoking status. Analyses also compared methylation with changes in DAS28 and changes in swollen joint count and tender joint count, and changes in CRP over the initial 6 months after MTX commencement. Differentially methylated positions showing significant differences with any response parameter were tested using pyrosequencing in an independent group of 100 patients from the Rheumatoid Arthritis Medication Study.

Results: In the discovery group, two CpG sites showed methylation changes at 4 weeks associated with clinical EULAR response by 6 months. Significant changes in methylation for three differentially methylated positions associated with change in tender joint counts, three with change in swollen joint count and a further four with change in CRP. Of the 12 CpGs, four showed replicated association in an independent dataset of samples from the Rheumatoid Arthritis Medication Study.

Conclusion: These data represent an advance on current practice by contributing to a personalized medicine strategy allowing an escalation or change in therapy as early as 4 weeks.
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http://dx.doi.org/10.1093/rheumatology/kez411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7244777PMC
June 2020

Malignancy and rheumatoid arthritis: Epidemiology, risk factors and management.

Best Pract Res Clin Rheumatol 2018 12 15;32(6):869-886. Epub 2019 Apr 15.

Arthritis Research UK Centre for Epidemiology, Centre for Musculoskeletal Research, University of Manchester, Manchester, United Kingdom; National Institute of Health Research Manchester Biomedical Research Centre, Manchester NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom. Electronic address:

Rheumatoid arthritis (RA) is a chronic inflammatory condition that can result in pain and functional disability. It is also associated with an increased occurrence of comorbidities, including an increased risk of certain cancers such as lung cancer and lymphoma. The aetiopathogenesis of this increased cancer risk is likely multifactorial and includes shared risk factors as well as chronic inflammation. There is also a concern that the treatment for RA itself may increase this risk further, particularly treatment with biologic disease-modifying anti-rheumatic drugs (DMARDs). This paper aims to review the evidence for the increased risk of cancer in RA as well as the latest evidence for the association between DMARDs and tumorigenesis. It also discusses the evidence for the management of patients with biologic DMARDs in the setting of existing cancer.
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http://dx.doi.org/10.1016/j.berh.2019.03.011DOI Listing
December 2018