ORCID Profile
0000-0002-7044-5801
Current Organisations
University College London
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University of New South Wales
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Publisher: Oxford University Press (OUP)
Date: 12-2017
Publisher: Wiley
Date: 25-06-2019
DOI: 10.1002/ART.40881
Publisher: Frontiers Media SA
Date: 18-12-2018
Publisher: BMJ
Date: 23-05-2022
DOI: 10.1136/ANNRHEUMDIS-2022-EULAR.1494
Abstract: There are currently ten biologic and targeted synthetic (b/ts)DMARDs acting via five different modes of action (MOA) available for the treatment of psoriatic arthritis (PsA) in Australia. b/tsDMARDs are government-subsidised, and once the patient reaches the eligibility requirements, the clinician can prescribe the agent deemed most appropriate. Available agents include TNF inhibitors (TNFi, adalimumab, etanercept, infliximab, golimumab, certolizumab pegol), IL-17A inhibitors (IL-17Ai, secukinumab, ixekizumab), and IL-12/23 inhibitor (IL-12/23i, ustekinumab). Two new MOAs were recently added to the rheumatologist’s armamentarium: the first JAK inhibitor (JAKi, tofacitinib) was subsidized from May 2019 followed by upadacitinib from Oct 2021, and an IL-23 inhibitor (IL-23i, guselkumab) was subsidized from July 2021. The aim of this analysis was to describe the changing patterns of b/tsDMARD use for the treatment of PsA in real-world practice in Australia. Deidentified clinical data were sourced from the OPAL dataset, which is collected in a custom-built electronic medical record during the routine consultation1. Data from patients years with a physician diagnosis of PsA who were prescribed a b/tsDMARD between Jan-2007 and Sept-2021 were included in the analysis. The software program Tableau was used to display the data. At Sept 2021, 6,150 (38% of the total) patients with PsA in the OPAL dataset were prescribed b/tsDMARDs. Of these patients, 3741 (61%) were currently prescribed a TNFi, 1503 (24%) an IL-17Ai, 556 (9%) a JAKi, 222 (4%) an IL-12/23i and 134 patients (2%) an IL-23i. Over time, the 1st line TNFi initiations have decreased from 79.5% in 2018 to 65.2% in 2021. Conversely, 1st line IL-17Ai initiations have increased from 14.4% in 2018 to 22.2% in 2021. In 2021, TNFi accounted for 53.4% of 2 nd line initiations and 38.2% of 3 rd line initiations. IL-17Ai accounted for 30.4% of 2 nd and 37.0% of 3 rd line initiations and JAKi accounted for 10.5% of 2 nd line and 14.2% of 3 rd line initiations. In the 3 months that IL-23i has been subsidised, this MOA was the most initiated agent for patients who had been treated with more than two prior b/tsDMARDs. In 2021, 52.1% of patients switching from a 1st line TNFi switched to an alternative TNFi, 33.3% switched to an IL-17Ai and 11.3% switched to a JAKi in 2 nd line. Of those switching from a 1 st line IL-17Ai, 59.6% initiated a TNFi, 21.2% switched to an alternative IL-17Ai and 11.5% switched to a JAKi. The patterns of b/tsDMARD utilisation for the treatment of PsA, when the choice of agent is at the discretion of the rheumatologist, remains dynamic and is evolving as new MOAs become available. TNFi remains the most prescribed b/tsDMARD for first line therapy. However an increase in first line use of alternative MOAs has been observed. TNFi cycling remains a commonly utilised real world treatment strategy but appears to be declining as new MOAs become available. [1]Littlejohn GO, Tymms KE, Smith T, Griffiths HT. Using big data from real-world Australian rheumatology encounters to enhance clinical care and research. Clin Exp Rheumatol. Sep-Oct 2020 (5):874-880. Figure 1. Percentage of patients initiating b/tsDMARDs by year and line of therapy. The authors acknowledge the members of OPAL Rheumatology Ltd and their patients for providing clinical data for this study, and Software4Specialists Pty Ltd for providing the Audit4 platform. Peter Youssef Speakers bureau: AbbVie, Novartis, Eli Lilly, Sabina Ciciriello: None declared, Gene-Siew Ngian: None declared, Juan Aw: None declared, Barry Kane: None declared, Catherine OSullivan: None declared, Tegan Smith: None declared, Claire Deakin: None declared, Geoff Littlejohn Consultant of: Abbvie, Janssen, Bristol Myers Squibb, Gilead, Eli Lilly, and MSD
Publisher: Wiley
Date: 16-09-2016
DOI: 10.1002/ACR.22867
Publisher: Springer Science and Business Media LLC
Date: 08-03-2021
Publisher: BMJ
Date: 23-12-2023
Abstract: To define the host mechanisms contributing to the pathological interferon (IFN) type 1 signature in Juvenile dermatomyositis (JDM). RNA-sequencing was performed on CD4 + , CD8 + , CD14 + and CD19 + cells sorted from pretreatment and on-treatment JDM (pretreatment n=10, on-treatment n=11) and age/sex-matched child healthy-control (CHC n=4) peripheral blood mononuclear cell (PBMC). Mitochondrial morphology and superoxide were assessed by fluorescence microscopy, cellular metabolism by 13 C glucose uptake assays, and oxidised mitochondrial DNA (oxmtDNA) content by dot-blot. Healthy-control PBMC and JDM pretreatment PBMC were cultured with IFN-α, oxmtDNA, cGAS-inhibitor, TLR-9 antagonist and/or n -acetyl cysteine (NAC). IFN-stimulated gene (ISGs) expression was measured by qPCR. Total numbers of patient and controls for functional experiments, JDM n=82, total CHC n=35. Dysregulated mitochondrial-associated gene expression correlated with increased ISG expression in JDM CD14+ monocytes. Altered mitochondrial-associated gene expression was paralleled by altered mitochondrial biology, including ‘megamitochondria’, cellular metabolism and a decrease in gene expression of superoxide dismutase ( SOD )1. This was associated with enhanced production of oxidised mitochondrial (oxmt)DNA. OxmtDNA induced ISG expression in healthy PBMC, which was blocked by targeting oxidative stress and intracellular nucleic acid sensing pathways. Complementary experiments showed that, under in vitro experimental conditions, targeting these pathways via the antioxidant drug NAC, TLR9 antagonist and to a lesser extent cGAS-inhibitor, suppressed ISG expression in pretreatment JDM PBMC. These results describe a novel pathway where altered mitochondrial biology in JDM CD14+ monocytes lead to oxmtDNA production and stimulates ISG expression. Targeting this pathway has therapeutical potential in JDM and other IFN type 1-driven autoimmune diseases.
Publisher: Springer Science and Business Media LLC
Date: 05-2017
Publisher: Research Square Platform LLC
Date: 20-04-2020
DOI: 10.21203/RS.3.RS-23651/V2
Abstract: A striking anecdotal feature of the Coronavirus disease 2019 (COVID-19) outbreak is the difference in morbidity and mortality between the sexes. Here, we present a meta-analysis of 206, 128 reported cases to demonstrate that whilst there is no difference in the proportion of males and females with confirmed COVID-19, male patients have more than double the odds of requiring intensive treatment unit admission (OR 2.5) and higher odds of death (OR 1.60) when compared to females. We review data revealing how previous Coronavirus outbreaks have demonstrated a similar pattern. Important differences in the immune response to infection exist between sexes, which are likely to contribute to this observation. In this review, we discuss these differences highlighting that females have a more robust innate antiviral response and a better adaptive immune response to infection. An appreciation of how sex is influencing COVID-19 outcomes will have important implications for clinical management and mitigation strategies for this disease.
Publisher: Research Square Platform LLC
Date: 17-04-2020
DOI: 10.21203/RS.3.RS-23651/V1
Abstract: A striking anecdotal feature of the Coronavirus disease 2019 (COVID-19) outbreak is the difference in morbidity and mortality between the sexes. Here, we present a meta-analysis of 206, 128 reported cases to demonstrate that whilst there is no difference in the proportion of males and females with confirmed COVID-19, male patients have more than double the odds of requiring intensive treatment unit admission (OR 2.5) and higher odds of death (OR 1.60) when compared to females. We review data revealing how previous Coronavirus outbreaks have demonstrated a similar pattern. Important differences in the immune response to infection exist between sexes, which are likely to contribute to this observation. In this review, we discuss these differences highlighting that females have a more robust innate antiviral response and a better adaptive immune response to infection. An appreciation of how sex is influencing COVID-19 outcomes will have important implications for clinical management and mitigation strategies for this disease.
Publisher: Oxford University Press (OUP)
Date: 09-01-2023
Publisher: American Society of Hematology
Date: 07-2007
DOI: 10.1182/BLOOD-2006-11-055442
Abstract: X-linked severe combined immunodeficiency (SCID-X1) results from mutations in the IL2RG gene, which encodes the common gamma chain (γc) of the receptors for interleukin (IL)-2, 4, 7, 9, 15, and 21. Affected infants typically lack T and natural killer (NK) cells as a consequence of loss of signaling via the IL-7 receptor (IL-7R) and the IL-15R, respectively. In some infants, however, autologous NK cells are observed despite failure of T-cell ontogeny. The mechanisms by which mutations in γc differentially impact T- and NK-cell ontogeny remain incompletely understood. We used SCID-X1 patient–derived EBV-transformed B cells to test the hypothesis that the IL-15R–mediated signaling is preferentially retained as γc expression becomes limiting. Signal transduction via the IL-15R was readily detected in control EBV-transformed B cells, and via the IL-7R when modified to express IL-7Rα. Under the same experimental conditions, patient-derived EBV-transformed B cells expressing trace amounts of γc proved incapable of signal transduction via the IL-7R while retaining the capacity for signal transduction via the IL-15R. An equivalent result was obtained in ED-7R cells modified to express varying levels of γc. Collectively, these results confirm that signal transduction via the IL-15R, and hence NK ontogeny, is preferentially retained relative to the IL-7R as γc expression becomes limiting.
Publisher: BMJ
Date: 19-05-2021
DOI: 10.1136/ANNRHEUMDIS-2021-EULAR.2253
Abstract: Registry studies and clinical trials are increasingly incorporating patient reported outcomes (PROs) to measure the full burden of disease and better measure the efficacy and value of medicines however, the burden of paper-based surveys, time constraints, and privacy concerns impede the widespread use of PROs in routine clinical care. To develop a simple and secure technological solution to incorporate validated PROs into routine clinical care for patients with rheumatic diseases, and to assess the patient response to functional assessment of chronic illness therapy fatigue (FACIT-F), patient health questionnaire-2 (PHQ-2), and healthcare resource utilization (HCRU) questionnaires delivered using this ePRO method. A novel ePRO questionnaire delivery system was developed by Software4Specialists in partnership with OPAL Rheumatology. Validated PRO questionnaires were sent from the patient’s electronic medical record (Audit4, Software4Specialists) and delivered to the patient’s email address at time intervals specified by the rheumatologist (defaults to quarterly) or completed in the clinic waiting room prior to the consultation using a tablet or the patient’s smart phone (in-practice). Completed questionnaires were encrypted and returned directly to the patient’s Audit4 electronic medical record held on the clinician’s server for review at the next clinical consultation. The link to the PRO questionnaire expired within 28 days if the questionnaire was not completed, and the questionnaires were automatically cancelled if 2 consecutive links expired. This technology was made available to up to 111 rheumatologists located in 42 clinics in 6 states/territories in Australia, and the use of this technology to furnish the clinical consultation was voluntary for clinicians and patients. Deidentified clinical data was extracted from the servers of participating rheumatologists and aggregated across all sites. 1 Data collected between April 2016-Dec 2020 was analysed descriptively. Between April 2016-Dec 2020, 99,505 FACIT-F, PHQ-2 and HCRU questionnaires have been delivered to 5,784 patients from 39 of 42 contributing clinics (93%). 85% of questionnaires were delivered via email and 15% in-practice. Overall, 85% of patients completed at least one questionnaire, and of all questionnaires sent, 73% were completed. These rates have remained consistent over time. The completion rates were higher when questionnaires were delivered to patients in-practice compared to email (96% vs 69%). Females were more likely to engage with the questionnaires than males (87% vs 81%), and older patients were slightly more likely to complete all questionnaires delivered. 69% of questionnaires sent via email were completed on the day they were delivered and 94% were completed within 7 days. The median (IQR) number of questionnaires completed per patient was 3 (1,7) and the median (IQR) time since the first questionnaire was completed was 13 months (5,26). The novel Audit4 ePRO delivery system is an effective tool for incorporating PROs into routine clinical care to capture data directly from the patient on the impact of their condition on their quality of life. The data generated provides a unique opportunity to understand the full burden of disease for patients in the real-world setting and the impact of interventions. [1]Littlejohn GO, Tymms KE, Smith T, Griffiths HT. Using big data from real-world Australian rheumatology encounters to enhance clinical care and research. Clin Exp Rheum 2020:38(5): 874 -880. The authors acknowledge the members of OPAL Rheumatology Ltd and their patients for providing clinical data for this study, and Software4Specialists Pty Ltd for providing the Audit4 platform. Kathleen Tymms: None declared, Tegan Smith: None declared, Claire Deakin: None declared, Tim Freeman: None declared, David Hoffman: None declared, Dana Segelov: None declared, Hedley Griffiths Consultant of: AbbVie, Gilead, Novartis and Lilly., Sabina Ciciriello: None declared, Peter Youssef: None declared, David Mathers: None declared, Catherine OSullivan: None declared, Geoff Littlejohn Consultant of: Over the last 5 years Geoffrey Littlejohn has received educational grants and consulting fees from AbbVie, Bristol Myers Squibb, Eli Lilly, Gilead, Novartis, Pfizer, Janssen, Sandoz, Sanofi and Seqirus
Publisher: Springer Science and Business Media LLC
Date: 25-09-2021
DOI: 10.1186/S12969-021-00637-8
Abstract: Juvenile Idiopathic Inflammatory Myopathies (IIM) are a group of rare diseases that are heterogeneous in terms of pathology that can include proximal muscle weakness, associated skin changes and systemic involvement. Despite options for treatment, many patients continue to suffer resistant disease and lasting side-effects. Advances in the understanding of the immunopathology and genetics underlying IIM may specify new therapeutic targets, particularly where conventional treatment has not achieved a clinical response. An upregulated type I interferon signature is strongly associated with disease and could be a prime target for developing more specific therapeutics. There are multiple components of the IFN pathway that could be targeted for blockade therapy. Downstream of the cytokine receptor complexes are the Janus kinase-signal transducers and activators of transcription (JAK-STAT) pathway, which consists of JAK1–3, TYK2, and STAT1–6. Therapeutic inhibitors have been developed to target components of this pathway. Promising results have been observed in case studies reporting the use of the JAK inhibitors, Baricitinib, Tofacitinib and Ruxolitinib in the treatment of refractory Juvenile Dermatomyositis (JDM). There is still the question of safety and efficacy for the use of JAK inhibitors in JDM that need to be addressed by clinical trials. Here we review the future for the use of JAK inhibitors as a treatment for JDM.
Publisher: Elsevier BV
Date: 11-2009
DOI: 10.1038/MT.2009.223
Publisher: BMJ
Date: 19-05-2021
DOI: 10.1136/ANNRHEUMDIS-2021-EULAR.2256
Abstract: There are currently eleven biologic and targeted synthetic (b/ts)DMARDs acting via five different modes of action available for the treatment of RA in Australia. The cost of b/tsDMARDs is subsidized by government for patients that have active RA despite six months of combination csDMARD therapy. Once a patient is eligible, the clinician can prescribe the b/tsDMARD they deem to be the most clinically appropriate for the patient. In Oct 2015 the first JAK inhibitor (JAKi) became available in Australia (tofacitinib, TOF), baricitinib (BARI) became available in Sept 2018, and upadacitinib (UPA) in May 2020. Each of these oral tsDMARDs possess different selectivity profiles towards different members of the JAK family (JAK1–3 and Tyk2). The aim of this analysis was to determine the patterns of JAKi cycling in real-world practice in Australia. Deidentified clinical data were sourced from the OPAL dataset, which is collected in a custom-built electronic medical record during the routine consultation 1 . Data from patients years with RA who commenced a b/tsDMARD between Jan-2007 and Dec-2020 were included in the analysis. A visual analytics software program was used to display data on medication initiation and cessation dates, and reasons for stopping tsDMARDs, which is recorded in the medical record at the time of the decision. At Dec 2020, 28% of the 52,190 patients with RA in the OPAL dataset were prescribed b/tsDMARDs. Of these patients, 3,850 (26.3%) were currently prescribed a JAKi with 51.4% receiving TOF, 29.2% BARI and 19.4% UPA. In 2020, JAKi initiations accounted for 48.8% of all initiations and 30.7% of 1 st line initiations an increase of 6.1% and 3.5% from 2019, respectively. The percentage of patients switching from a first line JAKi to a second line JAKi rather than an agent with another mode of action increased from 33.1% in 2019 to 42.6% in 2020. This is despite 26.2% in 2019 and 45.8% in 2020 of the patients switching to another JAKi citing lack of efficacy as the reason for JAKi discontinuation. In the period between May 2020, when a third JAKi (UPA) become available, and Dec 2020, the majority of patients switching from first line TOF or BARI to another JAKI switched to UPA (69.4% and 83.9%, respectively), whilst 30.6% of first line TOF patients switched to BARI (30.6%), and 16.1% of first line BARI patients switched to TOF in second line. The majority of patients switching from second line TOF or BARI to a third line JAKi switched to UPA (73% and 96%, respectively), with 27% of second line TOF patients switching to BARI and a very low number moving from second line BARI to TOF (4%). JAKi choice after a third line TOF or BARI was almost exclusively UPA (86.2% and 95.5%, respectively). There has been significant and sustained uptake of JAKi for the management of RA in Australia and JAKi cycling is increasingly common in routine clinical care. Clinical outcomes and persistence following JAKi cycling requires further investigation. [1]Littlejohn GO, Tymms KE, Smith T, Griffiths HT. Using big data from real-world Australian rheumatology encounters to enhance clinical care and research. Clin Exp Rheumatol. Sep-Oct 2020 (5):874-880. Figure 1. Patterns of JAKi cycling for the management of rheumatoid arthritis in first, second and third line switching. The authors acknowledge the members of OPAL Rheumatology Ltd and their patients for providing clinical data for this study, and Software4Specialists Pty Ltd for providing the Audit4 platform Sabina Ciciriello: None declared, Tegan Smith: None declared, Catherine OSullivan: None declared, Kathleen Tymms: None declared, Peter Youssef: None declared, David Mathers: None declared, Claire Deakin: None declared, Hedley Griffiths Consultant of: AbbVie, Gilead, Novartis and Lilly., Geoff Littlejohn Speakers bureau: Over the last 5 years Geoffrey Littlejohn has received educational grants and consulting fees from AbbVie, Bristol Myers Squibb, Eli Lilly, Gilead, Novartis, Pfizer, Janssen, Sandoz, Sanofi and Seqirus.
Publisher: Wiley
Date: 25-03-2018
DOI: 10.1002/ART.40418
Publisher: Oxford University Press (OUP)
Date: 10-2018
Publisher: Elsevier BV
Date: 09-2021
Publisher: Springer Science and Business Media LLC
Date: 09-12-2020
DOI: 10.1038/S41467-020-19741-6
Abstract: Anecdotal evidence suggests that Coronavirus disease 2019 (COVID-19), caused by the coronavirus SARS-CoV-2, exhibits differences in morbidity and mortality between sexes. Here, we present a meta-analysis of 3,111,714 reported global cases to demonstrate that, whilst there is no difference in the proportion of males and females with confirmed COVID-19, male patients have almost three times the odds of requiring intensive treatment unit (ITU) admission (OR = 2.84 95% CI = 2.06, 3.92) and higher odds of death (OR = 1.39 95% CI = 1.31, 1.47) compared to females. With few exceptions, the sex bias observed in COVID-19 is a worldwide phenomenon. An appreciation of how sex is influencing COVID-19 outcomes will have important implications for clinical management and mitigation strategies for this disease.
Publisher: Elsevier BV
Date: 2020
DOI: 10.2139/SSRN.3572881
Publisher: The Journal of Rheumatology
Date: 15-02-2017
Abstract: We aimed to establish the prevalence and clinical associations of anti-HMG-CoA-reductase (anti-HMGCR) in a large UK cohort with juvenile myositis. There were 381 patients investigated for anti-HMGCR using ELISA. Anti-HMGCR autoantibodies were detected in 4 patients (1%). These children had no or minimal rash and significant muscle disease. Muscle biopsies were considered distinctive, with widespread variation in fiber size, necrotic fibers, and chronic inflammatory cell infiltrates all had prolonged elevation of creatine kinase and all ultimately received biologic therapies. Anti-HMGCR in UK children with myositis are associated with severe disease that is poorly responsive to standard treatment.
Publisher: American Medical Association (AMA)
Date: 29-06-2023
DOI: 10.1001/JAMANETWORKOPEN.2023.20851
Abstract: There is a need for observational studies to supplement evidence from clinical trials, and the target trial emulation (TTE) framework can help avoid biases that can be introduced when treatments are compared crudely using observational data by applying design principles for randomized clinical trials. Adalimumab (ADA) and tofacitinib (TOF) were shown to be equivalent in patients with rheumatoid arthritis (RA) in a randomized clinical trial, but to our knowledge, these drugs have not been compared head-to-head using routinely collected clinical data and the TTE framework. To emulate a randomized clinical trial comparing ADA vs TOF in patients with RA who were new users of a biologic or targeted synthetic disease-modifying antirheumatic drug (b/tsDMARD). This comparative effectiveness study emulating a randomized clinical trial of ADA vs TOF included Australian adults aged 18 years or older with RA in the Optimising Patient Outcomes in Australian Rheumatology (OPAL) data set. Patients were included if they initiated ADA or TOF between October 1, 2015, and April 1, 2021 were new b/tsDMARD users and had at least 1 component of the disease activity score in 28 joints using C-reactive protein (DAS28-CRP) recorded at baseline or during follow-up. Treatment with either ADA (40 mg every 14 days) or TOF (10 mg daily). The main outcome was the estimated average treatment effect, defined as the difference in mean DAS28-CRP among patients receiving TOF compared with those receiving ADA at 3 and 9 months after initiating treatment. Missing DAS28-CRP data were multiply imputed. Stable balancing weights were used to account for nonrandomized treatment assignment. A total of 842 patients were identified, including 569 treated with ADA (387 [68.0%] female median age, 56 years [IQR, 47-66 years]) and 273 treated with TOF (201 [73.6%] female median age, 59 years [IQR, 51-68 years]). After applying stable balancing weights, mean DAS28-CRP in the ADA group was 5.3 (95% CI, 5.2-5.4) at baseline, 2.6 (95% CI, 2.5-2.7) at 3 months, and 2.3 (95% CI, 2.2-2.4) at 9 months in the TOF group, it was 5.3 (95% CI, 5.2-5.4) at baseline, 2.4 (95% CI, 2.2-2.5) at 3 months, and 2.3 (95% CI, 2.1-2.4) at 9 months. The estimated average treatment effect was −0.2 (95% CI, −0.4 to −0.03 P = .02) at 3 months and −0.03 (95% CI, −0.2 to 0.1 P = .60) at 9 months. In this study, there was a modest but statistically significant reduction in DAS28-CRP at 3 months for patients receiving TOF compared with those receiving ADA and no difference between treatment groups at 9 months. Three months of treatment with either drug led to clinically relevant average reductions in mean DAS28-CRP, consistent with remission.
Publisher: Wiley
Date: 09-10-2016
DOI: 10.1002/ART.39753
Publisher: BMJ
Date: 06-2016
Publisher: Elsevier BV
Date: 04-2013
DOI: 10.1038/MT.2012.230
Publisher: Springer Science and Business Media LLC
Date: 05-07-2023
DOI: 10.1007/S10067-023-06681-X
Abstract: To describe the demographics, disease burden and real-world management of patients with systemic lupus erythematosus (SLE) in Australian community practice. Patients with a physician diagnosis of SLE and at least 1 visit between 1 January 2009 and 31 March 2021 were identified in the OPAL dataset, an aggregated collection of data extracted from the electronic medical records of patients managed by 112 Australian rheumatologists. Demographics, basic clinical features and prescribed medications were described, with medication combinations used as a surrogate of disease severity. Of 5133 patients with a diagnosis of lupus, 4260 (83%) had SLE. Of these SLE patients, almost 90% of patients were female, with a median age of 49 years [IQR 37–61] at first-recorded visit. Of the 2285 SLE patients whose most recent visit was between 1 January 2019 and 31 March 2021, 52.5% had mild disease, 29.9% had moderate-severe disease and 7.4% had very severe disease. Visit frequency increased with disease severity. Most patients (85.8%) were treated with hydroxychloroquine, typically prescribed as first line-of-therapy. In this large real-world Australian cohort of patients with SLE, a substantial burden of disease was identified, with a significant proportion (almost one-third of patients) considered to have moderate to severe disease based on medication use. This study provides a greater understanding of the path from symptom onset to treatment and the heterogeneous presentation of patients with SLE who are treated in community practice in Australia. Key messages • Most published studies describing patients with SLE are derived from specialist lupus centres, typically in the hospital setting, therefore little is known about the characteristics of patients with SLE who are receiving routine care in community clinics. • The OPAL dataset is a large collection of clinical data from the electronic medical records of rheumatologists predominantly practising in private community clinics, which is where the majority (73–80%) of adult rheumatology services are conducted in Australia [1–3] . Since data from community care has not been widely available for SLE research, this study contributes important insight into this large and under-reported patient population. • To improve access to care and effective treatments, and reduce the burden of SLE in Australia, a greater understanding of the characteristics and unmet needs of patients with SLE managed in the community setting is required.
Publisher: Oxford University Press (OUP)
Date: 04-2017
Publisher: SAGE Publications
Date: 07-06-2017
Abstract: Juvenile dermatomyositis is the most common form of the juvenile idiopathic inflammatory myopathies characterised by muscle and skin inflammation, leading to symmetric proximal muscle weakness and cutaneous symptoms. It has a fluctuating course and varying prognosis. In a Bayesian framework, we develop a joint model for four longitudinal outcomes, which accounts for within in idual variability as well as inter-in idual variability. Correlations among the outcome variables are introduced through a subject-specific random effect. Moreover, we exploit an approach similar to a hurdle model to account for excess of a specific outcome in the response. Clinical markers and symptoms are used as covariates in a regression set-up. Data from an ongoing observational cohort study are available, providing information on 340 subjects, who contributed 2725 clinical visits. The model shows good performance and yields efficient estimations of model parameters, as well as accurate predictions of the disease activity parameters, corresponding well to observed clinical patterns over time. The posterior distribution of the by-subject random intercepts shows a substantial correlation between two of the outcome variables. A subset of clinical markers and symptoms are identified as associated with disease activity. These findings have the potential to influence clinical practice as they can be used to stratify patients according to their prognosis and guide treatment decisions, as well as contribute to on-going research about the most relevant outcome markers for patients affected by juvenile dermatomyositis.
Publisher: Springer Science and Business Media LLC
Date: 31-10-2017
Publisher: BMJ Publishing Group Ltd and European League Against Rheumatism
Date: 30-05-2023
DOI: 10.1136/ANNRHEUMDIS-2023-EULAR.2552
Abstract: Despite children and young people (CYP) having a low risk for severe Coronavirus disease 2019 (COVID-19) outcomes, there is still a degree of uncertainty related to their risk in the context of immunodeficiency or immunosuppression, primarily due to significant reporting bias in most studies, as CYP characteristically experience milder or asymptomatic COVID-19 infection and the severe outcomes tend to be overestimated. To systematically evaluate the impact of immunosuppression on severe COVID-19 infection outcomes in CYP and perform a meta-analysis to estimate differences in outcomes compared to general population. A comprehensive systematic review to identify globally relevant studies in immunosuppressed CYP and CYP in general population (defined as younger than 25 years of age) up to 31st October 2021 (to exclude vaccinated populations), was performed. Studies were included if they reported the two primary outcomes of our study, admission to intensive therapy unit (ITU) and mortality, while data on other outcomes, such as hospitalisation and need for mechanical ventilation were also collected. A meta-analysis estimated the pooled proportion for each severe COVID-19 outcome, using the inverse variance method. Random effects models were used to account for interstudy heterogeneity. The systematic review identified 30 eligible studies for each of the two populations investigated: immunosuppressed CYP (n=793) and CYP in general population (n=102,022). Our meta-analysis found higher estimated prevalence for hospitalization (46% vs. 16%), ITU admission (12% vs. 2%), mechanical ventilation (8% vs. 1%) and increased mortality due to severe COVID-19 infection (6.5% vs. 0.2%) in immunocompromised CYP compared to CYP in general population (Figure 1A-D depicts the pooled estimates for the above outcomes in immunocompromised CYP). This analysis shows an overall trend for more severe outcomes of COVID-19 infection in immunocompromised CYP, similar to adult studies. This is the only up to date meta-analysis in immunocompromised CYP with high global relevance, which excluded reports from hospitalised cohorts alone and included 35% studies from low- and medium-income countries. Future research is required to characterise in idual subgroups of immunocompromised patients, as well as impact of vaccination on severe COVID-19 outcomes. Special thanks to Prof. Lucy Wedderburn, Professor of Pediatric Rheumatology at University College London Institute of Child Health for providing useful comments. Coziana Ciurtin Speakers bureau: UCB, Grant/research support from: GSK, James Greenan- Barett: None declared, Samuel Aston: None declared, Claire Deakin: None declared.
Publisher: BMJ
Date: 19-05-2021
DOI: 10.1136/ANNRHEUMDIS-2021-EULAR.2265
Abstract: The availability of biosimilars as non-proprietary versions of established biologic disease-modifying anti-rheumatic drugs (bDMARDs) is enabling greater access for patients with rheumatic diseases to effective medications at a lower cost. Since April 2017 both the originator and a biosimilar for etanercept (trade names Enbrel and Brenzys, respectively) have been available for use in Australia. [1]To model effectiveness of etanercept originator or biosimilar in reducing Disease Activity Score 28-joint count C reactive protein (DAS28CRP) in patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) or ankylosing spondylitis (AS) treated with either drug as first-line bDMARD [2]To describe persistence on etanercept originator or biosimilar as first-line bDMARD in patients with RA, PsA or AS Clinical data were obtained from the Optimising Patient outcomes in Australian rheumatoLogy (OPAL) dataset, derived from electronic medical records. Eligible patients with RA, PsA or AS who initiated etanercept originator (n=856) or biosimilar (n=477) as first-line bDMARD between 1 April 2017 and 31 December 2020 were identified. Propensity score matching was performed to select patients on originator (n=230) or biosimilar (n=136) with similar characteristics in terms of diagnosis, disease duration, joint count, age, sex and concomitant medications. Data on clinical outcomes were recorded at 3 months after baseline, and then at 6-monthly intervals. Outcomes data that were missing at a recorded visit were imputed. Effectiveness of the originator, relative to the biosimilar, for reducing DAS28CRP over time was modelled in the matched population using linear mixed models with both random intercepts and slopes to allow for in idual heterogeneity, and weighting of in iduals by inverse probability of treatment weights to ensure comparability between treatment groups. Time was modelled as a combination of linear, quadratic and cubic continuous variables. Persistence on the originator or biosimilar was analysed using survival analysis (log-rank test). Reduction in DAS28CRP was associated with both time and etanercept originator treatment (Table 1). The conditional R-squared for the model was 0.31. The average predicted DAS28CRP at baseline, 3 months, 6 months, 9 months and 12 months were 4.0 and 4.4, 3.1 and 3.4, 2.6 and 2.8, 2.3 and 2.6, and 2.2 and 2.4 for the originator and biosimilar, respectively, indicating a clinically meaningful effect of time for patients on either drug and an additional modest improvement for patients on the originator. Median time to 50% of patients stopping treatment was 25.5 months for the originator and 24.1 months for the biosimilar (p=0.53). An adverse event was the reason for discontinuing treatment in 33 patients (14.5%) on the originator and 18 patients (12.9%) on the biosimilar. Analysis using a large national real-world dataset showed treatment with either the etanercept originator or the biosimilar was associated with a reduction in DAS28CRP over time, with the originator being associated with a further modest reduction in DAS28CRP that was not clinically significant. Persistence on treatment was not different between the two drugs. Table 1. Respondent characteristics. Fixed Effect Estimate 95% Confidence Interval p-value Time (linear) 0.90 0.89, 0.91 1.5e-63 Time (quadratic) 1.01 1.00, 1.01 1.3e-33 Time (cubic) 1.00 1.00, 1.00 7.1e-23 Originator 0.91 0.86, 0.96 0.0013 The authors acknowledge the members of OPAL Rheumatology Ltd and their patients for providing clinical data for this study, and Software4Specialists Pty Ltd for providing the Audit4 platform. Supported in part by a research grant from Investigator-Initiated Studies Program of Merck & Co Inc, Kenilworth, NJ, USA. The opinions expressed in this paper are those of the authors and do not necessarily represent those of Merck & Co Inc, Kenilworth, NJ, USA. Claire Deakin: None declared, Geoff Littlejohn Consultant of: Over the last 5 years Geoffrey Littlejohn has received educational grants and consulting fees from AbbVie, Bristol Myers Squibb, Eli Lilly, Gilead, Novartis, Pfizer, Janssen, Sandoz, Sanofi and Seqirus., Hedley Griffiths Consultant of: AbbVie, Gilead, Novartis and Lilly., Tegan Smith: None declared, Catherine OSullivan: None declared, Paul Bird Speakers bureau: Eli Lilly, abbvie, pfizer, BMS, UCB, Gilead, Novartis
Publisher: Oxford University Press (OUP)
Date: 20-04-2015
Publisher: Elsevier BV
Date: 08-2022
DOI: 10.1016/J.SEMARTHRIT.2022.152038
Abstract: To analyse and compare drug-survival of adalimumab and etanercept (and their biosimilars) in biologic-naïve patients with ERA (Enthesitis-Related Arthritis). In this retrospective observational study, conventional statistics and machine-learning were applied to compare drug-survival (adalimumab, etanercept and their biosimilars initiated: 2009-2019) in ERA and identify determinants. The primary outcome was discontinuation of treatment due to primary- or secondary-failure and adverse drug-reactions. During the observation period, 99 of 188 patients with ERA on first-line TNF inhibitors (etanercept-n=108, adalimumab-n=80) discontinued their treatment (median survival-time 3.9years, 95%CI 2.6-4.9years). Adalimumab was associated with longer drug-survival compared to etanercept especially after an initial positive response, with the median time to treatment discontinuation 4.9years (95% CI 3.9-5.7) for adalimumab, compared to 2years (95%CI 1.4-4.0) for etanercept (HR of treatment-discontinuation-0.49, 95%CI 0.32--0.75, p=0.001). Adjusted by propensity-score, adalimumab-methotrexate combination was associated with longer drug survival, compared to adalimumab-monotherapy (HR-0.41, 95%CI 0.20-0.85), etanercept-monotherapy (HR-0.28, 95%CI 0.15-0.53), and etanercept-methotrexate combination (HR-0.39, 95%CI 0.21-0.73). The presence of HLA-B27 was associated with longer drug-survival (HR-0.50, 95%CI 0.29-0.87) following an initial positive response. Higher-CRP at baseline was associated with higher rate of primary-failure (HR-1.68, 95%CI 1.08-2.62). Axial-ERA (sacroiliitis±spinal-involvement) was associated with poorer drug-survival for both primary- and secondary-failure (overall HR-2.03, 95%CI 1.22-3.40). Adjusted by propensity-score, shorter drug-survival was observed in patients with baseline-CRP≥12.15 mg/L, but only in the context of axial-ERA, not in peripheral-ERA (no sacroiliitis/spinal-involvement) (HR-2.28, 95%CI 1.13--3.64). Following an initial positive primary response, continuing methotrexate with adalimumab was associated with the longest drug-survival compared to adalimumab-monotherapy or etanercept-based regimens. Axial-ERA was associated with a poorer drug-survival. A CRP >12.15 in patients with axial-ERA was associated with a higher rate of primary-failure. Further prospective studies are required to confirm these findings.
Publisher: BMJ Publishing Group Ltd and European League Against Rheumatism
Date: 06-2019
Publisher: Frontiers Media SA
Date: 22-06-2018
Publisher: Springer Science and Business Media LLC
Date: 05-2017
Publisher: Oxford University Press (OUP)
Date: 10-2018
Publisher: BMJ
Date: 19-05-2021
DOI: 10.1136/ANNRHEUMDIS-2021-EULAR.964
Abstract: The myositis specific autoantibody anti-TIF1γ targets TRIM33, a TRIM family proetin with a PHDBromo domain at the C terminal end. Anti-TIF1γ is strongly associated with malignancy in adult patients with idiopathic inflammatory myopathies (IIM). Intriguingly, anti-TIF1γ is also the most common autoantibody in juvenile-onset IIM but younger patients with anti-TIF1γ do not have an increased risk of cancer (1-3). Genetic studies have consistently shown human leukocyte antigen (HLA) to be the strongest risk factor for IIM. Adult and juvenile-onset patients with anti-TIF1γ have recently been shown to have different associations at the HLA-DQB1 locus (4). This could be due to differences in the key TIF1γ epitopes and may relate to differences in aetiology, such as malignancy in adults versus other environmental factors in juvenile onset disease. To identify key epitopes targeted by anti-TIF1γ antibody in patients with IIM and establish if different TIF1γ epitopes are targeted in patients with and without malignancy. Patient plasma/serum s les were obtained from UK Juvenile Dermatomyositis Cohort and Biomarker and UKMyoNet studies. Autoantibody status had previously been determined by immunoprecipitation. Cancer data was collated from the UK Health and Social Care Information Centre and cancer associated IIM (CAM) defined as that occurring within 3 years of IIM diagnosis. An in house ELISA was developed using a purified TIF1γ fragment comprising residues 882-1090, produced in E.coli, corresponding to the PHDBromo protein domain. An ELISA cut-off of 5SD above the mean of 38 healthy control s les was used. 38 healthy controls, and 117 anti-TIF1γ IIM patient sera (60 juvenile onset) were analysed for reactivity to the TIF1γ PHDbromo domain. No healthy controls were positive. Anti-TIF1γPHDbromo was more common in JDM: 18 (30%) juvenile patients and 6 (10.5%) adult patients were positive, p=0.01. Additional data was available for 39 adult patients (82% female, median age 52 (IQR 38-64)). Anti-TIF1γPHDbromo was only found in CAM patients plus one young adult non-CAM patient aged 27 years at disease onset, p =0.07 (p=0.02 for patients years at disease onset), see Table 1. No juvenile patients had a history of malignancy. Table 1. Anti-TIF1γPHDbromo in 39 adult patients with cancer data available anti-TIF1γPHDbromo positive anti-TIF1γPHDbromo negative Cancer associated myositis n(%) 5 a (83) 12(36) Myositis not associated with cancer n(%) 1 b (17) 21(64) Total 6 33 a. Median age 64 yearsb. Age 27 years The TIF1γ PHDBromo domain is an important epitope and autoantibody reactivity is more common in patients with juvenile-onset disease and adults with CAM. The distinction between adult and juvenile-onset IIM is arbitrary and it is relevant that the only adult with anti-TIF1γPHDbromo not to have malignancy was just 27 years old. Our numbers are small and further work is needed to establish if anti-TIF1γPHDbromo, and indeed other TIF1γ epitopes, could help identify patients at highest risk of malignancy, and how this relates to our understanding of IIM aetiopathogenesis. Our findings may add weight to the theory that the development of IIM in younger patients occurs after immune-mediated resolution of a pre-cancer event. [1]Oldroyd A, Sergeant JC, New P et al. The temporal relationship between cancer and adult onset anti-transcriptional intermediary factor 1 antibody-positive dermatomyositis. Rheumatology. 2019 (4):650-655 [2]Tansley SL, Simou S, Shaddick G et al. Autoantibodies in juvenile-onset myositis: Their diagnostic value and associated clinical phenotype in a large UK cohort. J Autoimmun. 2017 :55-64 [3]Fujimoto M, Hamaguchi Y, Kaji K et al. Myositis-specific anti-155/140 autoantibodies target transcription intermediary factor 1 family proteins. Arthritis Rheum. 2012 (2):513-22. [4]Rothwell S, Chinoy H, Lamb JA et al. Focused HLA analysis in Caucasians with myositis identifies significant associations with autoantibody subgroups. Ann Rheum Dis. 2019 (7):996-1002. None declared
Publisher: Frontiers Media SA
Date: 25-08-2023
DOI: 10.3389/FIMMU.2023.1159269
Abstract: Despite children and young people (CYP) having a low risk for severe coronavirus disease 2019 (COVID-19) outcomes, there is still a degree of uncertainty related to their risk in the context of immunodeficiency or immunosuppression, primarily due to significant reporting bias in most studies, as CYP characteristically experience milder or asymptomatic COVID-19 infection and the severe outcomes tend to be overestimated. A comprehensive systematic review to identify globally relevant studies in immunosuppressed CYP and CYP in general population (defined as younger than 25 years of age) up to 31 October 2021 (to exclude vaccinated populations) was performed. Studies were included if they reported the two primary outcomes of our study, admission to intensive therapy unit (ITU) and mortality, while data on other outcomes, such as hospitalization and need for mechanical ventilation were also collected. A meta-analysis estimated the pooled proportion for each severe COVID-19 outcome, using the inverse variance method. Random effects models were used to account for interstudy heterogeneity. The systematic review identified 30 eligible studies for each of the two populations investigated: immunosuppressed CYP ( n = 793) and CYP in general population ( n = 102,022). Our meta-analysis found higher estimated prevalence for hospitalization (46% vs. 16%), ITU admission (12% vs. 2%), mechanical ventilation (8% vs. 1%), and increased mortality due to severe COVID-19 infection (6.5% vs. 0.2%) in immunocompromised CYP compared with CYP in general population. This shows an overall trend for more severe outcomes of COVID-19 infection in immunocompromised CYP, similar to adult studies. This is the only up-to-date meta-analysis in immunocompromised CYP with high global relevance, which excluded reports from hospitalized cohorts alone and included 35% studies from low- and middle-income countries. Future research is required to characterize in idual subgroups of immunocompromised patients, as well as impact of vaccination on severe COVID-19 outcomes. PROSPERO identifier, CRD42021278598.
Publisher: Wiley
Date: 12-06-2023
DOI: 10.1002/ACR2.11577
Abstract: To analyze comparative treatment persistence for first‐line baricitinib (BARI) versus first‐line tumor necrosis factor inhibitor (TNFi) in patients with rheumatoid arthritis (RA) and for first‐line BARI initiated as monotherapy versus first‐line BARI initiated with at least one conventional synthetic disease‐modifying antirheumatic drug (csDMARD). Patients with RA who initiated BARI or TNFi as first‐line biologic or targeted synthetic DMARD from October 1, 2015, to September 30, 2021, were identified in the OPAL data set. Drug survival times to 6, 12, and 24 months were analyzed using restricted mean survival time (RMST). Multiple imputation and inverse probability of treatment weighting were used to address missing data and nonrandom treatment assignment. A total of 545 patients initiated first‐line BARI, including 118 as monotherapy and 427 as csDMARD combination therapy. Three thousand five hundred patients initiated first‐line TNFi. There was no difference in drug survival to 6 or 12 months for BARI compared with TNFi differences in RMST were 0.02 months (95% CI: −0.08 to 0.013 P = 0.65) and 0.31 months (95% CI: −0.02 to 0.63 P = 0.06), respectively. Patients in the BARI group had 1.00 month (95% CI: 0.14 to 1.86 P = 0.02) longer drug survival to 24 months. There was no difference in drug survival for BARI monotherapy compared with combination therapy, with differences in RMST to 6, 12, and 24 months of −0.19 months (95% CI: −0.50 to 0.12 P = 0.12), −0.35 months (95% CI: −1.17 to 0.42 P = 0.41), and −0.56 months (95% CI: −2.66 to 1.54 P = 0.60), respectively. In this comparative analysis, treatment persistence up to 24 months was significantly longer for first‐line BARI compared with TNFi, but the effect size of 1.00 month is not clinically meaningful. There was no difference in persistence for BARI monotherapy versus combination therapy.
Publisher: BMJ
Date: 23-05-2022
DOI: 10.1136/ANNRHEUMDIS-2022-EULAR.2515
Abstract: There is increasing recognition of the complementary role for real-world evidence (RWE) in health care and regulatory decision-making (1). However, careful analysis is required when drugs are compared using observational data to account for differences between treatment groups. Electronic medical records (EMR) are an important source of real-world data (RWD), but outcomes are often recorded incompletely. We emulated a target trial of adalimumab (ADA) versus tofacitinib (TOF) in patients with rheumatoid arthritis (RA) using the OPAL dataset to illustrate the application of methodologies to address the challenges of non-random treatment assignment and incomplete data. The OPAL dataset is derived from EMR of 112 community-based rheumatologists around Australia, where practitioners have discretion to prescribe whichever b/tsDMARD they consider most clinically appropriate. To estimate the average treatment effect (ATE) of TOF compared to ADA at 3 and 9 months, defined as the difference in mean disease activity score (DAS28CRP), in patients with RA who are new users of a b/tsDMARD. This is equivalent to aiming to estimate the intention-to-treat effect in a randomised controlled trial. OPAL patients diagnosed with RA were included if they initiated ADA or TOF between 1 October 2015 and 1 April 2021, were new b/tsDMARD users (no prior recorded b/tsDMARD, at least 6 months of prior csDMARD treatment), and had at least 1 component of DAS28CRP recorded at baseline or during follow-up. Data were also extracted on baseline characteristics. Baseline characteristics were DAS28CRP, patient demographics, regional location, disease duration, prescriber characteristics (including gender, experience), prior recorded comorbidities, and prior and concomitant treatment with csDMARDs and oral corticosteroids. We used random forest multiple imputation to impute missing baseline and follow-up DAS28CRP components (2). Stable balancing weights (SBW) were then used to balance the treatment groups in terms of their baseline characteristics, including DAS28CRP (3). For each imputed dataset, the ATE at 3 months was estimated as the difference between the mean outcome in the two treatment groups after balancing (i.e. weighting) the s le, and then these estimates were averaged across the 10 imputed datasets. The ATE at 9 months was estimated similarly. The whole procedure was subsequently performed in 1000 bootstrap s les to estimate a 95% confidence interval (CI) for the ATEs using the percentile method (4). 842 patients were identified including n=569 treated with ADA and n=273 treated with TOF. After applying the SBW, the maximum difference between the mean of each baseline characteristic in the ADA and TOF groups was less than 0.03% of the corresponding standard deviation in the whole s le, indicating reasonable balance was achieved in this complex dataset. After weighting, mean DAS28CRP reduced from 5.3 at baseline (both ADA and TOF groups) to 2.6 and 2.3 at 3 and 9 months for ADA, and 2.4 and 2.3 at 3 and 9 months for TOF. The estimated ATE was -0.22 (95% CI -0.36, -0.03 p=0.02) at 3 months, indicating a modest but significant reduction in disease activity for patients on TOF. The estimated ATE was -0.03 (95% CI -0.19, 0.1 p=0.56) at 9 months, indicating no difference between groups. DAS28CRP was significantly lower at 3 months for patients treated with TOF compared to ADA. However, 3 months of treatment with either drug led to substantive average reductions in mean DAS28CRP, consistent with remission. There was no difference between drugs at 9 months. Future work will estimate a per-protocol effect. [1]Arlett et al. Clin Pharmacol Ther 2022 (1):21–3. [2]van Buuren and Groothuis-Oudshoorn J Stat Softw 201145(3):1–67 [3]Zubizarreta J Am Stat Assoc 2015 (511):910–22 [4]Bartlett and Hughes Stat Methods Med Res 2020 (12):3533–46 The authors acknowledge the members of OPAL Rheumatology Ltd and their patients for providing clinical data for this study, and Software4Specialists Pty Ltd for providing the Audit4 platform. Claire Deakin: None declared, Bianca De Stavola: None declared, Geoff Littlejohn Consultant of: Abbvie, Janssen, Bristol Myers Squibb, Gilead, Eli Lilly, and MSD, Hedley Griffiths Consultant of: AbbVie and Eli Lilly, Sabina Ciciriello: None declared, Peter Youssef Speakers bureau: AbbVie, Novartis, Eli Lilly, David Mathers: None declared, Paul Bird Speakers bureau: Abbvie, Janssen, Bristol Myers Squibb, Pfizer, Novartis, Gilead, Eli Lilly, Consultant of: Abbvie, Janssen, Bristol Myers Squibb, Pfizer, Novartis, Gilead, Eli Lilly, Imaging consulting for Synarc and Boston Imaging Core Lab., Tegan Smith: None declared, Catherine OSullivan: None declared, Tim Freeman: None declared, Dana Segelov: None declared, David Hoffman: None declared, Shaun Seaman: None declared
Publisher: Frontiers Media SA
Date: 09-01-2023
DOI: 10.3389/FDGTH.2022.1074931
Abstract: To develop a simple and secure technological solution to incorporate electronic patient-reported outcomes (ePROs) into routine clinical care. A novel ePRO questionnaire delivery system was developed by Software for Specialists (S4S) in partnership with OPAL Rheumatology Australia. Validated questionnaires were sent from the electronic medical record (EMR) (Audit4) of patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), lupus or giant cell arteritis (GCA) and delivered to the patient's email address or completed in the clinic waiting room using a smart device (in-practice). Completed questionnaires were encrypted and returned to the patient's Audit4. Deidentified clinical data was extracted and aggregated across all sites. Data collected between April 2016-Dec 2020 were analysed descriptively. Between April 2016 to Dec 2020, 221,352 Functional Assessment of Chronic Illness Therapy Fatigue (FACIT-F), Patient Health Questionnaire-2 (PHQ-2) and/or HealthCare Resource Utilization (HCRU) questionnaires were sent from 39 of 42 contributing clinics (93%). 85% of questionnaires were delivered via email and 15% in-practice. Overall, 85% of patients completed at least one questionnaire, and of all questionnaires sent, 73% were completed. Females were more likely to engage with the questionnaires than males (87% vs. 81%), and older patients were slightly more likely to complete all questionnaires delivered. The novel Audit4 ePRO delivery system is an effective tool for incorporating PROs into routine clinical care. The data generated provides a unique opportunity to understand the full burden of disease for patients in the real-world setting and the impact of interventions.
Publisher: Wiley
Date: 11-03-2019
DOI: 10.1111/NAN.12528
Publisher: Oxford University Press (OUP)
Date: 04-11-2020
DOI: 10.1093/RHEUMATOLOGY/KEAA497
Abstract: Uncertainty around clinical heterogeneity and outcomes for patients with JDM represents a major burden of disease and a challenge for clinical management. We sought to identify novel classes of patients having similar temporal patterns in disease activity and relate them to baseline clinical features. Data were obtained for n = 519 patients, including baseline demographic and clinical features, baseline and follow-up records of physician’s global assessment of disease (PGA), and skin disease activity (modified DAS). Growth mixture models (GMMs) were fitted to identify classes of patients with similar trajectories of these variables. Baseline predictors of class membership were identified using Lasso regression. GMM analysis of PGA identified two classes of patients. Patients in class 1 (89%) tended to improve, while patients in class 2 (11%) had more persistent disease. Lasso regression identified abnormal respiration, lipodystrophy and time since diagnosis as baseline predictors of class 2 membership, with estimated odds ratios, controlling for the other two variables, of 1.91 for presence of abnormal respiration, 1.92 for lipodystrophy and 1.32 for time since diagnosis. GMM analysis of modified DAS identified three classes of patients. Patients in classes 1 (16%) and 2 (12%) had higher levels of modified DAS at diagnosis that improved or remained high, respectively. Patients in class 3 (72%) began with lower DAS levels that improved more quickly. Higher proportions of patients in PGA class 2 were in DAS class 2 (19%, compared with 16 and 10%). GMM analysis identified novel JDM phenotypes based on longitudinal PGA and modified DAS.
Publisher: Springer Science and Business Media LLC
Date: 15-08-2018
Publisher: Springer Science and Business Media LLC
Date: 15-04-2020
DOI: 10.1186/S13075-020-02164-5
Abstract: Anti-TNF treatment may be useful for the treatment of patients with refractory juvenile dermatomyositis (JDM). The aim of this study was to describe the use of infliximab and adalimumab therapy in juvenile dermatomyositis as an adjunctive treatment. Sixty children recruited to the UK JDM Cohort and Biomarker Study that had received at least 3 months of anti-TNF treatment (infliximab or adalimumab) were studied. Childhood Myositis Assessment Scale (CMAS), Manual Muscle Testing (MMT8) and physician’s global assessment (PGA) were recorded. Skin disease was assessed using the modified skin disease activity score (DAS). Data were analysed using Friedman’s test for repeated measures analysis of variance. Compared to baseline, there were improvements at 6 and 12 months in skin disease ( χ 2 (2) = 15.52, p = 0.00043), global disease ( χ 2 (2) = 8.14, p = 0.017) and muscle disease (CMAS χ 2 (2) = 17.02, p = 0.0002 and MMT χ 2 (2) = 10.56, p = 0.005) in infliximab patients. For patients who switched from infliximab to adalimumab, there was improvement in global disease activity ( χ 2 (2) = 6.73, p = 0.03), and trends towards improvement in CMAS, MMT8 and modified DAS. The median initial prednisolone dose was 6 [0–10] mg, and final was 2.5 [0–7.5] mg ( p 0.0001). Fifty-four per cent of patients had a reduction in the number and/or size of calcinosis lesions. Twenty-five per cent switched their anti-TNF treatment from infliximab to adalimumab. 66.7%of the switches were to improve disease control, 26.7% due to adverse events and 6.6% due to patient preference. A total of 13.9 adverse reactions occurred in 100 patient-years, of which 5.7 were considered serious. Reductions in muscle and skin disease, including calcinosis, were seen following treatment with infliximab and adalimumab.
Publisher: Wiley
Date: 04-06-2018
DOI: 10.1111/NAN.12498
Publisher: BMJ Publishing Group Ltd and Royal College of Paediatrics and Child Health
Date: 11-2019
Publisher: Oxford University Press (OUP)
Date: 10-07-2014
DOI: 10.1093/NAR/GKU607
Publisher: The Journal of Rheumatology
Date: 15-08-2022
Abstract: To describe the phenotype, disease course, and treatment of a large cohort of children with sarcoidosis. Patients with biopsies consistent with sarcoidosis, performed between 2010 and 2020, were included in this study. Patients’ notes were reviewed retrospectively. Children with disease onset before 5 years of age were compared with older children. Regression analysis was performed to determine predictors of treatment outcome. In total, 48 children with a mean age at diagnosis of 9.5 years, with a male to female ratio of 0.71, were identified. In total, 72% of the children were of Black race and 94% had multiorgan disease, with an average of 4.8 organs involved, most commonly lymph nodes (65%), skin (63%), and eyes (60%). Laboratory findings of note included raised serum calcium in 23% of patients and raised angiotensin-converting enzyme in 76% of patients. Out of 14 patients tested, 6 had mutations in NOD2 . In total, 81% of patients received systemic steroids and 90% received conventional disease-modifying antirheumatic drugs (DMARDs) in 25% of patients, a biologic was added, mostly anti–tumor necrosis factor (anti-TNF). Although most patients could be weaned off steroids (58%), most remained on long-term DMARDs (85%). Children under the age of 5 years presented more often with splenomegaly ( P = 0.001), spleen involvement ( P = 0.003), and higher C-reactive protein ( P = 0.10). Weight loss was more common in adolescents ( P = 0.006). Kidney ( P = 0.004), eye ( P = 0.005), and liver involvement ( P = 0.03) were more common in Black patients. Regression analysis identified no single factor associated with positive treatment outcomes. Multiorgan involvement, response to steroids, and chronic course are hallmarks of pediatric sarcoidosis. The phenotype significantly varies by age and race. Where conventional DMARDs were not efficacious, the addition of an anti-TNF agent was beneficial.
Publisher: Oxford University Press (OUP)
Date: 2021
DOI: 10.1093/RAP/RKAB058
Abstract: This aim of this study was to gain a better understanding of how parents and carers feel about the effects and impact of the coronavirus disease 2019 (COVID-19) pandemic lockdown and how this impacted upon their child/young person with JDM. We approached 139 participants from the JDM Cohort Biomarker Study (JDCBS), with specific consent to approach electronically for research studies. A secure electronic questionnaire with study introduction was sent to participants for their parents and carers around the UK to complete. It consisted of 20 questions about the impact of the pandemic on their child or young person’s clinical care. Data were analysed quantitatively and qualitatively. There were 76 (55%) responses to the survey. More than 50% of participants were actively being treated for their JDM at the point of survey completion as recorded by their parent or carer. More than 40% attested to disrupted treatment owing to COVID-19. The biggest impact upon clinical care was cancellation of appointments, initiating virtual appointments and extension of time between blood tests. Parents and carers expressed their own feelings of worry, concern and anxiety, but also those of their child or young person. Families who have a child or young person with JDM have been affected by COVID-19. Qualitative comments highlight that it has been a very difficult time. Further investigation is required into this area and could be compared with research on the effects of COVID-19 on other patient groups with chronic disease.
Publisher: Elsevier BV
Date: 2022
DOI: 10.2139/SSRN.4048931
Publisher: BMJ Publishing Group Ltd and European League Against Rheumatism
Date: 30-05-2023
DOI: 10.1136/ANNRHEUMDIS-2023-EULAR.3359
Abstract: Guselkumab (GUS) is a novel anti-interleukin 23 (IL-23)p19 antibody that acts as a selective and specific inhibitor of the IL-23 cytokine. GUS has been shown to significantly improve signs and symptoms of active psoriatic arthritis (PsA) and became available for the treatment of PsA in Australia in July 2021. Limited data from large real-world patient populations exist to describe the utilisation of GUS for the management of PsA. To describe the patient demographics and treatment patterns of GUS in a large real-world cohort of Australian adult patients with PsA. The OPAL dataset is a collection of deidentified clinical data derived from the electronic medical records of 112 rheumatologists at 43 sites around Australia. Adult patients with a diagnosis of PsA who received at least one prescription of GUS or a biologic or targeted synthetic disease modifying anti-rheumatic drug (b/tsDMARD) between Jul 2021 and Jul 2022, were eligible for inclusion in the analysis. Results were summarised descriptively. A total of 1,868 patients with PsA, (GUS n=355, TNFi n=795, IL-17Ai n=371 and JAKi n=347) were eligible for inclusion in this study. The median [IQR] age of patients was 55 [44-63] years, and 70.1% were female. At baseline, median disease duration was 5[2-8], 2[1-6], 3[1-7] and 5[3-8] years, for patients treated with GUS, TNFi, IL-17Ai and JAKi, respectively. 17.7% of patients receiving GUS were first line compared with 58.7% of TNFi, 39.4% of IL-17Ai and 19.3% of JAKi treated patients (Table 1). At index, the majority of patients were treated as monotherapy. These are the first data describing the demographics and treatment patterns of real-world Australian patients with PsA treated with GUS. In this preliminary analysis, a higher proportion of GUS and JAKi were used in later lines of therapy, and patients who initiated GUS or JAKi had a longer median disease duration. This may be due to the different time periods of availability of the different b/tsDMARD, as both GUS and JAKi are newer treatment options for PsA compared with TNFi and IL17Ai. Persistence among patients with PsA treated with GUS is currently being investigated. Table 1. Demographic features of patients with psoriatic arthritis treated with GUS, TNFi, IL-17Ai or JAKi as any line of therapy. Feature Initiators of GUS (n=355) Initiators of TNFi (n=795) Initiators of IL-17Ai (n=371) Initiators of JAKi (n=347) Gender, Female (n, %) 250 (71.3%) 538 (69.2%) 240 (67%) 251 (73%) Age at Index, years (median [IQR]) 55 [45-63] 51 [41-61] 54 [45.5-64] 55 [48-64] Duration of disease recorded in Audit4 at Index, years (median [IQR]) 5 [2-8] 2 [1-6] 3 [1-7] 5 [3-8] Line of therapy (n, %) Line 1 63 (17.7%) 467 (58.7%) 146 (39.4%) 67 (19.3%) Line 2 57 (16.1%) 152 (19.1%) 99 (26.7%) 81 (23.3%) Line 3+ 235 (66.2%) 176 (22.1%) 126 (34%) 199 (57.3%) GUS guselkumab. The authors acknowledge the members of OPAL Rheumatology Ltd and their patients for providing clinical data for this study, and Software4Specialists Pty Ltd for providing the Audit4 platform. This study was conducted with financial support provided by Janssen Australia. Geoff Littlejohn: None declared, Nithila Anbumurali: None declared, Paul Bird Speakers bureau: GSK, AbbVie, Janssen, Eli-Lilly, Consultant of: AbbVie, Janssen, Pfizer, Eli-Lilly, GSK, BMS, Peter Youssef: None declared, Catherine OSullivan: None declared, Tegan Smith: None declared, Daniel Sumpton: None declared, Barry Kane: None declared, Andrew McGeachie Employee of: Current employee of Janssen Australia, Stefanie Spiers Employee of: Current employee of Janssen Australia, Claire Deakin: None declared.
Publisher: BMJ Publishing Group Ltd and European League Against Rheumatism
Date: 30-05-2023
DOI: 10.1136/ANNRHEUMDIS-2023-EULAR.1895
Abstract: Remission or low disease activity (LDA) are the common therapeutic targets in the treat-to-target strategy for patients with rheumatoid arthritis (RA). Despite achieving these targets however, some patients continue to experience residual symptoms including pain, fatigue and functional loss. Patient reported outcomes (PROs) are an important tool to better understand the lived experience of the patient which is often not adequately captured by traditional disease activity measurements. To describe the levels of pain, fatigue, mood disturbance and physical function in a large cohort of Australian patients with RA and how they correlate with traditional clinical disease activity measures. Clinical data were sourced from the OPAL dataset which is an aggregated collection of data extracted from the electronic medical record (EMR, Audit4, Software4Specialists Pty Ltd) of patients receiving routine care from 112 rheumatologists across Australia. Validated PRO questionnaires were electronically delivered to patients through their EMR via email or completed using a smart device in the waiting room prior to the consultation. Completed questionnaires were securely integrated into the patients EMR for review at the next consultation [1] . Patients with a physician diagnosis of RA and ≥6 months of disease activity recorded who had responded to at least one PRO (Functional Assessment of Chronic Illness Therapy Fatigue (FACIT-F), Patient Health Questionnaire-2 (PHQ-2), pain visual analogue scale (VAS) or the Multi-Dimensional Health Assessment Questionnaire (MD-HAQ)), between April 2020 and April 2022 were included. Disease activity was assessed using DAS28(3)-CRP which includes swollen and tender joint counts and CRP, but excludes the patient global assessment. 1,397 patients completed a pain VAS, 2,180 a FACIT-F, 2,101 a PHQ-2 and 2,243 a MD-HAQ during the study window. The median age of patients with a completed questionnaire was 62 years and 77.1% were female. Levels of pain, fatigue, mood disturbance and physical function for patients with RA are shown in Table 1. Overall, a substantial percentage of patients, (n=519, 37.2%), reported experiencing unacceptable pain ( mm VAS) and clinically relevant fatigue (FACIT-F ≤ 34) (n=867, 39.8%). Higher levels of pain, fatigue and mood disturbance was associated with higher DAS28(3)-CRP disease activity. Of patients in DAS28(3)-CRP remission or LDA, 32.7% reported unacceptable levels of pain, 36.1% reported clinically relevant fatigue and 11.2% reported possible depression. In general, we found that higher disease activity scores were associated with high levels of pain, fatigue, anhedonia and depressed moods. In addition, there exists a substantial cohort of patients in routine clinical care with swollen and tender joints counts and CRP levels indicative of remission or LDA that continued to experience unacceptable levels of pain and clinically relevant fatigue. [1]Tymms K, Smith T, Deakin C, et al. The Development Of A Novel ePRO Delivery System To Measure Patient Quality Of Life In Routine Clinical Care: An Analysis Of 5 Years Of Experience [Abstract] Annals of the Rheumatic Diseases. 2021 80(S1):1015-1016 Table 1. Levels of pain, fatigue, mood disturbance and physical function for patients with rheumatoid arthritis. Feature Category (n, %) Pain VAS (n = 1397) Unacceptable pain ( mm) 519 (37.2%) No pain or acceptable (≤ 40mm ) 878 (62.8% ) FACIT-F (n = 2180) Clinically-relevant fatigue (≤ 34) 867 (39.8%) No fatigue or not clinically-relevant ( 34 ) 1313 (60.2% ) PHQ-2 Category (n = 2101) Possible depression (≥3) 250 (11.9%) No depression ( 3 ) 1857 (88.1% ) MD-HAQ Category (n = 2243) Severe 14 (0.6%) Moderate 438 (19.5%) Mild 913 (40.7% ) Minimal 878 (39.1% ) Functional Assessment of Chronic Illness Therapy Fatigue (FACIT-F) Patient Health Questionnaire-2 (PHQ-2) pain visual analogue scale (VAS) Multi-Dimensional Health Assessment Questionnaire (MD-HAQ). The authors acknowledge the members of OPAL Rheumatology Ltd and their patients for providing clinical data for this study, and Software4Specialists Pty Ltd for providing the Audit4 platform. This study was conducted with the support of an investigator-initiated study grant provided by AbbVie Australia. None Declared.
Publisher: Cambridge University Press (CUP)
Date: 30-01-2017
DOI: 10.1017/CJN.2017.17
Publisher: Cold Spring Harbor Laboratory
Date: 16-02-2021
DOI: 10.1101/2021.02.15.431291
Abstract: Differences in humoral immunity to coronaviruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), between children and adults remain unexplained and the impact of underlying immune dysfunction or suppression unknown. Here, we examined the antibody immune competence of children and adolescents with prevalent inflammatory rheumatic diseases, juvenile idiopathic arthritis (JIA), juvenile dermatomyositis (JDM) and juvenile systemic lupus erythematosus (JSLE), against the seasonal human coronavirus (HCoV)-OC43 that frequently infects this age group. Despite immune dysfunction and immunosuppressive treatment, JIA, JDM and JSLE patients mounted comparable or stronger responses than healthier peers, dominated by IgG antibodies to HCoV-OC43 spike, and harboured IgG antibodies that cross-reacted with SARS-CoV-2 spike. In contrast, responses to HCoV-OC43 and SARS-CoV-2 nucleoproteins exhibited delayed age-dependent class-switching and were not elevated in JIA, JDM and JSLE patients, arguing against increased exposure. Consequently, autoimmune rheumatic diseases and their treatment were associated with a favourable ratio of spike to nucleoprotein antibodies.
Publisher: BMJ
Date: 28-05-2019
DOI: 10.1136/ANNRHEUMDIS-2019-215046
Abstract: Idiopathic inflammatory myopathies (IIM) are a spectrum of rare autoimmune diseases characterised clinically by muscle weakness and heterogeneous systemic organ involvement. The strongest genetic risk is within the major histocompatibility complex (MHC). Since autoantibody presence defines specific clinical subgroups of IIM, we aimed to correlate serotype and genotype, to identify novel risk variants in the MHC region that co-occur with IIM autoantibodies. We collected available autoantibody data in our cohort of 2582 Caucasian patients with IIM. High resolution human leucocyte antigen (HLA) alleles and corresponding amino acid sequences were imputed using SNP2HLA from existing genotyping data and tested for association with 12 autoantibody subgroups. We report associations with eight autoantibodies reaching our study-wide significance level of p .9×10 –5 . Associations with the 8.1 ancestral haplotype were found with anti-Jo-1 (HLA-B*08:01, p=2.28×10 –53 and HLA-DRB1*03:01, p=3.25×10 –9 ), anti-PM/Scl (HLA-DQB1*02:01, p=1.47×10 –26 ) and anti-cN1A autoantibodies (HLA-DRB1*03:01, p=1.40×10 –11 ). Associations independent of this haplotype were found with anti-Mi-2 (HLA-DRB1*07:01, p=4.92×10 –13 ) and anti-HMGCR autoantibodies (HLA-DRB1*11, p=5.09×10 –6 ). Amino acid positions may be more strongly associated than classical HLA associations for ex le with anti-Jo-1 autoantibodies and position 74 of HLA-DRB1 (p=3.47×10 –64 ) and position 9 of HLA-B (p=7.03×10 –11 ). We report novel genetic associations with HLA-DQB1 anti-TIF1 autoantibodies and identify haplotypes that may differ between adult-onset and juvenile-onset patients with these autoantibodies. These findings provide new insights regarding the functional consequences of genetic polymorphisms within the MHC. As autoantibodies in IIM correlate with specific clinical features of disease, understanding genetic risk underlying development of autoantibody profiles has implications for future research.
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Claire Deakin.