The safety of glucocorticoids in patients with inflammatory musculoskeletal conditions
Lead Research Organisation:
University of Manchester
Department Name: Medical and Human Sciences
Abstract
Glucocorticoids, also known as steroids, are drugs commonly used for the treatment of rheumatoid arthritis and other inflammatory conditions. Steroids are a good treatment because they quickly ease joint pain, swelling and stiffness, thus improving disability. However, as with most medication, there are potential side effects.
When starting medication, most patients want to know their chance of developing side effects. However, we don‘t know accurately how commonly side effects occur, what dose of steroid leads to side effects, or what sort of person is particularly at risk. The chance of side effects probably varies according to many factors, including how old a patient is, their gender, whether they have other diseases, or are taking other medication. This research aims to answer these questions, and to provide a likelihood of side effects tailored to the individual.
Only patients themselves know whether they take their medicines, at what dose, or whether they develop side effects. In order to improve risk measurement, we need to collect such information directly from patients. Then, having measured risk, we need to improve the way we communicate this information to patients. This project aims to develop electronic systems to advance this two-way communication.
When starting medication, most patients want to know their chance of developing side effects. However, we don‘t know accurately how commonly side effects occur, what dose of steroid leads to side effects, or what sort of person is particularly at risk. The chance of side effects probably varies according to many factors, including how old a patient is, their gender, whether they have other diseases, or are taking other medication. This research aims to answer these questions, and to provide a likelihood of side effects tailored to the individual.
Only patients themselves know whether they take their medicines, at what dose, or whether they develop side effects. In order to improve risk measurement, we need to collect such information directly from patients. Then, having measured risk, we need to improve the way we communicate this information to patients. This project aims to develop electronic systems to advance this two-way communication.
Technical Summary
Aim
To quantify the risk of single and multiple adverse events in patients with inflammatory musculoskeletal conditions treated with glucocorticoid (GC) therapy.
Objectives
To explore the association between time-varying GC dosage and route of administration of GC and outcome.
To develop and validate a predictive tool to estimate likelihood of GC-associated adverse events.
To address the influence of adherence upon risk estimates.
To better understand the benefit/ harm balance of GC use.
To improve risk communication through development of an electronic visual tool
Design and Methodology
The planned analyses will use databases that are established or in development. First, nested case-control and cohort studies, with modelling of time-varying GC exposure including dose, will be undertaken using respected UK primary care databases: the General Practice Research Database and The Health Improvement Network. Prediction modelling will be used to identify patients at risk of GC-associated adverse events (including infection, cardiovascular disease, diabetes, fractures), in one dataset with validation in the second dataset. In order to address the influence of factors captured only in secondary care, such as parenteral GC therapy and disease severity measures, further analysis will be undertaken in two additional databases under development, the arc Early Inflammatory Arthritis Information System and the NorthWest e-Health e-Labs project. Additional funding will be sought to develop and implement novel technology to capture patient reported outcome measures and adherence data, and to develop an electronic visual tool for risk communication.
Scientific and medical opportunities
It is not clear which GC treatment regimes place patients at risk of adverse events, what degree of risk is conferred, or what predisposes patients to such events. This makes accurate communication of risk difficult. The work described above will unpick some of the complexities of GC-associated adverse events. It will also move risk estimation towards personalised risk assessment, whereby patients can be informed of their individual risk of side effects given their profile, including demographics, disease characteristics and co-morbidity.
Pharmacoepidemiology is currently limited by the scope of available datasets. These projects will improve capture of clinical data, both from clinicians and directly from patients. Although focussed on GC safety, the skills, techniques and visual tools developed in these projects will have wider application for investigating the safety of other medications.
To quantify the risk of single and multiple adverse events in patients with inflammatory musculoskeletal conditions treated with glucocorticoid (GC) therapy.
Objectives
To explore the association between time-varying GC dosage and route of administration of GC and outcome.
To develop and validate a predictive tool to estimate likelihood of GC-associated adverse events.
To address the influence of adherence upon risk estimates.
To better understand the benefit/ harm balance of GC use.
To improve risk communication through development of an electronic visual tool
Design and Methodology
The planned analyses will use databases that are established or in development. First, nested case-control and cohort studies, with modelling of time-varying GC exposure including dose, will be undertaken using respected UK primary care databases: the General Practice Research Database and The Health Improvement Network. Prediction modelling will be used to identify patients at risk of GC-associated adverse events (including infection, cardiovascular disease, diabetes, fractures), in one dataset with validation in the second dataset. In order to address the influence of factors captured only in secondary care, such as parenteral GC therapy and disease severity measures, further analysis will be undertaken in two additional databases under development, the arc Early Inflammatory Arthritis Information System and the NorthWest e-Health e-Labs project. Additional funding will be sought to develop and implement novel technology to capture patient reported outcome measures and adherence data, and to develop an electronic visual tool for risk communication.
Scientific and medical opportunities
It is not clear which GC treatment regimes place patients at risk of adverse events, what degree of risk is conferred, or what predisposes patients to such events. This makes accurate communication of risk difficult. The work described above will unpick some of the complexities of GC-associated adverse events. It will also move risk estimation towards personalised risk assessment, whereby patients can be informed of their individual risk of side effects given their profile, including demographics, disease characteristics and co-morbidity.
Pharmacoepidemiology is currently limited by the scope of available datasets. These projects will improve capture of clinical data, both from clinicians and directly from patients. Although focussed on GC safety, the skills, techniques and visual tools developed in these projects will have wider application for investigating the safety of other medications.
Organisations
- University of Manchester, Manchester, United Kingdom (Collaboration, Fellow, Lead Research Organisation)
- University of Oxford, United Kingdom (Collaboration)
- McGill University, Canada (Collaboration)
- University College London, United Kingdom (Collaboration)
- The European League Against Rheumatism (EULAR) (Collaboration)
- The Office for Creative Research (OCR) (Collaboration)
- uMotif (Collaboration)
- Health Unlocked (Collaboration)
- London School of Economics & Pol Sci, United Kingdom (Collaboration)
- Google (Collaboration)
Publications

Askling J
(2011)
Influence of biological agents on cardiovascular disease in rheumatoid arthritis.
in Annals of the rheumatic diseases

Black RJ
(2015)
Half of U.K. patients with rheumatoid arthritis are prescribed oral glucocorticoid therapy in primary care: a retrospective drug utilisation study.
in Arthritis research & therapy


Bluett J
(2014)
Association of a complement receptor 1 gene variant with baseline erythrocyte sedimentation rate levels in patients starting anti-TNF therapy in a UK rheumatoid arthritis cohort: results from the Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate cohort.
in The pharmacogenomics journal

Costello R
(2017)
Patient perceptions of glucocorticoid side effects: a cross-sectional survey of users in an online health community.
in BMJ open


Davies R
(2013)
Influence of anti-TNF patient warning regarding avoidance of high risk foods on rates of listeria and salmonella infections in the UK.
in Annals of the rheumatic diseases

Dixon W
(2015)
Rheumatoid arthritis: biological drugs and risk of infection
in The Lancet

Dixon W
(2011)
Is anti-TNF therapy safer than previously thought?
in JAMA

Dixon WG
(2012)
Immediate and delayed impact of oral glucocorticoid therapy on risk of serious infection in older patients with rheumatoid arthritis: a nested case-control analysis.
in Annals of the rheumatic diseases
Title | Bedrock: Exhibition of Nicola Dale's artist-in-residence time in the Centre for Epidemiology |
Description | This innovative arts-science collaboration allowed visual artist Nicola Dale to undertake a residency in the Arthritis Research UK Centre for Epidemiology (CfE) that was founded in 1954. The initial aim was to research, develop and create artworks inspired by the CfE's archive, and to reflect the relevance of the archive in today's medical and epidemiological practice. Nicola focussed on an x-ray archive collected by the first Director, Dr John Lawrence, in a 1950's study of rheumatism in local miners. Further supported by a Wellcome Trust ISSF Public Engagement Award, the work extended to include interviews and workshops with patients and local miners in collaboration with the Centre for History of Science, Technology & Medicine. Local miners were invited through a live discussion on BBC Radio Manchester. These interviews significantly influenced several art pieces. A further collaboration with the Granada Centre for Visual Anthropology allowed students to document the project through short films, shown in the final exhibition. The project was conceived to make epidemiology accessible through a creative collaboration interweaving art, history, science and medicine. |
Type Of Art | Artwork |
Year Produced | 2016 |
Impact | The work culminated with a public exhibition "Bedrock" in Salford from 28-31st January that featured sculptures and 2-D artwork, an artist's talk as well as films of the creative process and an uncovered 1952 film of Dr Lawrence at the Walkden Miners Clinic from the BFI archive. The exhibition had significant press interest including the BBC and Manchester Evening News. There were 188 visitors over three days including members of the public, arthritis patients, miners, artists, MA students from the Granada Centre, clinicians and UoM researchers. During the show there were 1052 visitors to www.nicoladale.com. Visitor book comments included: "Such a well researched project and so painstakingly, imaginatively and beautifully executed" "An epic subject well deserving the epic exposition." "Moving, insightful, reflective, poetic. Wonderful collaboration between Nicola, Manchester University and a range of audiences." Nicola has maintained a project blog and is producing a commemorative publication. In addition to the exhibition, further engagement and impact included visits to the artist's studio for the research group, encouraging their own involvement in traditional and creative public engagement. The project has an important legacy in the artwork to be mounted in the CfE and within outpatients at Salford Royal Hospital. The work will also be showcased during the European City of Science Festival (July 2016) and will be included in the Manchester Histories Festival (June 2016). |
URL | http://www.nicoladale.com/bedrock---work-in-progress.html |
Description | CHM Working Group on the safety and efficacy of insulins |
Geographic Reach | National |
Policy Influence Type | Participation in advisory committee |
Description | EULAR recommendations for core dataset in RA |
Geographic Reach | Multiple continents/international |
Policy Influence Type | Membership of a guideline committee |
Description | EULAR taskforce on steroid safety |
Geographic Reach | Europe |
Policy Influence Type | Membership of a guideline committee |
Impact | Guidelines on the safe prescribing of glucocorticoid therapy will improve outcomes for patients treated with such therapies, avoiding unnecessary doses through guiding clinical practice |
Description | Glucocorticoid infection risk included in UpToDate |
Geographic Reach | Multiple continents/international |
Policy Influence Type | Influenced training of practitioners or researchers |
Description | Guidelines for giant cell arteritis |
Geographic Reach | Multiple continents/international |
Policy Influence Type | Membership of a guideline committee |
Description | MHRA Ad Hoc Committee for the review of over the counter analgesics |
Geographic Reach | National |
Policy Influence Type | Implementation circular/rapid advice/letter to e.g. Ministry of Health |
Impact | Improved balance of benefits and harms of prescribed over the counter medication |
Description | Arthritis Research UK Centre for Epidemiology |
Amount | £2,500,000 (GBP) |
Organisation | Versus Arthritis |
Start | 08/2012 |
End | 07/2017 |
Description | Centres of Excellence |
Amount | £1,999,419 (GBP) |
Funding ID | 21755 |
Organisation | Versus Arthritis |
Start | 08/2018 |
End | 07/2023 |
Description | Cross-Farr small awards |
Amount | £15,000 (GBP) |
Organisation | Farr Institute of Health Informatics Research |
Sector | Academic/University |
Country | United Kingdom |
Start | 07/2016 |
End | 07/2017 |
Description | E-Health Centres of Excellence |
Amount | £4,500,000 (GBP) |
Organisation | Medical Research Council (MRC) |
Sector | Academic/University |
Country | United Kingdom |
Start | 03/2013 |
End | 03/2018 |
Description | Evaluating the Accuracy of New Methods of Pharmacosurveillance: Computerized Administrative Data and Electronic Prescribing and Drug Management Systems |
Amount | £747,000 (GBP) |
Funding ID | 99305 |
Organisation | Canadian Institutes of Health Research |
Sector | Public |
Country | Canada |
Start | 04/2011 |
End | 04/2015 |
Description | Generic roll-out of the Arthritis Research UK Catalogue of Studies |
Amount | £15,000 (GBP) |
Funding ID | 20878 |
Organisation | Versus Arthritis |
Start | 07/2014 |
End | 01/2016 |
Description | Granulomatosis with Polyangiitis: Defining the risk of infection associated with the disease and treatment, Arthritis Research UK |
Amount | £30,182 (GBP) |
Funding ID | 20613 |
Organisation | Versus Arthritis |
Start | 04/2014 |
End | 03/2015 |
Description | HS&DR |
Amount | £618,424 (GBP) |
Organisation | National Institute for Health Research |
Sector | Public |
Country | United Kingdom |
Start | 09/2015 |
End | 08/2017 |
Description | INBANK Project Manager & Project Support Officer |
Amount | £269,382 (GBP) |
Organisation | Versus Arthritis |
Start | 10/2011 |
End | 10/2014 |
Description | INBANK Scientific Lead (Research Funding Award) |
Amount | £53,876 (GBP) |
Organisation | Versus Arthritis |
Start | 04/2012 |
End | 12/2014 |
Description | ISSF |
Amount | £3,450 (GBP) |
Organisation | Wellcome Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 07/2015 |
End | 01/2016 |
Description | MRC Confidence in Concept 2 |
Amount | £106,270 (GBP) |
Organisation | Medical Research Council (MRC) |
Sector | Academic/University |
Country | United Kingdom |
Start | 10/2014 |
End | 06/2015 |
Description | Project Grant: Psoriasis in UK BIobank |
Amount | £165,670 (GBP) |
Organisation | Versus Arthritis |
Start | 03/2016 |
End | 02/2019 |
Description | Project Grant: Sleep-RA |
Amount | £249,990 (GBP) |
Funding ID | 21188 |
Organisation | Versus Arthritis |
Start | 04/2016 |
End | 03/2019 |
Description | Salford EPR for research |
Amount | £43,416 (GBP) |
Organisation | Salford Royal NHS Foundation Trust |
Sector | Public |
Country | United Kingdom |
Start | 08/2013 |
End | 08/2014 |
Description | Special Strategic Award: Cloudy with a Chance of Pain |
Amount | £199,212 (GBP) |
Funding ID | 21225 |
Organisation | Versus Arthritis |
Start | 09/2015 |
End | 08/2017 |
Description | Special Strategic Award: REMORA |
Amount | £394,000 (GBP) |
Organisation | Versus Arthritis |
Start | 02/2015 |
End | 02/2017 |
Title | Drug preparation algorithm |
Description | Algorithm and reporting framework for increasing the efficiency and transparency of drug data preparation methods |
Type Of Material | Improvements to research infrastructure |
Year Produced | 2017 |
Provided To Others? | Yes |
Impact | Markedly increased the efficiency of data preparation for users |
Title | DrugPrep |
Description | Framework to improve the efficiency and transparency of drug exposure data preparation |
Type Of Material | Improvements to research infrastructure |
Year Produced | 2018 |
Provided To Others? | Yes |
Impact | Marked reduction in the time spent to prepare drug exposure data, leading to more efficient use of funders' money |
URL | https://zenodo.org/record/1313712#.XHZOtFP7Txo |
Description | Anna Cox |
Organisation | University College London |
Department | Department of Computer Science |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Connection made with research group interested in studying Citizen Science projects |
Collaborator Contribution | Contribution to design and evaluation of Citizen Science experiment |
Impact | None to date |
Start Year | 2015 |
Description | Dynamic consent |
Organisation | London School of Economics and Political Science (University of London) |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Provided clinical setting for application of dymanic consent model |
Collaborator Contribution | Established the model of dynamic consent and its practical application through a RTSB award |
Impact | Publications |
Start Year | 2012 |
Description | Dynamic consent |
Organisation | University of Oxford |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Provided clinical setting for application of dymanic consent model |
Collaborator Contribution | Established the model of dynamic consent and its practical application through a RTSB award |
Impact | Publications |
Start Year | 2012 |
Description | EULAR Registers and Observational Drug Studies (RODS) |
Organisation | The European League Against Rheumatism (EULAR) |
Country | Switzerland |
Sector | Charity/Non Profit |
PI Contribution | Co-Lead of EULAR RODS Study Group |
Collaborator Contribution | Community of registers and observational drug studies across European rheumatology. Inaugural meeting (convened by me) in Prague Nov 14/15th 2013 |
Impact | Inaugural meeting of RODS Working Groups in progress |
Start Year | 2012 |
Description | EULAR taskforce on steroid safety |
Organisation | The European League Against Rheumatism (EULAR) |
Country | Switzerland |
Sector | Charity/Non Profit |
PI Contribution | Contributed to guidelines for the use of steroids in inflammatory musculoskeletal disease |
Collaborator Contribution | Contributed to guidelines for the use of steroids in inflammatory musculoskeletal disease |
Impact | Publication in draft |
Start Year | 2014 |
Description | Google Android Wear |
Organisation | |
Country | United States |
Sector | Private |
PI Contribution | Established new collaboration between University of Manchester and Google Android Wear. Co-designed a smartwatch app for self-reported pain and activity alongside passively collected activity data. Will be Google Android Wear's first health study with a view to ongoing collaboration. The study will be nested within Cloudy with a Chance of Pain |
Collaborator Contribution | Developed partnership through direct contact with lead engineer at Google Android Wear, proposing the research study and partnership |
Impact | Project is expected to launch in April 2017. Google providing 100 smartwatches and in kind contributions from software and hardware engineering |
Start Year | 2016 |
Description | Goran Nenadic |
Organisation | University of Manchester |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Collaborative working on multiple projects: automated deidentification of EPR letters, extracting dose information from prescriptions, narratives within HealthUnlocked |
Collaborator Contribution | Computer Science methods to help solve epidemiological challenges |
Impact | One publication to date |
Start Year | 2015 |
Description | Health Unlocked |
Organisation | Health Unlocked |
Country | United Kingdom |
Sector | Private |
PI Contribution | Surveys within HU platform. Analysis of narratives within HU communities |
Collaborator Contribution | Data provision and extension of their HealthGraph |
Impact | No outputs to date |
Start Year | 2016 |
Description | Michal Abrahamowicz |
Organisation | McGill University |
Department | Department of Epidemiology, Biostatistics and Occupational Health |
Country | Canada |
Sector | Academic/University |
PI Contribution | Input of clinical and epidemiological challenges that require biostatistical solutions |
Collaborator Contribution | Biostatistical solutions to clinical and epidemiological challenges |
Impact | Publications |
Start Year | 2010 |
Description | Robyn Tamblyn |
Organisation | McGill University |
Department | Department of Epidemiology, Biostatistics and Occupational Health |
Country | Canada |
Sector | Academic/University |
PI Contribution | Co-applicant on international pharmacosurveillance project. Run UK arm of three international sites |
Collaborator Contribution | Co-applicant on international pharmacosurveillance project. Coordinated by Robyn Tamblyn @ McGill |
Impact | Publications in progress. Abstracts accepted at ISPE meeting |
Start Year | 2010 |
Description | The Office for Creative Research |
Organisation | The Office for Creative Research (OCR) |
Country | United States |
Sector | Private |
PI Contribution | Established connection with OCR in 2015 to explore opportunities for collaboration around Cloudy with a Chance of Pain and implementation of Dynamic Consent interface |
Collaborator Contribution | Developing data visualisations and citizen science project |
Impact | No outputs yet |
Start Year | 2015 |
Description | uMotif |
Organisation | uMotif |
Country | United Kingdom |
Sector | Private |
PI Contribution | Co-design of smartphone application to collect data on musculoskeletal disease, including use of accelerometer and GPS data |
Collaborator Contribution | Use of their configurable smartphone application and supporting systems |
Impact | MRC Confidence in Concept award Funding for Cloudy with a Chance of Pain, extending work to linkage to wearable devices |
Start Year | 2013 |
Description | BBC Breakfast |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Media (as a channel to the public) |
Results and Impact | Video feature and then interview on the 'BBC Breakfast couch'. Viewing figures of 7M. Significant public response following broadcast with recruitment spike of around 4000 new registrants that day. Recruiting one new user per second following the show |
Year(s) Of Engagement Activity | 2016 |
Description | BBC2's Trust Me I'm a Doctor |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Media (as a channel to the public) |
Results and Impact | Broadcast planned for January 2016. Should drive recruitment Due to broadcast Jan 2016 |
Year(s) Of Engagement Activity | 2015 |
Description | Bedrock: Public exhibition of artwork from Centre for Epidemiology artist in residence |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | Three-day public exhibition "Bedrock" in Jan 2016, with BBC coverage (funded by the Wellcome Trust) Legacy artwork to be mounted in Centre for Epidemiology & Salford Royal Hospital Due to feature in Manchester Histories Festival June 2016 & European City of Science Festival 2016 |
Year(s) Of Engagement Activity | 2016 |
URL | http://www.nicoladale.com/uploads/1/0/3/6/10361696/ndale_uom_residency_info_2015.pdf |
Description | National newspaper coverage |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Media (as a channel to the public) |
Results and Impact | Articles about Cloudy with a Chance of Pain features in multiple national newspapers, both print and online editions. National papers included the Independent, The Mirror, Daily Express and Daily Mail. |
Year(s) Of Engagement Activity | 2016 |
URL | http://www.independent.co.uk/life-style/health-and-families/health-news/smartphone-app-could-help-un... |