COVID-19 therapeutics: Challenges and directions for the future.

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.

COVID-19 vaccine hesitancy in inflammatory arthritis patients: serial surveys from a large longitudinal national Australian cohort.

OBJECTIVES: To determine COVID-19 vaccine hesitancy rates in inflammatory arthritis patients and identify factors associated with changing vaccine hesitancy over time. METHODS: This investigation was a prospective cohort study of inflammatory arthritis patients from community and public hospital outpatient rheumatology clinics enrolled in the Australian Rheumatology Association Database (ARAD). Two surveys were conducted, one immediately prior to (pre-pandemic) and another approximately 1 year after the start of the pandemic (follow-up). Coronavirus disease 2019 (COVID-19) vaccine hesitancy was measured at follow-up, and general vaccine hesitancy was inferred pre-pandemic; these were used to identify factors associated with fixed and changing vaccine beliefs, including sources of information and broader beliefs about medication. RESULTS: Of the 594 participants who completed both surveys, 74 (12%) were COVID-19 vaccine hesitant. This was associated with pre-pandemic beliefs about medications being harmful (P < 0.001) and overused (P = 0.002), with stronger beliefs resulting in vaccine hesitancy persistent over two time points (P = 0.008, P = 0.005). For those not vaccine hesitant pre-pandemic, the development of COVID-19 vaccine hesitancy was associated with a lower likelihood of seeking out vaccine information from health-care professionals (P < 0.001). COVID-19 vaccine hesitancy was not associated with new influenza vaccine hesitancy (P = 0.138). CONCLUSION: In this study of vaccine beliefs before and during the COVID-19 pandemic, factors associated with COVID-19 vaccine hesitancy in inflammatory arthritis patients varied, depending on vaccine attitudes immediately prior to the start of the pandemic. Fixed beliefs reflected broader views about medications, while fluid beliefs were highly influenced by whether they sought out information from health-care professionals, including rheumatologists.

Gout and the COVID-19 pandemic.

PURPOSE OF REVIEW: This review gives an overview of recently published articles on COVID-19 and gout. RECENT FINDINGS: People with gout are likely to be at an increased risk of poor outcomes after COVID-19 infection due to comorbid cardiometabolic conditions. The effects of chronic hyperuricemia on trained immunity, and the hyperinflammatory state induced by gout itself may also play a role. Frequent courses of glucocorticoids for gout flares may be associated with adverse outcomes after COVID-19 infection and reduced immunogenicity to the COVID-19 vaccination. Similarities between the pathophysiology of gout flares and the dysregulated inflammatory response of severe COVID-19 have been identified. Medications used in the treatment of gout, including colchicine and interleukin-1 inhibitors, have shown promise in the treatment of COVID-19 in clinical trials. Overall, the COVID-19 pandemic has had a negative impact on gout care, with patients reporting more difficulty with disease control, accessing medications and healthcare, and poorer quality of life. SUMMARY: The COVID-19 pandemic has created many challenges for people with gout. At present, there is a lack of guidance on the management of gout during the pandemic and paucity of research assessing outcomes of COVID-19 infection in people with gout.

Temporal trends in COVID-19 outcomes in people with rheumatic diseases in Ireland: data from the COVID-19 Global Rheumatology Alliance registry.

OBJECTIVES: Although evidence is accumulating globally, data on outcomes in rheumatic disease and COVID-19 in Ireland are limited. We used data from the COVID-19 Global Rheumatology Alliance (C19-GRA) to describe time-varying COVID-19 outcomes for people with rheumatic disease in Ireland. METHODS: Data entered into the C19-GRA provider registry from Ireland between 24 March 2020 and 9 July 2021 were analysed. Differences in the likelihood of hospitalization and mortality according to demographic and clinical variables were investigated using Chi-squared test or Fisher's exact test, as appropriate. Trends in odds of hospitalization and mortality over time were investigated using logistic regression with the time period as a categorical variable. RESULTS: Of 212 cases included, 59.4% were female and median age was 58.0 years (range 13-96). Of the 212 cases, 92 (43%) were hospitalized and 22 (10.4%) died. Increasing age, a diagnosis of gout, ever smoking, glucocorticoid use, having comorbidities and specific comorbidities of cancer, cardiovascular and pulmonary disease were more common in those hospitalized. A diagnosis of inflammatory arthritis, csDMARD and/or b/tsDMARD use were less frequent in those hospitalized. Increasing age, a diagnosis of gout, ever smoking, having comorbidities and specific comorbidities of obesity, cardiovascular and pulmonary disease were more common in those who died. Odds of hospitalization or mortality did not change over time. CONCLUSION: No temporal trend was observed in either COVID-19-related hospitalization or mortality outcomes for people with rheumatic disease in Ireland.

Inhibiting IL-17A and IL-17F in Rheumatic Disease: Therapeutics Help to Elucidate Disease Mechanisms.

PURPOSE OF REVIEW: Psoriatic arthritis and ankylosing spondylitis belong to a family of rheumatological diseases that lead to painful joint inflammation that impacts on patient function and quality of life. Recent studies have shown that the pro-inflammatory cytokine IL-17 is involved in the inflammatory joint changes in spondyloarthritides. We will review the pathophysiology of IL-17 and review the biological therapies targeting IL-17. RECENT FINDINGS: IL-17 is produced and released from T cells and is dependent on multiple upstream cytokines, which include IL-23. There are six members of the IL-17 family that are secreted from multiple populations of T cells. The initial biologic medications have been developed against IL-17A, which is the best-studied member of this family. These medications appear to be effective in controlling joint inflammation, improving patient quality of life, and are generally well tolerated. More recently, medications have been developed that target both IL-17A and IL-17F. In addition, brodalumab, an antibody targeting the IL-17 receptor, has had a resurgence after initial concerns for an increased risk of suicide. IL-17 is an inflammatory cytokine that is critical in the pathobiology of axial spondyloarthritides. Recent biological therapies targeting IL-17A are effective and well tolerated in patients with axial spondyloarthritis. Specific targeting of the Il-17A/F heterodimer is also effective and provides another viable option in the clinician's armamentarium.

Global research collaboration in a pandemic-challenges and opportunities: the COVID-19 Global Rheumatology Alliance.

PURPOSE OF REVIEW: This review discusses the coronavirus disease-2019 (COVID-19) Global Rheumatology Alliance (GRA), the reason for its formation, the challenges with running the registry, and future opportunities for global collaborative research in rheumatology. RECENT FINDINGS: The GRA has been successful in collecting and publishing a large volume of case data on patients with rheumatic disease with COVID-19. In addition, the GRA has published reviews, opinion pieces, and patient-directed summaries of research to further assist in disseminating timely and accurate information about COVID-19 in rheumatic diseases. There have been numerous challenges in the journey but they have been addressed through a collaborative problem-solving approach. SUMMARY: The initial objectives of the GRA to describe the outcomes in patients with rheumatic disease who developed COVID-19 have been achieved. There has been extensive use of the data in the clinic and also to try and understand the mechanisms of disease and opportunities for drug repurposing. There remain numerous important areas for research which the GRA will continue to pursue as the pandemic evolves.

Coronavirus disease 2019: update on coronavirus disease 2019 outcomes and vaccine efficacy in patients with immune-mediated inflammatory disease.

PURPOSE OF REVIEW: Although the literature to date on COVID-19 outcomes in those with immune-mediated inflammatory disease has been largely reassuring there remain many unanswered questions. These include the impact of specific medications on outcomes and the antibody response after COVID-19 vaccination. RECENT FINDINGS: We summarized the current literature related to COVID-19 outcomes in immune-mediated inflammatory diseases in rheumatology, gastroenterology, dermatology, and neurology. Overall, we found either no difference or modest differences in risk for severe COVID-19 for people with immune-mediated diseases compared with the general population. When considering disease-specific factors, glucocorticoid use and underlying immune-mediated disease activity were generally associated with worse outcomes. Specific medications varied in associations: tumor necrosis factor inhibitors generally had lower odds for severe COVID-19 outcomes, whereas rituximab use generally had higher odds for severe outcomes. We also detailed the recent reports of antibody response to COVID-19 vaccination in people with immune-mediated inflammatory diseases. SUMMARY: Investigations of immune-mediated inflammatory diseases across several organ systems have offered important insight into the COVID-19 disease course. Overall, these studies have provided reassurance to patients and clinicians while also identifying groups who may be at higher risk for poor outcomes.

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

OBJECTIVES: To determine factors associated with COVID-19-related death in people with rheumatic diseases. METHODS: Physician-reported registry of adults with rheumatic disease and confirmed or presumptive COVID-19 (from 24 March to 1 July 2020). The primary outcome was COVID-19-related death. Age, sex, smoking status, comorbidities, rheumatic disease diagnosis, disease activity and medications were included as covariates in multivariable logistic regression models. Analyses were further stratified according to rheumatic disease category. RESULTS: Of 3729 patients (mean age 57 years, 68% female), 390 (10.5%) died. Independent factors associated with COVID-19-related death were age (66-75 years: OR 3.00, 95% CI 2.13 to 4.22; >75 years: 6.18, 4.47 to 8.53; both vs ≤65 years), male sex (1.46, 1.11 to 1.91), hypertension combined with cardiovascular disease (1.89, 1.31 to 2.73), chronic lung disease (1.68, 1.26 to 2.25) and prednisolone-equivalent dosage >10 mg/day (1.69, 1.18 to 2.41; vs no glucocorticoid intake). Moderate/high disease activity (vs remission/low disease activity) was associated with higher odds of death (1.87, 1.27 to 2.77). Rituximab (4.04, 2.32 to 7.03), sulfasalazine (3.60, 1.66 to 7.78), immunosuppressants (azathioprine, cyclophosphamide, ciclosporin, mycophenolate or tacrolimus: 2.22, 1.43 to 3.46) and not receiving any disease-modifying anti-rheumatic drug (DMARD) (2.11, 1.48 to 3.01) were associated with higher odds of death, compared with methotrexate monotherapy. Other synthetic/biological DMARDs were not associated with COVID-19-related death. CONCLUSION: Among people with rheumatic disease, COVID-19-related death was associated with known general factors (older age, male sex and specific comorbidities) and disease-specific factors (disease activity and specific medications). The association with moderate/high disease activity highlights the importance of adequate disease control with DMARDs, preferably without increasing glucocorticoid dosages. Caution may be required with rituximab, sulfasalazine and some immunosuppressants.

The COVID-19 Global Rheumatology Alliance: evaluating the rapid design and implementation of an international registry against best practice.

OBJECTIVES: As the coronavirus disease 2019 pandemic developed there was a paucity of data relevant to people living with rheumatic disease. This led to the development of a global, online registry to meet these information needs. This manuscript provides a detailed description of the coronavirus disease 2019 Global Rheumatology Alliance registry development, governance structure, and data collection, and insights into new ways of rapidly establishing global research collaborations to meet urgent research needs. METHODS: We use previously published recommendations for best practices for registry implementation and describe the development of the Global Rheumatology Alliance registry in terms of these steps. We identify how and why these steps were adapted or modified. In Phase 1 of registry development, the purpose of the registry and key stakeholders were identified on online platforms, Twitter and Slack. Phase 2 consisted of protocol and data collection form development, team building and the implementation of governance and policies. RESULTS: All key steps of the registry development best practices framework were met, though with the need for adaptation in some areas. Outputs of the registry, two months after initial conception, are also described. CONCLUSION: The Global Rheumatology Alliance registry will provide highly useful, timely data to inform clinical care and identify further research priorities for people with rheumatic disease with coronavirus disease 2019. The formation of an international team, easily able to function in online environments and resulting in rapid deployment of a registry is a model that can be adapted for other disease states and future global collaborations.

Value-Based Healthcare in Rheumatology: Axial Spondyloarthritis and Beyond.

PURPOSE OF REVIEW: This review examines axial spondyloarthritis (axSpA) and the wider field of rheumatology through a value-based healthcare (VBHC) lens. VBHC is focused on ensuring patients receive high quality care to improve outcomes and reduce unnecessary costs. RECENT FINDINGS: There are many opportunities to apply the principles of VBHC in axSpA. These include the appropriate utilization of diagnostic investigations, such as HLA-B27 and magnetic resonance imaging, assessing outcomes meaningful to patients, and optimizing care pathways. Multidisciplinary care may improve value, and reduced specialist review and medication tapering may be appropriate. Increasing the value of the care we provide to patients can occur across domains and directly and indirectly improves patient outcomes. Taking the time to integrate principles of VBHC into our practice will allow us to justifiably gain and maintain access to diagnostic and therapeutic advances for the benefit of all our patients.

Healthcare access and attitudes towards telehealth during the early phase of the COVID-19 pandemic among an Australian cohort with inflammatory arthritis.

Community restrictions due to COVID-19 have changed healthcare, including increased telehealth use. During the early pandemic phase, a cohort of Australian patients with inflammatory arthritis was surveyed. Self-reported access to healthcare was maintained and physical health was more likely to be self-rated poorly than mental health. There was a high level of support for telehealth during and after the pandemic.

Epidemiology and outcomes of novel coronavirus 2019 in patients with immune-mediated inflammatory diseases.

PURPOSE OF REVIEW: The novel coronavirus 2019 (COVID-19) pandemic is of special concern for patients with immune-mediated inflammatory disease (IMID) and those who care for them because of the potential for worse outcomes. This article analyzes peer-reviewed research on the epidemiology and outcomes of COVID-19 in those with IMID. RECENT FINDINGS: Published literature on approximately 1400 patients was included from rheumatology, gastroenterology, and dermatology. Data suggest that those who are older and have comorbidities have poorer outcomes. This is consistent with the reports from the general population of patients with COVID-19. Adjusted analyses from the largest published studies demonstrate independent effects of systemic glucocorticoids, as well as age and comorbidities with poorer COVID-19 outcomes (SECURE-IBD registry, n = 525; COVID-19 Global Rheumatology Alliance registry, n = 600); biologic or targeted synthetic disease-modifying antirheumatic drug therapy has not been associated with more severe outcomes. These early results will require validation in population-based studies as more data becomes available. SUMMARY: Current data suggest that similar to the general population, age, and comorbidities are risk factors for poorer COVID-19 outcomes in patients with IMID. Additional research is needed to quantify outcomes and risk across rheumatic disease types, comorbidities, and immunosuppressive drugs.

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

OBJECTIVES: COVID-19 outcomes in people with rheumatic diseases remain poorly understood. The aim was to examine demographic and clinical factors associated with COVID-19 hospitalisation status in people with rheumatic disease. METHODS: Case series of individuals with rheumatic disease and COVID-19 from the COVID-19 Global Rheumatology Alliance registry: 24 March 2020 to 20 April 2020. Multivariable logistic regression was used to estimate ORs and 95% CIs of hospitalisation. Age, sex, smoking status, rheumatic disease diagnosis, comorbidities and rheumatic disease medications taken immediately prior to infection were analysed. RESULTS: A total of 600 cases from 40 countries were included. Nearly half of the cases were hospitalised (277, 46%) and 55 (9%) died. In multivariable-adjusted models, prednisone dose ≥10 mg/day was associated with higher odds of hospitalisation (OR 2.05, 95% CI 1.06 to 3.96). Use of conventional disease-modifying antirheumatic drug (DMARD) alone or in combination with biologics/Janus Kinase inhibitors was not associated with hospitalisation (OR 1.23, 95% CI 0.70 to 2.17 and OR 0.74, 95% CI 0.37 to 1.46, respectively). Non-steroidal anti-inflammatory drug (NSAID) use was not associated with hospitalisation status (OR 0.64, 95% CI 0.39 to 1.06). Tumour necrosis factor inhibitor (anti-TNF) use was associated with a reduced odds of hospitalisation (OR 0.40, 95% CI 0.19 to 0.81), while no association with antimalarial use (OR 0.94, 95% CI 0.57 to 1.57) was observed. CONCLUSIONS: We found that glucocorticoid exposure of ≥10 mg/day is associated with a higher odds of hospitalisation and anti-TNF with a decreased odds of hospitalisation in patients with rheumatic disease. Neither exposure to DMARDs nor NSAIDs were associated with increased odds of hospitalisation.

Management of patients with gout and achievement of target serum urate levels at a tertiary rheumatology service in Australia.

BACKGROUND: Gout is common crystal arthritis that is often managed sub-optimally. AIMS: To determine what proportion of patients treated for gout by the tertiary level rheumatology service at the Royal Brisbane Hospital between 2014 and 2018 reached target serum urate (SU) levels. Secondary aims included exploring the demographic characteristics of those who did and did not reach target. METHOD: The records of patients who were treated at least once either as in inpatient or outpatient by the rheumatology service at the Royal Brisbane Hospital between 1 January 2014 and 31 December 2018 were reviewed. Clinical status, treatment characteristics and outcome were recorded and analysed. RESULTS: There were 129 patients who met the inclusion criteria for the study, the majority of patients were male and 39% had tophaceous gout. Fifty-four (42%) had been intentionally discharged from clinic, 50 (85%) of those patients had reached their SU target, the remaining eight (15%) were discharged with a plan for other services to continue their therapy to reach SU target. Forty patients (31%) had ongoing follow up, with 16 (40%) of these at target and 24 (60%) not at target. Thirty-five (27%) were not attending, five (4%) had died and 30 (23%) had failed to attend follow-up appointments, none of these patients was at target at their last known SU level. CONCLUSION: Despite effective therapy the number of patients treated for gout at a large public metropolitan teaching hospital reaching SU target was low. Almost one-quarter of patients in the study discontinued contact with the clinic. The reasons for this are not clear and are likely multifactorial.