Fragility of randomised controlled trials for systemic lupus erythematosus and lupus nephritis therapies.

OBJECTIVE: We aimed to evaluate the robustness of phase III randomised controlled trials (RCTs) for SLE and lupus nephritis (LN) using the fragility index (FI), the reverse FI (RFI) and the fragility quotient (FQ). METHODS: We searched for phase III RCTs that included patients with active SLE or LN. Data on primary endpoints, total participants and the number of events for each arm were obtained. We calculated the FI score for RCTs with statistically significant results (number of patients required to change from event to non-event to make the study lose statistical significance), the RFI for RCTs without statistically significant results (number of patients required to change from non-event to event to make study gain statistical significance) and the FQ score for both (FI or RFI score divided by the sample size). RESULTS: We evaluated 20 RCTs (16 SLE, four LN). The mean FI/RFI score was 13.6 (SD 6.6). There were nine RCTs with statistically significant results (seven SLE, two LN), and the mean FI score was 10.2 (SD 6.2). The lowest FI was for the ILLUMINATE-2 trial (FI=2), and the highest FI was for the BLISS-52 trial (FI=17).Twelve studies had non-statistically significant results (10 SLE, two LN) with a mean RFI score of 15.6 (SD 6.1). The lowest RFI was for the ILLUMINATE-1 trial (RFI=4), and the highest RFI was for the TULIP-1 trial (RFI=27). The lowest FQ scores were found in the ILLUMINATE trials and the highest in the Rituximab trials (EXPLORER and LUNAR), meaning that the last ones were the most robust results after accounting for sample size. CONCLUSIONS: The evidence of therapies for patients with SLE and LN is derived mostly from fragile RCTs. Clinicians and trialists must be aware of the fragility of these RCTs for clinical decision-making and designing trials for novel therapeutics.

Prolonged COVID-19 symptom duration in people with systemic autoimmune rheumatic diseases: results from the COVID-19 Global Rheumatology Alliance Vaccine Survey.

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.

COVID-19 Vaccine Uptake Among Patients With Systemic Lupus Erythematosus in the American Midwest: The Lupus Midwest Network (LUMEN).

OBJECTIVE: Patients with systemic lupus erythematosus (SLE) are at higher risk of poor outcomes from coronavirus disease 2019 (COVID-19). The vaccination rate among such patients is unknown. We aimed to assess COVID-19 vaccine uptake among patients with SLE. METHODS: We included 342 patients with SLE from the Lupus Midwest Network (LUMEN) and 350 age-, sex-, race-, and county-matched comparators. Vaccination uptake for influenza, pneumococcal, and zoster vaccines before pandemic restrictions began (up to February 29, 2020) was assessed. First-dose COVID-19 vaccine uptake was electronically retrieved and manually ascertained (December 15, 2020, to July 31, 2021). Time to COVID-19 vaccination, demographics, SLE manifestations, medications, Charlson Comorbidity Index, Area Deprivation Index, and Rural-Urban Commuting Area codes were compared. RESULTS: On July 31, 2021, 83.3% of patients with SLE and 85.5% of comparators were vaccinated against COVID-19. The COVID-19 vaccination rates were similar among SLE and comparators (hazard ratio 0.93, 95% CI 0.79-1.10). Unvaccinated patients with SLE were more likely than vaccinated patients to be men (27.3% vs 14.1%), younger (mean age 54.1 vs 58.8 yrs), have a shorter SLE duration (median 7.3 vs 10.7 yrs), and be less frequently vaccinated with influenza and pneumococcal vaccines. CONCLUSION: Patients with SLE in the Lupus Midwest Network had similar COVID-19 vaccination uptake as matched comparators, most of whom were vaccinated early when the vaccine became available. One in 6 patients with SLE remain unvaccinated.

Association Between Payments by Pharmaceutical Manufacturers and Prescribing Behavior in Rheumatology.

OBJECTIVE: To evaluate the association between pharmaceutical industry payments to rheumatologists and their prescribing behaviors. METHODS: A cross-sectional analysis was conducted of Medicare Part B Public Use File, Medicare Part D Public Use File, and Open Payments data for 2013 to 2015. Prescription drugs responsible for 80% of the total Medicare pharmaceutical expenditures in rheumatology were analyzed. We calculated the mean annual drug cost per beneficiary per year, the percentage of rheumatologists who received payments, and the median annual payment per physician per drug per year. Industry payments were categorized as food/beverage and consulting/compensation. Multivariable regression models were used to assess associations between industry payments and both prescribing patterns and prescription drug expenditures. RESULTS: Of 4822 rheumatologists in the Medicare prescribing databases, 3729 received any payment from a pharmaceutical company during this time frame. Food/beverage payments were associated with an increased proportion of prescriptions for the related drugs (range, 1.5% to 4.5%) and an increased proportion of annual Medicare spending for the related drugs (range, 3% to 23%). For every $100 in food/beverage payments, the probability of prescribing increased (range, 1.5% to 14% for most drugs) and Medicare reimbursements increased (range, 6% to 44% for most drugs). Consulting/compensation payments were associated with an increased proportion of prescriptions (range, 1.2% to 1.6%) and an increased proportion of annual Medicare spending (range, 1% to 2%). For every $1000 in consulting/compensation payments, both the probability of prescribing increased (5% or less for most drugs) and Medicare reimbursements increased (less than 10% for most drugs). CONCLUSION: Payments to rheumatologists by pharmaceutical companies are associated with increased probability of prescribing and Medicare spending.

Clinicopathologic Associations in a Large International Cohort of Patients With Giant Cell Arteritis.

OBJECTIVE: In addition to aiding in diagnosis, histopathologic findings from temporal artery biopsy (TAB) specimens in giant cell arteritis (GCA) may be valuable for their associations with clinical features of the disease. This study was undertaken to compare histopathologic findings on TAB with biopsy interpretation and demographic, clinical, and imaging features at time of diagnosis. METHODS: Patients with a clinical diagnosis of GCA who had a TAB were selected from an international, multicenter observational cohort of vasculitis. Associations between demographic, clinical, radiographic, and histopathologic features were identified using bivariate testing and multivariate regression modeling. RESULTS: Of 705 patients with GCA who underwent TAB, 69% had histopathologic evidence of definite vasculitis. Specific histopathologic findings included the presence of giant cells (51%), fragmentation of the internal elastic lamina (41%), intimal thickening (33%), and predominantly mononuclear leukocyte infiltration (32%). Histopathologic interpretation of definite vasculitis was independently associated with giant cells (odds ratio [OR] 151.8 [95% confidence interval (95% CI) 60.2-551.6]), predominantly mononuclear leukocyte infiltration (OR 11.8 [95% CI 5.9-24.9]), and fragmentation of the internal elastic lamina (OR 3.7 [95% CI 1.9-7.4]). A halo sign on temporal artery ultrasound and luminal damage of large arteries on angiography were significantly associated with presence of giant cells (OR 2.6 [95% CI 1.1-6.5] and OR 2.4 [95% CI 1.1-5.2], respectively). Specific histopathologic findings were associated with older age, but no associations were identified with vision loss or other clinical features. CONCLUSION: Histopathologic findings in GCA are strongly associated with the clinical diagnosis of GCA but have a limited role in identifying patterns of disease.

Social Media for Research Discourse, Dissemination, and Collaboration in Rheumatology.

Social media has become an important venue for rheumatologists, patients, organizations, and other stakeholders to discuss recent research advances in diagnosis and management of rheumatic disorders. In this article, we describe the current state of how social media may enhance dissemination, discourse, and collaboration in rheumatology research. Social media may refer to social platforms like Twitter and Instagram or digital media like podcasts and other websites that are operated for providing as free, open-access medical education (FOAM). Twitter has been one of the most active social media venues and continues to host a vibrant rheumatology community. Examples of research discussions on Twitter include organic user tweets, educational threads ("tweetorials"), live-tweeting academic conferences, and journals posting recently-accepted articles. Some research collaborations have been initiated through social media interactions. Social media may also directly contribute to research by facilitating the recruitment of study participants and the collection of survey-based data. Thus, social media is an evolving and important tool to enhance research discourse, dissemination, and collaboration in rheumatology.

Industry involvement in rheumatology consensus-based recommendations: a systematic review.

Consensus-based recommendations guide standards of care for clinical practice. Pharmaceutical industry involvement in producing such recommendations might undermine their objectivity. We did a systematic review of rheumatology consensus-based recommendations that were published in English from 2000 to 2020. We compared those that were endorsed by major professional societies to those that were sponsored by industry using the validated Appraisal of Guidelines for Research & Evaluation (AGREE) II instrument. Of 234 consensus-based recommendation projects, 51 (22%) were endorsed by major societies and 74 (32%) were sponsored by the pharmaceutical industry. Among industry-sponsored projects, the sponsor was involved in the consensus-based process in 21 (28%), provided a medical writer in 12 (16%), offered honoraria for participation in five (7%), and was allowed to approve the final draft of one project. When compared with projects endorsed by major societies, industry-sponsored projects were less likely to have a high quality assessment on the AGREE II instrument. These results suggest that industry sponsorship of consensus-based recommendations is common in projects that do not receive endorsement by major societies. Such projects are often of lower quality than guidelines endorsed by major professional societies. Medical journals should consider steps to encourage greater rigour of development and to limit undue influence by industry sponsors.

Outcomes of COVID-19 in patients with primary systemic vasculitis or polymyalgia rheumatica from the COVID-19 Global Rheumatology Alliance physician registry: a retrospective cohort study.

BACKGROUND: Patients with primary systemic vasculitis or polymyalgia rheumatica might be at a high risk for poor COVID-19 outcomes due to the treatments used, the potential organ damage cause by primary systemic vasculitis, and the demographic factors associated with these conditions. We therefore aimed to investigate factors associated with COVID-19 outcomes in patients with primary systemic vasculitis or polymyalgia rheumatica. METHODS: In this retrospective cohort study, adult patients (aged ≥18 years) diagnosed with COVID-19 between March 12, 2020, and April 12, 2021, who had a history of primary systemic vasculitis (antineutrophil cytoplasmic antibody [ANCA]-associated vasculitis, giant cell arteritis, Behçet's syndrome, or other vasculitis) or polymyalgia rheumatica, and were reported to the COVID-19 Global Rheumatology Alliance registry were included. To assess COVID-19 outcomes in patients, we used an ordinal COVID-19 severity scale, defined as: (1) no hospitalisation; (2) hospitalisation without supplemental oxygen; (3) hospitalisation with any supplemental oxygen or ventilation; or (4) death. Multivariable ordinal logistic regression analyses were used to estimate odds ratios (ORs), adjusting for age, sex, time period, number of comorbidities, smoking status, obesity, glucocorticoid use, disease activity, region, and medication category. Analyses were also stratified by type of rheumatic disease. FINDINGS: Of 1202 eligible patients identified in the registry, 733 (61·0%) were women and 469 (39·0%) were men, and their mean age was 63·8 years (SD 17·1). A total of 374 (31·1%) patients had polymyalgia rheumatica, 353 (29·4%) had ANCA-associated vasculitis, 183 (15·2%) had giant cell arteritis, 112 (9·3%) had Behçet's syndrome, and 180 (15·0%) had other vasculitis. Of 1020 (84·9%) patients with outcome data, 512 (50·2%) were not hospitalised, 114 (11·2%) were hospitalised and did not receive supplemental oxygen, 239 (23·4%) were hospitalised and received ventilation or supplemental oxygen, and 155 (15·2%) died. A higher odds of poor COVID-19 outcomes were observed in patients who were older (per each additional decade of life OR 1·44 [95% CI 1·31-1·57]), were male compared with female (1·38 [1·05-1·80]), had more comorbidities (per each additional comorbidity 1·39 [1·23-1·58]), were taking 10 mg/day or more of prednisolone compared with none (2·14 [1·50-3·04]), or had moderate, or high or severe disease activity compared with those who had disease remission or low disease activity (2·12 [1·49-3·02]). Risk factors varied among different disease subtypes. INTERPRETATION: Among patients with primary systemic vasculitis and polymyalgia rheumatica, severe COVID-19 outcomes were associated with variable and largely unmodifiable risk factors, such as age, sex, and number of comorbidities, as well as treatments, including high-dose glucocorticoids. Our results could be used to inform mitigation strategies for patients with these diseases. FUNDING: American College of Rheumatology and the European Alliance of Associations for Rheumatology.

Industry Payments to Practicing US Rheumatologists, 2014-2019.

OBJECTIVE: Payments from the pharmaceutical industry to practicing physicians may influence prescribing behavior. This study was undertaken to investigate the nature, quantity, and geographic distribution of payments to US rheumatologists. METHODS: General payments from industry sponsors to US rheumatologists from 2014 to 2019 were extracted from the Centers for Medicare and Medicaid Services Open Payments database. Gender was identified by linking physicians to the National Plan and Provider Enumeration System registry. Data were reported in aggregate, trends over time were assessed using linear regression models, and differences by gender were analyzed using the Wilcoxon rank sum test. RESULTS: Over the 6-year time period from 2014 to 2019, a total of 1,610,668 payments totaling $221,254,966 were made to 5,723 rheumatologists. The median payment was $15 (interquartile range [IQR] $10 to $22), and the median total amount received by individual rheumatologists over the 6-year period was $2,818 (IQR $464 to $11,560). The majority of rheumatologists (3,416 of 5,723 [60%]) received less than $5,000, but 368 of 5,723 (6%) received more than $100,000 each and accounted for 78% of the total. The yearly value of payments increased over time ($3,703,264 per year; P < 0.001), and the median payment to male rheumatologists was significantly higher than the median payment to female rheumatologists ($3,723 [IQR $542 to $15,841] versus $2,084 [IQR $394 to $8,186]; P < 0.001). CONCLUSION: The value of industry payments has increased over time, and a large amount is concentrated among a small number of rheumatologists. Future studies should investigate the degree to which industry payments have influenced prescribing in the field of rheumatology.

Long-Term Care Resident Awareness and Interest in Spasticity Treatments.

Spasticity is common in long-term care settings (affecting up to one in three residents), yet it remains under-treated despite safe and effective, Food and Drug Administration (FDA)-approved therapies. One barrier to treatment may be lack of awareness of available therapies for long-term care residents living with spasticity. A standardized spasticity treatment awareness and interest interview was conducted with 18 nursing home residents and 11 veterans' home residents in this cross-sectional study. Veterans' home residents were also asked about potential barriers to receiving spasticity treatment. Many residents across both long-term care facilities were unaware of most of the treatment options for spasticity. Participants were most aware of physical/occupational therapy (83%, 95% CI: 65-93%) and least aware of intrathecal baclofen (21%, 95% CI: 9-39%). After learning about treatments, only 7% of participants (95% CI: 0-23%) were not interested in receiving any form of spasticity treatment. Among residents previously unaware of spasticity treatments, at least one quarter became interested in receiving treatment and at least one-fifth indicated possibly being interested in the treatment after learning about it. Potential barriers to receiving treatment included traveling to see a doctor and limited knowledge of insurance coverage of spasticity treatments. These results suggest that patient-centered approaches, including education and discerning patient preferences, may improve spasticity treatment in long-term care settings.

The protective effect of rheumatic disease agents in COVID-19.

Several immunosuppressive therapies have been investigated as potential treatments for patients with severe and critical coronavirus disease 2019 (COVID-19). Notable examples include corticosteroids, interleukin 6 (IL-6), interleukin 1 (IL-1), Janus kinase (JAK), and tumor necrosis factor alpha (TNF-α) inhibitors. The aim of this narrative review is to analyze the mechanistic rationale and available evidence for these selected anti-rheumatic drugs for the treatment of COVID-19. Currently, only corticosteroids have consistently proven to be effective in decreasing mortality and are recommended in clinical guidelines for the treatment of severe and critical COVID-19. Multiple randomized controlled trials (RCTs) are ongoing to determine the role of other immunosuppressants.

Giant Cell Arteritis and COVID-19: Similarities and Discriminators. A Systematic Literature Review.

OBJECTIVE: To identify shared and distinct features of giant cell arteritis (GCA) and coronavirus disease 2019(COVID-19) to reduce diagnostic errors that could cause delays in correct treatment. METHODS: Two systematic literature reviews determined the frequency of clinical features of GCA and COVID-19 in published reports. Frequencies in each disease were summarized using medians and ranges. RESULTS: Headache was common in GCA but was also observed in COVID-19 (GCA 66%, COVID-19 10%). Jaw claudication or visual loss (43% and 26% in GCA, respectively) generally were not reported in COVID-19. Both diseases featured fatigue (GCA 38%, COVID-19 43%) and elevated inflammatory markers (C-reactive protein [CRP] elevated in 100% of GCA, 66% of COVID-19), but platelet count was elevated in 47% of GCA but only 4% of COVID-19 cases. Cough and fever were commonly reported in COVID-19 and less frequently in GCA (cough, 63% for COVID-19 vs 12% for GCA; fever, 83% for COVID-19 vs 27% for GCA). Gastrointestinal upset was occasionally reported in COVID-19 (8%), rarely in GCA (4%). Lymphopenia was more common in COVID-19 than GCA (53% in COVID-19, 2% in GCA). Alteration of smell and taste have been described in GCA but their frequency is unclear. CONCLUSION: Overlapping features of GCA and COVID-19 include headache, fever, elevated CRP and cough. Jaw claudication, visual loss, platelet count and lymphocyte count may be more discriminatory. Physicians should be aware of the possibility of diagnostic confusion. We have designed a simple checklist to aid evidence-based evaluation of patients with suspected GCA.

Swinging the pendulum: lessons learned from public discourse concerning hydroxychloroquine and COVID-19.

INTRODUCTION: Several months into the COVID-19 pandemic, safe and effective treatments against this global health disaster have yet to be identified. Clinical research trials around the world are underway testing a wide array of possible medications. In particular, the off-label use of hydroxychloroquine for COVID-19 prophylaxis and treatment has created many unprecedented challenges for the scientific community and the public. AREAS COVERED: We critically assessed major events from February - May 2020 that contributed to widespread use of hydroxychloroquine for the treatment and prophylaxis of COVID-19. We aimed to explore how opinions toward hydroxychloroquine may shift from early enthusiasm (based on in vitro and preliminary clinical data) to the hope for a miracle cure (through communication and promotion of questionable results) and, finally, to a rise of skepticism as more in-depth analyses are emerging. EXPERT OPINION: Mindful and rigorous acquisition of data, as well as its interpretation, are essential to an effective pandemic response. The rapid and premature promotion of results has had major implications for global crisis management, even creating distrust among the public. It is crucial for the medical and scientific community to incorporate the lessons learned from this situation.

The Quality of Randomized Controlled Trials in High-impact Rheumatology Journals, 1998-2018.

OBJECTIVE: Well-designed randomized controlled trials (RCT) mitigate bias and confounding, but previous evaluations of rheumatology trials found high rates of methodological flaws. Outside of rheumatoid arthritis, no studies in the modern era have assessed the quality of rheumatology RCT over time or regarding industry funding. METHODS: We identified all RCT published in 3 high-impact rheumatology journals from 1998, 2008, and 2018. Quality metrics derived from a modified Jadad scale were analyzed by year of publication and by funding source. RESULTS: Ninety-six publications met inclusion criteria; 82 of these described the primary analysis of an RCT. Over time (1998-2008-2018), trials were less likely to adequately report dropouts and withdrawals (100% vs 82% vs 60%; p < 0.01) or include an active comparator (44% vs 12% vs 13%; p = 0.01). Later trials were more likely to evaluate biologic therapy (11% vs 38% vs 83%; p < 0.01) and report adequate randomization procedures (39% vs 29% vs 60%; p = 0.04). Seventy-nine percent of trials received industry funding. Industry-funded trials were more likely to report double-blinding (86% vs 53%; p < 0.01), patient-reported outcome measures (77% vs 41%; p < 0.01), and intention-to-treat analyses (86% vs 65%; p = 0.04). CONCLUSION: Industry-funded trials comprise the majority of RCT published in high-impact rheumatology journals and more frequently report metrics associated with RCT quality. RCT assessing active comparators and nonbiologic therapies have become less common in high-impact rheumatology journals.