Baricitinib for systemic lupus erythematosus: a double-blind, randomised, placebo-controlled, phase 3 trial (SLE-BRAVE-I).

BACKGROUND: Baricitinib is an oral selective inhibitor of Janus kinase 1 and 2 approved for the treatment of rheumatoid arthritis, atopic dermatitis, and alopecia areata. In a 24-week phase 2 study in patients with systemic lupus erythematosus (SLE), baricitinib 4 mg significantly improved SLE disease activity compared with placebo. The objective of this trial was to evaluate the efficacy and safety of baricitinib in patients with active SLE in a 52-week phase 3 study. METHODS: In a multicentre, double-blind, randomised, placebo-controlled, parallel-group, phase 3 study, SLE-BRAVE-I, patients (aged ≥18 years) with active SLE receiving stable background therapy were randomly assigned 1:1:1 to baricitinib 4 mg, 2 mg, or placebo once daily for 52 weeks with standard of care. Glucocorticoid tapering was encouraged but not required per protocol. The primary endpoint was the proportion of patients reaching an SLE Responder Index (SRI)-4 response at week 52 in the baricitinib 4 mg treatment group compared with placebo. The primary endpoint was assessed by logistic regression analysis with baseline disease activity, baseline corticosteroid dose, region, and treatment group in the model. Efficacy analyses were done on a modified intention-to-treat population, comprising all participants who were randomly assigned and received at least one dose of investigational product. Safety analyses were done on all randomly assigned participants who received at least one dose of investigational product and who did not discontinue from the study for the reason of lost to follow-up at the first post-baseline visit. This study is registered with ClinicalTrials.gov, NCT03616912. FINDINGS: 760 participants were randomly assigned and received at least one dose of baricitinib 4 mg (n=252), baricitinib 2 mg (n=255), or placebo (n=253). A significantly greater proportion of participants who received baricitinib 4 mg (142 [57%]; odds ratio 1·57 [95% CI 1·09 to 2·27]; difference with placebo 10·8 [2·0 to 19·6]; p=0·016), but not baricitinib 2 mg (126 [50%]; 1·14 [0·79 to 1·65]; 3·9 [-4·9 to 12·6]; p=0·47), reached SRI-4 response compared with placebo (116 [46%]). There were no significant differences between the proportions of participants in either baricitinib group reaching any of the major secondary endpoints compared with placebo, including glucocorticoid tapering and time to first severe flare. 26 (10%) participants receiving baricitinib 4 mg had serious adverse events, 24 (9%) participants receiving baricitinib 2 mg, and 18 (7%) participants receiving placebo. The safety profile of baricitinib in participants with SLE was consistent with the known baricitinib safety profile. INTERPRETATION: The primary endpoint in this study was met for the 4 mg baricitinib group. However, key secondary endpoints were not. No new safety signals were observed. FUNDING: Eli Lilly and Company.

Deucravacitinib, a Tyrosine Kinase 2 Inhibitor, in Systemic Lupus Erythematosus: A Phase II, Randomized, Double-Blind, Placebo-Controlled Trial.

OBJECTIVE: To assess the efficacy and safety of deucravacitinib, an oral, selective, allosteric inhibitor of TYK2, in a phase II trial in adult patients with active systemic lupus erythematosus (SLE). METHODS: Adults with active SLE were enrolled from 162 sites in 17 countries. Patients (n = 363) were randomized 1:1:1:1 to receive deucravacitinib 3 mg twice daily, 6 mg twice daily, 12 mg once daily, or placebo. The primary end point was SLE Responder Index 4 (SRI-4) response at week 32. Secondary outcomes assessed at week 48 included SRI-4, British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) response, Cutaneous Lupus Erythematosus Disease Area and Severity Index 50 (CLASI-50), Lupus Low Disease Activity State (LLDAS), and improvements in active (swollen plus tender), swollen, and tender joint counts. RESULTS: At week 32, the percentage of patients achieving SRI-4 response was 34% with placebo compared to 58% with deucravacitinib 3 mg twice daily (odds ratio [OR] 2.8 [95% confidence interval (95% CI) 1.5, 5.1]; P < 0.001 versus placebo), 50% with 6 mg twice daily (OR 1.9 [95% CI 1.0, 3.4]; P = 0.02 versus placebo), and 45% with 12 mg once daily (OR 1.6 [95% CI 0.8, 2.9]; nominal P = 0.08 versus placebo). Response rates were higher with deucravacitinib treatment for BICLA, CLASI-50, LLDAS, and joint counts compared to placebo. Rates of adverse events were similar across groups, except higher rates of infections and cutaneous events, including rash and acne, with deucravacitinib treatment. Rates of serious adverse events were comparable, with no deaths, opportunistic infections, tuberculosis infections, major adverse cardiovascular events, or thrombotic events reported. CONCLUSION: Deucravacitinib treatment elicited higher response rates for SRI-4 and other end points compared with placebo, with an acceptable safety profile, in adult patients with active SLE.

A Randomized, Placebo-Controlled Phase III Extension Trial of the Long-Term Safety and Tolerability of Anifrolumab in Active Systemic Lupus Erythematosus.

OBJECTIVE: To explore long-term safety and tolerability of anifrolumab 300 mg compared with placebo in patients with systemic lupus erythematosus (SLE) who completed a Treatment of Uncontrolled Lupus via the Interferon Pathway (TULIP) trial and enrolled in the placebo-controlled 3-year long-term extension (LTE) study (ClinicalTrials.gov identifier: NCT02794285). METHODS: In the blinded LTE study, patients continued anifrolumab 300 mg, switched from anifrolumab 150 mg to 300 mg, or were re-randomized from placebo to receive either anifrolumab 300 mg or to continue placebo, administered every 4 weeks. Primary comparisons in the LTE study were between patients who received anifrolumab 300 mg or placebo throughout the TULIP and LTE studies. For rare safety events, comparisons included patients who received any anifrolumab dose during TULIP or LTE. When exposure differed, exposure-adjusted incidence rates (EAIRs) per 100 patient-years were calculated. RESULTS: In the LTE study, EAIRs of serious adverse events (SAEs) were 8.5 with anifrolumab compared with 11.2 with placebo; likewise, EAIRs of AEs leading to treatment discontinuation were 2.5 versus 3.2, respectively. EAIRs of non-opportunistic serious infections were comparable between groups (3.7 with anifrolumab versus 3.6 with placebo). Exposure-adjusted event rates of COVID-related AEs, including asymptomatic infections, were 15.5 with anifrolumab compared with 9.8 with placebo. No COVID-related AEs occurred in fully vaccinated individuals. EAIRs of malignancy and major acute cardiovascular events were low and comparable between groups. Anifrolumab was associated with lower cumulative glucocorticoid use and greater mean improvement in the SLE Disease Activity Index 2000, compared with placebo. CONCLUSION: This LTE study represents the longest placebo-controlled clinical trial performed in SLE to date. No new safety findings were identified in the LTE study, supporting the favorable benefit-risk profile of anifrolumab for patients with moderate-to-severe SLE receiving standard therapy.

Lung Ultrasound to Assist ICU Admission Decision-Making Process of COVID-19 Patients With Acute Respiratory Failure.

There is only low-certainty evidence on the use of predictive models to assist COVID-19 patient's ICU admission decision-making process. Accumulative evidence suggests that lung ultrasound (LUS) assessment of COVID-19 patients allows accurate bedside evaluation of lung integrity, with the added advantage of repeatability, absence of radiation exposure, reduced risk of virus dissemination, and low cost. Our goal is to assess the performance of a quantified indicator resulting from LUS data compared with standard clinical practice model to predict critical respiratory illness in the 24 hours following hospital admission. DESIGN: Prospective cohort study. SETTING: Critical Care Unit from University Hospital Purpan (Toulouse, France) between July 2020 and March 2021. PATIENTS: Adult patients for COVID-19 who were in acute respiratory failure (ARF), defined as blood oxygen saturation as measured by pulse oximetry less than 90% while breathing room air or respiratory rate greater than or equal to 30 breaths/min at hospital admission. Linear multivariate models were used to identify factors associated with critical respiratory illness, defined as death or mild/severe acute respiratory distress syndrome (Pao2/Fio2 < 200) in the 24 hours after patient's hospital admission. INTERVENTION: LUS assessment. MEASUREMENTS AND MAIN RESULTS: One hundred and forty COVID-19 patients with ARF were studied. This cohort was split into two independent groups: learning sample (first 70 patients) and validation sample (last 70 patients). Interstitial lung water, thickening of the pleural line, and alveolar consolidation detection were strongly associated with patient's outcome. The LUS model predicted more accurately patient's outcomes than the standard clinical practice model (DeLong test: Testing: z score = 2.50, p value = 0.01; Validation: z score = 2.11, p value = 0.03). CONCLUSIONS: LUS assessment of COVID-19 patients with ARF at hospital admission allows a more accurate prediction of the risk of critical respiratory illness than standard clinical practice. These results hold the promise of improving ICU resource allocation process, particularly in the case of massive influx of patients or limited resources, both now and in future anticipated pandemics.

SARS-COV-2 vaccine acceptance in patients with rheumatic diseases: a cross-sectional study.

OBJECTIVES: To evaluate severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine acceptance among patients with rheumatic diseases (RMD). METHODS: All rheumatology patients attending a large suburban health network were invited to participate in an anonymized online survey. The primary outcome of interest was SARS-COV-2 vaccine acceptance. RESULTS: The mean (SD) age of respondents (n = 641) was 52.7 (15.1) years and 74.4% (n = 474) were female. Sixty-five percent were willing to have a SARS-COV-2 vaccine, while 34.4% were vaccine-hesitant (unwilling or undecided). On multivariate analysis, vaccine acceptance was associated with smoking (OR: 2.25 [95% CI: 1.22-4.15; p = .009]), history of malignancy (OR: 2.51 [95% CI: 1.19-5.26; p = .015]), influenza or pneumococcal vaccination in the preceding year (OR: 2.69 [95% CI: 1.78-4.05; p < .001]) and number of COVID-Safe measures practiced (OR: 1.54 [95% CI: 1.05-2.26; p = .027]). Vaccine acceptance correlated with positive beliefs regarding vaccine efficacy (r = 0.40; p < .001) and safety (r = 0.36; p < .001). Vaccine acceptance correlated negatively with concerns regarding side-effects (r = -0.30; p < .001) and vaccine-associated RMD flare (r = -0.21; p < .001). In vaccine-hesitant respondents, 39.2% were more likely to accept vaccination if given a choice of which vaccine they receive and 54.5% if their rheumatologist recommended it. Twenty-seven percent of patients on immunomodulators were willing to withhold medications while 42.1% were willing if advised by their rheumatologist. CONCLUSION: SARS-COV-2 vaccine hesitancy is prevalent amongst RMD patients and associated with concerns regarding vaccine safety, efficacy, side effects and RMD flare. Clinician recommendation, vaccine choice and communications targeting patient concerns could facilitate vaccine acceptance.Significance and Innovations Vaccine hesitancy is prevalent in RMD patientsVaccine acceptance is associated with beliefs regarding vaccine safety and efficacy and concerns regarding RMD flare and vaccine-associated side effectsVaccine choice and clinician recommendation have the potential to improve vaccine acceptance in patients who are hesitant.

Impact of COVID-19 telehealth on outpatient test completion.

BACKGROUND: Pathology and imaging tests are frequently requested in the outpatient setting despite historically poor completion rates. The impact of COVID-19 telehealth on test completion rates is unknown. AIMS: To examine the impact of the COVID-19 pandemic and telehealth transition on pathology and imaging test request and completion rates in Australian outpatient clinics. METHODS: We performed a prospective cohort study with historical controls between March-May 2019 and March-May 2020. Pathology and imaging request and completion rates were collected in review consultation patients attending gastroenterology and rheumatology outpatient clinics at a tertiary healthcare system prior and during the early phases of the COVID-19 pandemic in Melbourne. RESULTS: A total of 1376 patients was included in the study. Pathology tests were requested more frequently in the COVID-19 group (n = 582/684, 85.2%) than the control group (n = 492/692, 71.1%, P < 0.001), but completion rates were lower in the COVID-19 group (n = 443/582, 76.1%) than the control group (n = 426/492 (86.6%), P < 0.001). Imaging tests were requested more frequently in the COVID-19 group (n = 345/682, 50.6%) than the control group (n = 295/692, 42.6%, P = 0.003), with lower rates of completion in the COVID-19 group (n = 229/345, 66.4%) than the control group (n = 247/295, 83.7%, P < 0.001). CONCLUSIONS: The COVID-19 pandemic and telehealth transition have resulted in more frequent pathology and imaging requests but fewer test completion in the outpatients setting. This study has identified new clinical risks associated with the abrupt transition to telehealth during COVID-19 that should be explored in future studies and appropriately mitigated.

Breaking the chain of transmission within a tertiary health service: An approach to contact tracing during the COVID-19 pandemic.

BACKGROUND: Tertiary referral health service. INTERVENTION(S): An approach to hospital based contact tracing is described along with tools employed to streamline the process and including the development of an outbreak management team (OMT) for each contact trace. RESULTS: Forty-one OMTs occurred, involving 23 HCW and 18 patient index cases. The total furloughed HCWs arising from these contact traces was 383, with individual contact traces furloughing a mean (range) of 10 (0-80) HCWs. Importantly, 15 furloughed HCWs subsequently became COVID-19 positive during their 14-day isolation period, showing the importance of the contact tracing process and the ability to remove workers from the workplace before they become infectious. CONCLUSIONS: A standardised, streamlined contact tracing procedure in healthcare settings ensures any impacts of COVID-19 positive cases are consistently managed. This response framework may be of use to other health services and help reduce the transmission of COVID-19 in the workplace.

Perspectives of Patients With Rheumatic Diseases in the Early Phase of COVID-19.

OBJECTIVE: To determine health perceptions of patients with rheumatic diseases in the early phase of the coronavirus disease 2019 (COVID-19) pandemic. METHODS: Rheumatology patients at a single center received via text message the Australian Rheumatology Association COVID-19 information sheet and an invitation to participate in a deidentified survey. Patient concerns regarding risks conferred by their rheumatologic disease or medications, impact of receiving the information sheet on the likelihood of staying on medication, and acceptance of telehealth were ascertained. RESULTS: A total of 2,630 patients received the text message, and the survey response rate was 21% (n = 550). The mean ± SD age of the participants was 52 ± 15.2 years, and 75.3% were female. Participants' highest ranked concern was that their medications would increase the severity of their COVID-19 symptoms (76.1%). The highest levels of concern were seen in patients taking combination conventional synthetic disease-modifying antirheumatic drugs (DMARDs) and/or a biologic/targeted synthetic DMARD. There was no association between prednisolone dose and concern. While 63% of patients planned to continue their antirheumatic medications, a further 30% were more likely to continue taking their medications because of receiving the information. Telehealth was acceptable to 98.4% of patients, but 28.1% felt this was only appropriate while infection control measures were in place. CONCLUSION: Concerns regarding the risk of COVID-19 among patients taking antirheumatic drugs are common. Proactive dissemination of information is needed to address misconceptions related to medication risk, improve medication adherence, and minimize the risk of flares. Telehealth is acceptable to most patients during the COVID-19 pandemic.