Medicine, Dentistry & Health Sciences Collected Works - Research Publications
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ItemAttitudes and practices in the laboratory monitoring of conventional synthetic disease modifying anti-rheumatic drugs by rheumatologists and rheumatology trainees(SPRINGERNATURE, 2022-10-17)OBJECTIVES: There is scant research about laboratory monitoring in people taking conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) for rheumatic disease. Our objective was to conduct a scoping study to assess the range of current attitudes and the variation in practice of laboratory monitoring of csDMARDs by rheumatologists and trainees. METHODS: Australian and overseas rheumatologists or trainees were invited through newsletter, Twitter and personal e-mail, to complete an anonymous online survey between 1 February and 22 March 2021. Questions focused on laboratory tests requested by csDMARD prescribed, frequency/pattern of monitoring, influence of additional factors and combination therapy, actions in response to abnormal tests, and attitudes to monitoring frequencies. Results were presented descriptively and analysed using linear and logistic regression. RESULTS: There were 221 valid responses. Most respondents were from Australia (n = 53, 35%) followed by the US (n = 39, 26%), with a slight preponderance of women (n = 84, 56%), ≥ 11 years in rheumatology practice (n = 83, 56%) and in mostly public practice (n = 79, 53%). Respondents had a wide variation in the frequency and scheduling of tests. In general, respondents reported increasing monitoring frequency if patients had numerous comorbidities or if both methotrexate and leflunomide were being taken concurrently. There was a wide variety of responses to abnormal monitoring results and 27 (40%) considered that in general, monitoring tests are performed too frequently. CONCLUSIONS: The results demonstrated a wide variation in the frequency of testing, factors that should influence this, and what responses to abnormal test results are appropriate, indicates a likely lack of evidence and the need to define the risks, benefits and costs of different csDMARD monitoring regimens.
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ItemProlonged COVID-19 symptom duration in people with systemic autoimmune rheumatic diseases: results from the COVID-19 Global Rheumatology Alliance Vaccine Survey(BMJ PUBLISHING GROUP, 2022-09)OBJECTIVE: We investigated prolonged COVID-19 symptom duration, defined as lasting 28 days or longer, among people with systemic autoimmune rheumatic diseases (SARDs). METHODS: We analysed data from the COVID-19 Global Rheumatology Alliance Vaccine Survey (2 April 2021-15 October 2021) to identify people with SARDs reporting test-confirmed COVID-19. Participants reported COVID-19 severity and symptom duration, sociodemographics and clinical characteristics. We reported the proportion experiencing prolonged symptom duration and investigated associations with baseline characteristics using logistic regression. RESULTS: We identified 441 respondents with SARDs and COVID-19 (mean age 48.2 years, 83.7% female, 39.5% rheumatoid arthritis). The median COVID-19 symptom duration was 15 days (IQR 7, 25). Overall, 107 (24.2%) respondents had prolonged symptom duration (≥28 days); 42/429 (9.8%) reported symptoms lasting ≥90 days. Factors associated with higher odds of prolonged symptom duration included: hospitalisation for COVID-19 vs not hospitalised and mild acute symptoms (age-adjusted OR (aOR) 6.49, 95% CI 3.03 to 14.1), comorbidity count (aOR 1.11 per comorbidity, 95% CI 1.02 to 1.21) and osteoarthritis (aOR 2.11, 95% CI 1.01 to 4.27). COVID-19 onset in 2021 vs June 2020 or earlier was associated with lower odds of prolonged symptom duration (aOR 0.42, 95% CI 0.21 to 0.81). CONCLUSION: Most people with SARDs had complete symptom resolution by day 15 after COVID-19 onset. However, about 1 in 4 experienced COVID-19 symptom duration 28 days or longer; 1 in 10 experienced symptoms 90 days or longer. Future studies are needed to investigate the possible relationships between immunomodulating medications, SARD type/flare, vaccine doses and novel viral variants with prolonged COVID-19 symptoms and other postacute sequelae of COVID-19 among people with SARDs.
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ItemArtificial Intelligence and Deep Learning for Rheumatologists(WILEY, 2022-12)Deep learning has emerged as the leading method in machine learning, spawning a rapidly growing field of academic research and commercial applications across medicine. Deep learning could have particular relevance to rheumatology if correctly utilized. The greatest benefits of deep learning methods are seen with unstructured data frequently found in rheumatology, such as images and text, where traditional machine learning methods have struggled to unlock the trove of information held within these data formats. The basis for this success comes from the ability of deep learning to learn the structure of the underlying data. It is no surprise that the first areas of medicine that have started to experience impact from deep learning heavily rely on interpreting visual data, such as triaging radiology workflows and computer-assisted colonoscopy. Applications in rheumatology are beginning to emerge, with recent successes in areas as diverse as detecting joint erosions on plain radiography, predicting future rheumatoid arthritis disease activity, and identifying halo sign on temporal artery ultrasound. Given the important role deep learning methods are likely to play in the future of rheumatology, it is imperative that rheumatologists understand the methods and assumptions that underlie the deep learning algorithms in widespread use today, their limitations and the landscape of deep learning research that will inform algorithm development, and clinical decision support tools of the future. The best applications of deep learning in rheumatology must be informed by the clinical experience of rheumatologists, so that algorithms can be developed to tackle the most relevant clinical problems.
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ItemCOVID-19 therapeutics: Challenges and directions for the future(NATL ACAD SCIENCES, 2022-04-12)The emergence of SARS-CoV-2 triggering the COVID-19 pandemic ranks as arguably the greatest medical emergency of the last century. COVID-19 has highlighted health disparities both within and between countries and will leave a lasting impact on global society. Nonetheless, substantial investment in life sciences over recent decades has facilitated a rapid scientific response with innovations in viral characterization, testing, and sequencing. Perhaps most remarkably, this permitted the development of highly effective vaccines, which are being distributed globally at unprecedented speed. In contrast, drug treatments for the established disease have delivered limited benefits so far. Innovative and rapid approaches in the design and execution of large-scale clinical trials and repurposing of existing drugs have saved many lives; however, many more remain at risk. In this review we describe challenges and unmet needs, discuss existing therapeutics, and address future opportunities. Consideration is given to factors that have hindered drug development in order to support planning for the next pandemic challenge and to allow rapid and cost-effective development of new therapeutics with equitable delivery.
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Item817 Activated osteoarthritis following immune checkpoint inhibitor treatment: an observational study(BMJ, 2021-11)Background Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy but can result in toxicities, known as immune-related adverse events (irAEs), due to a hyperactivated immune system. ICI-related inflammatory arthritis has been described in literature, but herewith we introduce and characterize post-ICI activated osteoarthritis (ICI-aOA). Methods We conducted a multi-center, retrospective, observational study of patients with cancer treated with ICIs and diagnosed with ICI-aOA by a rheumatologist. ICI-aOA was defined by (1) an increase in non-inflammatory joint pain after ICI initiation, (2) in joints characteristically affected by osteoarthritis and (3) lack of inflammation on exam. Cases were graded using the CTCAE (Common Terminology Criteria for Adverse Events) V6.0 rubric for arthralgia. RECIST (Response evaluation criteria in solid tumors) V.1.1 (v.4.03) guidelines determined tumor response. Results were analyzed using Chi-squared tests of association and multivariate logistic regression. Results Thirty-six patients had ICI-aOA with mean age at time of rheumatology presentation of 66 years (51–81yrs). Most patients had metastatic melanoma (10/36, 28%) and had received a PD1/PDL1 inhibitor monotherapy (31/36, 86%) with 5/36 (14%) combination therapy. Large joint involvement (hip/knee) was noted in 53% (19/36), small joints of hand 25% (9/36), and spine 14% (5/36). Two-thirds (24/36) suffered multiple joint involvement. Three of 36 (8%) had CTCAE grade 3, 14 (39%) grade 2 and 19 (53%) grade 1 manifestations. Symptom onset ranged from six days to 33.8 months with median of 5.2 months after ICI initiation; 5 patients suffered ICI-aOA after ICI cessation (0.6, 3.5, 4.4, 7.3 and 15.4 months after ICI cessation) (figure 1). Most common form of therapy was intra-articular corticosteroid injections only (15/36, 42%) followed by NSAIDs only (7/36, 20%) (figure 2). Twenty patients (56%) experienced other irAEs, with rheumatic and dermatologic being the most common. All three patients with high-grade ICI-aOA also had another irAE diagnosis at some point after ICI initiation. Conclusions ICI-aOA should be recognized as an adverse event of ICI immunotherapy. Early referral to a rheumatologist can facilitate the distinction between ICI induced inflammatory arthritis from post-ICI mechanical arthropathy, the latter of which can be managed with local therapy that will not compromise ICI efficacy. Ethics Approval Collection of patient data was approved by local Institutional Review Boards at respective institutions: Hospital for Special Surgery in New York (HSS IRB # 2017–1898), University of Chicago in Chicago, Illinois (IRB150837) and Austin Health in Melbourne, Victoria, Australia (HREC/18/Austin/102). Abstract 817 Figure 1Incidence of ICI-aOA (activated osteoarthritis after immune-checkpoint inhibitor) ranged from the first month after ICI initiation up until month 22 after ICI initiation, with most cases occurring in the first 6 months after start of ICI. Five of 36 patients experienced ICI-aOA after ICI cessation (0.6, 3.5, 4.4, 7.3 and 15.4 months after ICI cessation), corresponding to presentation after ICI initiation as follows: 2.0, 9.6, 19.1, 8.7 and 16.1 months after ICI initiation, respectively (as denoted in darker color). ICI: Immune-checkpoint inhibitor, NSAIDs: Non-steroidal anti-inflammatory drugs, DMARDs: Disease modifying anti-rheumatic drugs Abstract 817 Figure 2Therapeutic option most used was local or intra-articular corticosteroid therapy, followed by conservative management with physical therapy only then NSAIDs. Most patients experienced improvement in signs and symptoms with treatment. ICI: Immune-checkpoint inhibitor, NSAIDs: Non-steroidal anti-inflammatory drugs, DMARDs: Disease modifying anti-rheumatic drugs
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ItemEvolving evidence for immunosuppressants in COVID-19(NATL PRESCRIBING SERVICE LTD, 2021-02)The novel coronavirus SARS-CoV-2, the cause of the COVID-19 pandemic, is a highly infectious human respiratory pathogen to which the global population had no prior immunity. The virus will likely continue to cause significant morbidity until there is a broadly effective vaccine As of mid-December 2020, more than 200 COVID-19 vaccine candidates are in development and 11 have entered phase III clinical trials globally. All generate immunity to the viral spike glycoprotein Three vaccine candidates have agreements for procurement and use in Australia if efficacy and safety requirements are met - one protein-based vaccine, one vaccine using a simian-derived adenovirus vector and one messenger RNA vaccine. The latter two vaccines have published interim analyses and efficacy results of their phase III trials. The messenger RNA vaccine is being rolled out in the UK, USA and Canada Significant uncertainties remain. How well will some of those at highest risk of severe disease (such as older people aged >75 years and those with immunocompromising conditions) be protected by a vaccine, and for how long? Also, to what extent will vaccination protect against infection? This will determine the degree of indirect 'herd' protection needed through broad vaccine coverage of younger age groups.
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ItemWaiting for JAK inhibitor safety data(BMJ PUBLISHING GROUP, 2022-02)The US Food and Drug Administration (FDA) has recently added a new 'black box warning' on all currently approved Janus kinase (JAK) inhibitors indicated for the treatment of arthritis and other inflammatory conditions based on results from the ORAL Surveillance study of tofacitinib versus tumour necrosis factor alpha inhibitors in rheumatoid arthritis. This is a warning difficult to ignore because the data, being from a randomised controlled trial, are of high fidelity and hard to reproach. It is especially problematic because safety data for all the other JAK inhibitors will be pending for several years. So how might we proceed, without being bound by our stasis? The lack of absolute certainty seems to require a pragmatic approach to the routine care use of JAK inhibitors. The patients who were at greatest risk were older and had other risk factors for the corresponding adverse events, in keeping with effect modification. This highlights the need to focus on risk stratification when tailoring therapy. In this viewpoint, we propose a simple illustration to guide clinical decision-making. First, identify general risk factors for venous thromboembolic event (VTE), major adverse cardiac event (MACE) and cancer (age>65 years and smoking) and whether there is a previous history of VTE, MACE or cancer. Then, evaluate risk based on the number of other risk factors for VTE and the number of other risk factors for MACE. Ultimately, 'treat-to-target' will in the end always be 'treat-to-agreement'. As we have done in the past, and will do in the future, the optimal treatment strategy will have to be tailored based on individual patient risk factors and preferences in a shared-decision process.
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ItemActivated osteoarthritis following immune checkpoint inhibitor treatment: an observational study(BMJ PUBLISHING GROUP, 2021-09)Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy but can result in toxicities, known as immune-related adverse events (irAEs), due to a hyperactivated immune system. ICI-related inflammatory arthritis has been described in literature, but herewith we introduce and characterize post-ICI-activated osteoarthritis (ICI-aOA). We conducted a multicenter, retrospective, observational study of patients with cancer treated with ICIs and diagnosed with ICI-aOA by a rheumatologist. ICI-aOA was defined by (1) an increase in non-inflammatory joint pain after ICI initiation, (2) in joints characteristically affected by osteoarthritis, and (3) lack of inflammation on exam. Cases were graded using the Common Terminology Criteria for Adverse Events (CTCAE) V.6.0 rubric for arthralgia. Response Evaluation Criteria in Solid Tumors V.1.1 (v.4.03) guidelines determined tumor response. Results were analyzed using χ2 tests of association and multivariate logistic regression. Thirty-six patients had ICI-aOA with a mean age at time of rheumatology presentation of 66 years (51-81 years). Most patients had metastatic melanoma (10/36, 28%) and had received a PD-1/PD-L1 inhibitor monotherapy (31/36, 86%) with 5/36 (14%) combination therapy. Large joint involvement (hip/knee) was noted in 53% (19/36), small joints of hand 25% (9/36), and spine 14% (5/36). Two-thirds (24/36) suffered multiple joint involvement. Three of 36 (8%) had CTCAE grade 3, 14 (39%) grade 2 and 19 (53%) grade 1 manifestations. Symptom onset ranged from 6 days to 33.8 months with a median of 5.2 months after ICI initiation; five patients suffered from ICI-aOA after ICI cessation (0.6, 3.5, 4.4, 7.3, and 15.4 months after ICI cessation). The most common form of therapy was intra-articular corticosteroid injections only (15/36, 42%) followed by non-steroidal anti-inflammatory drugs only (7/36, 20%). Twenty patients (56%) experienced other irAEs, with rheumatic and dermatological being the most common. All three patients with high-grade ICI-aOA also had another irAE diagnosis at some point after ICI initiation. ICI-aOA should be recognized as an adverse event of ICI immunotherapy. Early referral to a rheumatologist can facilitate the distinction between ICI induced inflammatory arthritis from post-ICI mechanical arthropathy, the latter of which can be managed with local therapy that will not compromise ICI efficacy.
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ItemSystematic Review and Meta-Analysis of Inflammatory Bowel Disease Adverse Events with Anti-Interleukin 17A Agents and Tumor Necrosis Factor Inhibitors in Rheumatic Disease and Skin Psoriasis(SPRINGER, 2021-12)INTRODUCTION: The aim of this work is to perform a systematic review and meta-analysis of anti-tumor necrosis factor (anti-TNF) and anti-interleukin-17 (anti-IL-17) trials for spondyloarthritis, psoriatic arthritis, and psoriasis comparing rates of inflammatory bowel disease (IBD) events compared to placebo. METHODS: MEDLINE, EMBASE, and The Cochrane Library were searched for double-blind, randomized placebo-controlled anti-TNF and anti-IL-17 trials of included diseases. Inflammatory bowel disease events from the RCT period were pooled and meta-analyzed using statistical methods suitable for low-event-rate meta-analysis (Peto's, Mantel-Haenszel, hypergeometric-normal model, and Shuster-Guo-Skyler). When observed data were insufficient, we performed an exploratory sensitivity analysis to compare methods. RESULTS: We identified 9551 original papers, and included 96 publications: 65 anti-TNF and 31 anti-IL-17 trials, containing 21 new and 12 flare IBD events in 28,209 participants. New IBD on anti-IL-17 occurred 0.23/100 patient-years (PY) in psoriasis, 0.61/100 PY in PsA and 1.63/100 PY in spondyloarthritis, rates similar to observational cohorts, and less commonly on anti-TNF (0/100 PY, 0/100 PY, 0.32/100 PY, respectively). No evidence of difference between groups was found, with wide CI from many pooled counts of zero, especially in placebo arms. CONCLUSIONS: IBD events were rare, occurring at rates similar to biologic-naive groups. We could not find statistically significant differences in risk of new or recurrent IBD between treatment and control groups using selected meta-analytical methods for low event rate scenarios. Meta-analyses of this topic require more IBD events, ideally without pooling heterogeneous groups. Larger, thoroughly reported trials with systematic and detailed safety reporting are required to improve risk estimation and to make accurate inferences.
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ItemNo Preview AvailableImmediate effect of the COVID-19 pandemic on patient health, health-care use, and behaviours: results from an international survey of people with rheumatic diseases(ELSEVIER, 2021-10)BACKGROUND: The impact and consequences of the COVID-19 pandemic on people with rheumatic disease are unclear. We developed the COVID-19 Global Rheumatology Alliance Patient Experience Survey to assess the effects of the COVID-19 pandemic on people with rheumatic disease worldwide. METHODS: Survey questions were developed by key stakeholder groups and disseminated worldwide through social media, websites, and patient support organisations. Questions included demographics, rheumatic disease diagnosis, COVID-19 diagnosis, adoption of protective behaviours to mitigate COVID-19 exposure, medication access and changes, health-care access and communication with rheumatologists, and changes in employment or schooling. Adults age 18 years and older with inflammatory or autoimmune rheumatic diseases were eligible for inclusion. We included participants with and without a COVID-19 diagnosis. We excluded participants reporting only non-inflammatory rheumatic diseases such as fibromyalgia or osteoarthritis. FINDINGS: 12 117 responses to the survey were received between April 3 and May 8, 2020, and of these, 10 407 respondents had included appropriate age data. We included complete responses from 9300 adults with rheumatic disease (mean age 46·1 years; 8375 [90·1%] women, 893 [9·6%] men, and 32 [0·3%] participants who identified as non-binary). 6273 (67·5%) of respondents identified as White, 1565 (16·8%) as Latin American, 198 (2·1%) as Black, 190 (2·0%) as Asian, and 42 (0·5%) as Native American or Aboriginal or First Nation. The most common rheumatic disease diagnoses included rheumatoid arthritis (3636 [39·1%] of 9300), systemic lupus erythematosus (2882 [31·0%]), and Sjögren's syndrome (1290 [13·9%]). Most respondents (6921 [82·0%] of 8441) continued their antirheumatic medications as prescribed. Almost all (9266 [99·7%] of 9297) respondents adopted protective behaviours to limit SARS-CoV-2 exposure. A change in employment status occurred in 2524 (27·1%) of 9300) of respondents, with a 13·6% decrease in the number in full-time employment (from 4066 to 3514). INTERPRETATION: People with rheumatic disease maintained therapy and followed public health advice to mitigate the risks of COVID-19. Substantial employment status changes occurred, with potential implications for health-care access, medication affordability, mental health, and rheumatic disease activity. FUNDING: American College of Rheumatology.