Phase 3 Trial of Crinecerfont in Pediatric Congenital Adrenal Hyperplasia.

BACKGROUND: Children with classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency require treatment with glucocorticoids, usually at supraphysiologic doses, to address cortisol insufficiency and reduce excess adrenal androgens. However, such treatment confers a predisposition to glucocorticoid-related complications. In 2-week phase 2 trials, patients with CAH who received crinecerfont, a new oral corticotropin-releasing factor type 1 receptor antagonist, had decreases in androstenedione levels. METHODS: In this phase 3, multinational, randomized trial, we assigned pediatric participants with CAH, in a 2:1 ratio, to receive crinecerfont or placebo for 28 weeks. A stable glucocorticoid dose was maintained for 4 weeks, and the dose was then adjusted to a target of 8.0 to 10.0 mg per square meter of body-surface area per day (hydrocortisone dose equivalents), provided that the androstenedione level was controlled (≤120% of the baseline level or within the reference range). The primary efficacy end point was the change in the androstenedione level from baseline to week 4. A key secondary end point was the percent change in the glucocorticoid dose from baseline to week 28 while androstenedione control was maintained. RESULTS: A total of 103 participants underwent randomization, of whom 69 were assigned to crinecerfont and 34 to placebo; 100 (97%) remained in the trial at 28 weeks. At baseline, the mean glucocorticoid dose was 16.4 mg per square meter per day, and the mean androstenedione level was 431 ng per deciliter (15.0 nmol/liter). At week 4, androstenedione was substantially reduced in the crinecerfont group (-197 ng per deciliter [-6.9 nmol/liter]) but increased in the placebo group (71 ng per deciliter [2.5 nmol/liter]) (least-squares mean difference [LSMD], -268 ng per deciliter [-9.3 nmol/liter]; P<0.001); the observed mean androstenedione value, obtained before the morning glucocorticoid dose, was 208 ng per deciliter (7.3 nmol/liter) in the crinecerfont group, as compared with 545 ng per deciliter (19.0 nmol/liter) in the placebo group. At week 28, the mean glucocorticoid dose had decreased (while androstenedione control was maintained) by 18.0% with crinecerfont but increased by 5.6% with placebo (LSMD, -23.5 percentage points; P<0.001). Headache, pyrexia, and vomiting were the most common adverse events. CONCLUSIONS: In this phase 3 trial, crinecerfont was superior to placebo in reducing elevated androstenedione levels in pediatric participants with CAH and was also associated with a decrease in the glucocorticoid dose from supraphysiologic to physiologic levels while androstenedione control was maintained. (Funded by Neurocrine Biosciences; CAHtalyst Pediatric ClinicalTrials.gov number, NCT04806451.).

Phase 3 Trial of Crinecerfont in Adult Congenital Adrenal Hyperplasia.

BACKGROUND: Adrenal insufficiency in patients with classic 21-hydroxylase deficiency congenital adrenal hyperplasia (CAH) is treated with glucocorticoid replacement therapy. Control of adrenal-derived androgen excess usually requires supraphysiologic glucocorticoid dosing, which predisposes patients to glucocorticoid-related complications. Crinecerfont, an oral corticotropin-releasing factor type 1 receptor antagonist, lowered androstenedione levels in phase 2 trials involving patients with CAH. METHODS: In this phase 3 trial, we randomly assigned adults with CAH in a 2:1 ratio to receive crinecerfont or placebo for 24 weeks. Glucocorticoid treatment was maintained at a stable level for 4 weeks to evaluate androstenedione values, followed by glucocorticoid dose reduction and optimization over 20 weeks to achieve the lowest glucocorticoid dose that maintained androstenedione control (≤120% of the baseline value or within the reference range). The primary efficacy end point was the percent change in the daily glucocorticoid dose from baseline to week 24 with maintenance of androstenedione control. RESULTS: All 182 patients who underwent randomization (122 to the crinecerfont group and 60 to the placebo group) were included in the 24-week analysis, with imputation of missing values; 176 patients (97%) remained in the trial at week 24. The mean glucocorticoid dose at baseline was 17.6 mg per square meter of body-surface area per day of hydrocortisone equivalents; the mean androstenedione level was elevated at 620 ng per deciliter. At week 24, the change in the glucocorticoid dose (with androstenedione control) was -27.3% in the crinecerfont group and -10.3% in the placebo group (least-squares mean difference, -17.0 percentage points; P<0.001). A physiologic glucocorticoid dose (with androstenedione control) was reported in 63% of the patients in the crinecerfont group and in 18% in the placebo group (P<0.001). At week 4, androstenedione levels decreased with crinecerfont (-299 ng per deciliter) but increased with placebo (45.5 ng per deciliter) (least-squares mean difference, -345 ng per deciliter; P<0.001). Fatigue and headache were the most common adverse events in the two trial groups. CONCLUSIONS: Among patients with CAH, the use of crinecerfont resulted in a greater decrease from baseline in the mean daily glucocorticoid dose, including a reduction to the physiologic range, than placebo following evaluation of adrenal androgen levels. (Funded by Neurocrine Biosciences; CAHtalyst ClinicalTrials.gov number, NCT04490915.).

Sarilumab for Relapse of Polymyalgia Rheumatica during Glucocorticoid Taper.

BACKGROUND: More than half of patients with polymyalgia rheumatica have a relapse during tapering of glucocorticoid therapy. Previous studies have suggested that interleukin-6 blockade may be clinically useful in the treatment of polymyalgia rheumatica. Sarilumab, a human monoclonal antibody, binds interleukin-6 receptor α and efficiently blocks the interleukin-6 pathway. METHODS: In this phase 3 trial, we randomly assigned patients in a 1:1 ratio to receive 52 weeks of a twice-monthly subcutaneous injection of either sarilumab (at a dose of 200 mg) plus a 14-week prednisone taper or placebo plus a 52-week prednisone taper. The primary outcome at 52 weeks was sustained remission, which was defined as the resolution of signs and symptoms of polymyalgia rheumatica by week 12 and sustained normalization of the C-reactive protein level, absence of disease flare, and adherence to the prednisone taper from weeks 12 through 52. RESULTS: A total of 118 patients underwent randomization (60 to receive sarilumab and 58 to receive placebo). At week 52, sustained remission occurred in 28% (17 of 60 patients) in the sarilumab group and in 10% (6 of 58 patients) in the placebo group (difference, 18 percentage points; 95% confidence interval, 4 to 32; P = 0.02). The median cumulative glucocorticoid dose at 52 weeks was significantly lower in the sarilumab group than in the placebo group (777 mg vs. 2044 mg; P<0.001). The most common adverse events with sarilumab as compared with placebo were neutropenia (15% vs. 0%), arthralgia (15% vs. 5%), and diarrhea (12% vs. 2%). More treatment-related discontinuations were observed in the sarilumab group than in the placebo group (12% vs. 7%). CONCLUSIONS: Sarilumab showed significant efficacy in achieving sustained remission and reducing the cumulative glucocorticoid dose in patients with a relapse of polymyalgia rheumatica during glucocorticoid tapering. (Funded by Sanofi and Regeneron Pharmaceuticals; SAPHYR ClinicalTrials.gov number, NCT03600818.).

Inhaled Fluticasone Furoate for Outpatient Treatment of Covid-19.

BACKGROUND: The effectiveness of inhaled glucocorticoids in shortening the time to symptom resolution or preventing hospitalization or death among outpatients with mild-to-moderate coronavirus disease 2019 (Covid-19) is unclear. METHODS: We conducted a decentralized, double-blind, randomized, placebo-controlled platform trial in the United States to assess the use of repurposed medications in outpatients with confirmed coronavirus disease 2019 (Covid-19). Nonhospitalized adults 30 years of age or older who had at least two symptoms of acute infection that had been present for no more than 7 days before enrollment were randomly assigned to receive inhaled fluticasone furoate at a dose of 200 µg once daily for 14 days or placebo. The primary outcome was the time to sustained recovery, defined as the third of 3 consecutive days without symptoms. Key secondary outcomes included hospitalization or death by day 28 and a composite outcome of the need for an urgent-care or emergency department visit or hospitalization or death through day 28. RESULTS: Of the 1407 enrolled participants who underwent randomization, 715 were assigned to receive inhaled fluticasone furoate and 692 to receive placebo, and 656 and 621, respectively, were included in the analysis. There was no evidence that the use of fluticasone furoate resulted in a shorter time to recovery than placebo (hazard ratio, 1.01; 95% credible interval, 0.91 to 1.12; posterior probability of benefit [defined as a hazard ratio >1], 0.56). A total of 24 participants (3.7%) in the fluticasone furoate group had urgent-care or emergency department visits or were hospitalized, as compared with 13 participants (2.1%) in the placebo group (hazard ratio, 1.9; 95% credible interval, 0.8 to 3.5). Three participants in each group were hospitalized, and no deaths occurred. Adverse events were uncommon in both groups. CONCLUSIONS: Treatment with inhaled fluticasone furoate for 14 days did not result in a shorter time to recovery than placebo among outpatients with Covid-19 in the United States. (Funded by the National Center for Advancing Translational Sciences and others; ACTIV-6 ClinicalTrials.gov number, NCT04885530.).

Albuterol-Budesonide Fixed-Dose Combination Rescue Inhaler for Asthma.

BACKGROUND: As asthma symptoms worsen, patients typically rely on short-acting ß2-agonist (SABA) rescue therapy, but SABAs do not address worsening inflammation, which leaves patients at risk for severe asthma exacerbations. The use of a fixed-dose combination of albuterol and budesonide, as compared with albuterol alone, as rescue medication might reduce the risk of severe asthma exacerbation. METHODS: We conducted a multinational, phase 3, double-blind, randomized, event-driven trial to evaluate the efficacy and safety of albuterol-budesonide, as compared with albuterol alone, as rescue medication in patients with uncontrolled moderate-to-severe asthma who were receiving inhaled glucocorticoid-containing maintenance therapies, which were continued throughout the trial. Adults and adolescents (≥12 years of age) were randomly assigned in a 1:1:1 ratio to one of three trial groups: a fixed-dose combination of 180 µg of albuterol and 160 µg of budesonide (with each dose consisting of two actuations of 90 µg and 80 µg, respectively [the higher-dose combination group]), a fixed-dose combination of 180 µg of albuterol and 80 µg of budesonide (with each dose consisting of two actuations of 90 µg and 40 µg, respectively [the lower-dose combination group]), or 180 µg of albuterol (with each dose consisting of two actuations of 90 µg [the albuterol-alone group]). Children 4 to 11 years of age were randomly assigned to only the lower-dose combination group or the albuterol-alone group. The primary efficacy end point was the first event of severe asthma exacerbation in a time-to-event analysis, which was performed in the intention-to-treat population. RESULTS: A total of 3132 patients underwent randomization, among whom 97% were 12 years of age or older. The risk of severe asthma exacerbation was significantly lower, by 26%, in the higher-dose combination group than in the albuterol-alone group (hazard ratio, 0.74; 95% confidence interval [CI], 0.62 to 0.89; P = 0.001). The hazard ratio in the lower-dose combination group, as compared with the albuterol-alone group, was 0.84 (95% CI, 0.71 to 1.00; P = 0.052). The incidence of adverse events was similar in the three trial groups. CONCLUSIONS: The risk of severe asthma exacerbation was significantly lower with as-needed use of a fixed-dose combination of 180 µg of albuterol and 160 µg of budesonide than with as-needed use of albuterol alone among patients with uncontrolled moderate-to-severe asthma who were receiving a wide range of inhaled glucocorticoid-containing maintenance therapies. (Funded by Avillion; MANDALA ClinicalTrials.gov number, NCT03769090.).

Hydrocortisone to Improve Survival without Bronchopulmonary Dysplasia.

BACKGROUND: Bronchopulmonary dysplasia is a prevalent complication after extremely preterm birth. Inflammation with mechanical ventilation may contribute to its development. Whether hydrocortisone treatment after the second postnatal week can improve survival without bronchopulmonary dysplasia and without adverse neurodevelopmental effects is unknown. METHODS: We conducted a trial involving infants who had a gestational age of less than 30 weeks and who had been intubated for at least 7 days at 14 to 28 days. Infants were randomly assigned to receive either hydrocortisone (4 mg per kilogram of body weight per day tapered over a period of 10 days) or placebo. Mandatory extubation thresholds were specified. The primary efficacy outcome was survival without moderate or severe bronchopulmonary dysplasia at 36 weeks of postmenstrual age, and the primary safety outcome was survival without moderate or severe neurodevelopmental impairment at 22 to 26 months of corrected age. RESULTS: We enrolled 800 infants (mean [±SD] birth weight, 715±167 g; mean gestational age, 24.9±1.5 weeks). Survival without moderate or severe bronchopulmonary dysplasia at 36 weeks occurred in 66 of 398 infants (16.6%) in the hydrocortisone group and in 53 of 402 (13.2%) in the placebo group (adjusted rate ratio, 1.27; 95% confidence interval [CI], 0.93 to 1.74). Two-year outcomes were known for 91.0% of the infants. Survival without moderate or severe neurodevelopmental impairment occurred in 132 of 358 infants (36.9%) in the hydrocortisone group and in 134 of 359 (37.3%) in the placebo group (adjusted rate ratio, 0.98; 95% CI, 0.81 to 1.18). Hypertension that was treated with medication occurred more frequently with hydrocortisone than with placebo (4.3% vs. 1.0%). Other adverse events were similar in the two groups. CONCLUSIONS: In this trial involving preterm infants, hydrocortisone treatment starting on postnatal day 14 to 28 did not result in substantially higher survival without moderate or severe bronchopulmonary dysplasia than placebo. Survival without moderate or severe neurodevelopmental impairment did not differ substantially between the two groups. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT01353313.).

Reliever-Triggered Inhaled Glucocorticoid in Black and Latinx Adults with Asthma.

BACKGROUND: Black and Latinx patients bear a disproportionate burden of asthma. Efforts to reduce the disproportionate morbidity have been mostly unsuccessful, and guideline recommendations have not been based on studies in these populations. METHODS: In this pragmatic, open-label trial, we randomly assigned Black and Latinx adults with moderate-to-severe asthma to use a patient-activated, reliever-triggered inhaled glucocorticoid strategy (beclomethasone dipropionate, 80 µg) plus usual care (intervention) or to continue usual care. Participants had one instructional visit followed by 15 monthly questionnaires. The primary end point was the annualized rate of severe asthma exacerbations. Secondary end points included monthly asthma control as measured with the Asthma Control Test (ACT; range, 5 [poor] to 25 [complete control]), quality of life as measured with the Asthma Symptom Utility Index (ASUI; range, 0 to 1, with lower scores indicating greater impairment), and participant-reported missed days of work, school, or usual activities. Safety was also assessed. RESULTS: Of 1201 adults (603 Black and 598 Latinx), 600 were assigned to the intervention group and 601 to the usual-care group. The annualized rate of severe asthma exacerbations was 0.69 (95% confidence interval [CI], 0.61 to 0.78) in the intervention group and 0.82 (95% CI, 0.73 to 0.92) in the usual-care group (hazard ratio, 0.85; 95% CI, 0.72 to 0.999; P = 0.048). ACT scores increased by 3.4 points (95% CI, 3.1 to 3.6) in the intervention group and by 2.5 points (95% CI, 2.3 to 2.8) in the usual-care group (difference, 0.9; 95% CI, 0.5 to 1.2); ASUI scores increased by 0.12 points (95% CI, 0.11 to 0.13) and 0.08 points (95% CI, 0.07 to 0.09), respectively (difference, 0.04; 95% CI, 0.02 to 0.05). The annualized rate of missed days was 13.4 in the intervention group and 16.8 in the usual-care group (rate ratio, 0.80; 95% CI, 0.67 to 0.95). Serious adverse events occurred in 12.2% of the participants, with an even distribution between the groups. CONCLUSIONS: Among Black and Latinx adults with moderate-to-severe asthma, provision of an inhaled glucocorticoid and one-time instruction on its use, added to usual care, led to a lower rate of severe asthma exacerbations. (Funded by the Patient-Centered Outcomes Research Institute and others; PREPARE ClinicalTrials.gov number, NCT02995733.).

Rheumatology: What You May Have Missed in 2023.

Many patients with rheumatologic conditions receive care from physicians other than rheumatologists. Here we note key findings from 6 studies in rheumatology published in 2023 that offer valuable insights for internal medicine specialists and subspecialists outside of rheumatology. The first study investigated the effect of low-dose glucocorticoids on patients with rheumatoid arthritis (RA) over 2 years and challenged existing perceptions about the risks of glucocorticoids in this setting. The second study focused on the updated guideline for preventing and treating glucocorticoid-induced osteoporosis. With the chronic and widespread use of glucocorticoids, the American College of Rheumatology emphasized the importance of assessing fracture risk and initiating pharmacologic therapy when appropriate. The third study explored the potential use of methotrexate in treating inflammatory hand osteoarthritis, suggesting a novel approach to managing this challenging and common condition. The results of the fourth article we highlight suggest that sarilumab has promise as an adjunct treatment of polymyalgia rheumatica relapse during glucocorticoid dosage tapering. The fifth study evaluated sublingual cyclobenzaprine for fibromyalgia treatment, noting both potential benefits and risks. Finally, the sixth article is a systematic review and meta-analysis that assessed the therapeutic equivalence of biosimilars and reference biologics in the treatment of patients with RA. Knowledge of this recent literature will be useful to clinicians regardless of specialty who care for patients with these commonly encountered conditions.

The Effect of Perioperative Dexamethasone on Postoperative Complications After Pancreaticoduodenectomy: A Multicenter Randomized Controlled Trial.

OBJECTIVE: To evaluate the effect of perioperative dexamethasone on postoperative complications after pancreaticoduodenectomy. BACKGROUND: The glucocorticoid dexamethasone has been shown to improve postoperative outcomes in surgical patients, but its effects on postoperative complications after pancreaticoduodenectomy are unclear. METHODS: This multicenter, double-blind, randomized controlled trial was conducted in four Chinese high-volume pancreatic centers. Adults undergoing elective pancreaticoduodenectomy were randomized to receive either 0.2 mg/kg dexamethasone or a saline placebo as an intravenous bolus within 5 minutes after anesthesia induction. The primary outcome was the Comprehensive Complication Index (CCI) score within 30 days after the operation, analyzed using the modified intention-to-treat principle. RESULTS: Among 428 patients for eligibility, 300 participants were randomized and 265 were included in the modified intention-to-treat analyses. One hundred thirty-four patients received dexamethasone and 131 patients received a placebo. The mean (SD) CCI score was 14.0 (17.5) in the dexamethasone group and 17.9 (20.3) in the placebo group (mean difference: -3.8; 95% CI: -8.4 to 0.7; P = 0.100). The incidence of major complications (Clavien-Dindo grade ≥III; 12.7% vs 16.0%, risk ratio: 0.79; 95% CI: 0.44 to 1.43; P = 0.439) and postoperative pancreatic fistula (25.4% vs 31.3%, risk ratio: 0.81; 95% CI: 0.55 to 1.19; P = 0.286) were not significantly different between the two groups. In the stratum of participants with a main pancreatic duct ≤3 mm (n = 202), the CCI score was significantly lower in the dexamethasone group (mean difference: -6.4; 95% CI: -11.2 to -1.6; P = 0.009). CONCLUSIONS: Perioperative dexamethasone did not significantly reduce postoperative complications within 30 days after pancreaticoduodenectomy.

Rituximab versus Mycophenolate Mofetil in Patients with Pemphigus Vulgaris.

BACKGROUND: Rituximab and mycophenolate mofetil are used to treat pemphigus vulgaris, but they have not been adequately compared in clinical trials. METHODS: In a randomized, controlled trial, we assigned patients with moderate-to-severe pemphigus vulgaris in a 1:1 ratio to receive intravenous rituximab (1000 mg on days 1, 15, 168, and 182) or oral mycophenolate mofetil (2 g per day), in addition to an oral glucocorticoid administered on the same tapering schedule in the two groups. The primary end point was sustained complete remission at week 52, defined as the healing of lesions with no new active lesions, as reflected by a Pemphigus Disease Area Index (PDAI) activity score of 0 (on a scale of 0 to 250, with higher scores indicating greater disease severity), for at least 16 weeks without the use of glucocorticoids. Secondary end points were the cumulative dose of glucocorticoids, the number of disease flares, and the change from baseline in the score on the Dermatology Life Quality Index (DLQI; scores range from 0 to 30, with higher scores indicating greater impairment). RESULTS: Of the 135 patients who underwent randomization, 67 were assigned to receive rituximab and 68 to receive mycophenolate mofetil. The primary outcome was assessed in the modified intention-to-treat population: 62 patients in the rituximab group and 63 in the mycophenolate mofetil group. The median PDAI activity scores at baseline were 22.7 in the rituximab group and 18.3 in the mycophenolate mofetil group. At week 52, sustained complete remission was observed in 25 patients (40%) in the rituximab group and in 6 (10%) in the mycophenolate mofetil group (difference, 31 percentage points; 95% confidence interval [CI], 15 to 45; P<0.001). The mean cumulative glucocorticoid dose during the 52-week treatment period was 3545 mg in the rituximab group and 5140 mg in the mycophenolate mofetil group (difference, -1595 mg; 95% CI, -2838 to -353; P<0.001). There were 6 disease flares in the rituximab group and 44 in the mycophenolate mofetil group (adjusted rate ratio, 0.12; 95% CI, 0.05 to 0.29; P<0.001). The mean change in DLQI score was -8.87 points and -6.00 points, respectively (difference, -2.87 points; 95% CI, -4.58 to -1.17; P = 0.001). Serious adverse events occurred in 15 of 67 patients (22%) in the rituximab group and in 10 of 68 (15%) in the mycophenolate mofetil group. CONCLUSIONS: Rituximab was superior to mycophenolate mofetil in producing sustained complete remission at 52 weeks in patients with pemphigus vulgaris. Rituximab resulted in a greater reduction in glucocorticoid use than mycophenolate mofetil, but more patients in the rituximab group had serious adverse events. Further trials are needed to determine the comparative efficacy and safety of rituximab and mycophenolate mofetil beyond 52 weeks of treatment. (Funded by F. Hoffmann-La Roche; PEMPHIX ClinicalTrials.gov number, NCT02383589.).

Avacopan for the Treatment of ANCA-Associated Vasculitis.

BACKGROUND: The C5a receptor inhibitor avacopan is being studied for the treatment of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. METHODS: In this randomized, controlled trial, we assigned patients with ANCA-associated vasculitis in a 1:1 ratio to receive oral avacopan at a dose of 30 mg twice daily or oral prednisone on a tapering schedule. All the patients received either cyclophosphamide (followed by azathioprine) or rituximab. The first primary end point was remission, defined as a Birmingham Vasculitis Activity Score (BVAS) of 0 (on a scale from 0 to 63, with higher scores indicating greater disease activity) at week 26 and no glucocorticoid use in the previous 4 weeks. The second primary end point was sustained remission, defined as remission at both weeks 26 and 52. Both end points were tested for noninferiority (by a margin of 20 percentage points) and for superiority. RESULTS: A total of 331 patients underwent randomization; 166 were assigned to receive avacopan, and 165 were assigned to receive prednisone. The mean BVAS at baseline was 16 in both groups. Remission at week 26 (the first primary end point) was observed in 120 of 166 patients (72.3%) receiving avacopan and in 115 of 164 patients (70.1%) receiving prednisone (estimated common difference, 3.4 percentage points; 95% confidence interval [CI], -6.0 to 12.8; P<0.001 for noninferiority; P = 0.24 for superiority). Sustained remission at week 52 (the second primary end point) was observed in 109 of 166 patients (65.7%) receiving avacopan and in 90 of 164 patients (54.9%) receiving prednisone (estimated common difference, 12.5 percentage points; 95% CI, 2.6 to 22.3; P<0.001 for noninferiority; P = 0.007 for superiority). Serious adverse events (excluding worsening vasculitis) occurred in 37.3% of the patients receiving avacopan and in 39.0% of those receiving prednisone. CONCLUSIONS: In this trial involving patients with ANCA-associated vasculitis, avacopan was noninferior but not superior to prednisone taper with respect to remission at week 26 and was superior to prednisone taper with respect to sustained remission at week 52. All the patients received cyclophosphamide or rituximab. The safety and clinical effects of avacopan beyond 52 weeks were not addressed in the trial. (Funded by ChemoCentryx; ADVOCATE ClinicalTrials.gov number, NCT02994927.).

Dexamethasone in Hospitalized Patients with Covid-19.

BACKGROUND: Coronavirus disease 2019 (Covid-19) is associated with diffuse lung damage. Glucocorticoids may modulate inflammation-mediated lung injury and thereby reduce progression to respiratory failure and death. METHODS: In this controlled, open-label trial comparing a range of possible treatments in patients who were hospitalized with Covid-19, we randomly assigned patients to receive oral or intravenous dexamethasone (at a dose of 6 mg once daily) for up to 10 days or to receive usual care alone. The primary outcome was 28-day mortality. Here, we report the final results of this assessment. RESULTS: A total of 2104 patients were assigned to receive dexamethasone and 4321 to receive usual care. Overall, 482 patients (22.9%) in the dexamethasone group and 1110 patients (25.7%) in the usual care group died within 28 days after randomization (age-adjusted rate ratio, 0.83; 95% confidence interval [CI], 0.75 to 0.93; P<0.001). The proportional and absolute between-group differences in mortality varied considerably according to the level of respiratory support that the patients were receiving at the time of randomization. In the dexamethasone group, the incidence of death was lower than that in the usual care group among patients receiving invasive mechanical ventilation (29.3% vs. 41.4%; rate ratio, 0.64; 95% CI, 0.51 to 0.81) and among those receiving oxygen without invasive mechanical ventilation (23.3% vs. 26.2%; rate ratio, 0.82; 95% CI, 0.72 to 0.94) but not among those who were receiving no respiratory support at randomization (17.8% vs. 14.0%; rate ratio, 1.19; 95% CI, 0.92 to 1.55). CONCLUSIONS: In patients hospitalized with Covid-19, the use of dexamethasone resulted in lower 28-day mortality among those who were receiving either invasive mechanical ventilation or oxygen alone at randomization but not among those receiving no respiratory support. (Funded by the Medical Research Council and National Institute for Health Research and others; RECOVERY ClinicalTrials.gov number, NCT04381936; ISRCTN number, 50189673.).

Vascular responsiveness to low-dose dexamethasone in extremely premature infants: negative influence of fetal growth restriction.

Dexamethasone is frequently prescribed for preterm infants to wean from respiratory support and/or to facilitate extubation. This pre-/postintervention prospective study ascertained the impact on clinical (respiratory support) and echocardiographic parameters after dexamethasone therapy in preterm fetal growth restriction (FGR) infants compared with appropriate for gestational age (AGA) infants. Echocardiography was performed within 24 h before the start and after completion of 10-day therapy. Parameters assessed included those reflecting pulmonary vascular resistance and right ventricular output. Seventeen FGR infants (birth gestation and birth weight, 25.2 ± 1.1 wk and 497 ± 92 g, respectively) were compared with 22 AGA infants (gestation and birth weight, 24.5 ± 0.8 and 663 ± 100 g, respectively). Baseline respiratory severity score (mean airway pressure × fractional inspired oxygen) was comparable between the groups, (median [interquartile range] FGR, 10 [6, 13] vs. AGA, 8 ± 2.8, P = 0.08). Pre-dexamethasone parameters of pulmonary vascular resistance (FGR, 0.19 ± 0.03 vs. AGA, 0.2 ± 0.03, P = 0.16) and right ventricular output (FGR, 171 ± 20 vs. 174 ± 17 mL/kg/min, P = 0.6) were statistically comparable. At post-dexamethasone assessments, the decrease in the respiratory severity score was significantly greater in AGA infants (median [interquartile range] FGR, 10 [6, 13] to 9 [2.6, 13.5], P = 0.009 vs. AGA, 8 ± 2.8 to 3 ± 1, P < 0.0001). Improvement in measures of pulmonary vascular resistance (ratio of time to peak velocity to right ventricular ejection time) was greater in AGA infants (FGR, 0.19 ± 0.03 to 0.2 ± 0.03, P = 0.13 vs. AGA 0.2 ± 0.03 to 0.25 ± 0.03, P < 0.0001). The improvement in right ventricular output was significantly greater in AGA infants (171 ± 20 to 190 ± 21, P = 0.014 vs. 174 ± 17 to 203 ± 22, P < 0.0001). This highlights differential cardiorespiratory responsiveness to dexamethasone in extremely preterm FGR infants, which may reflect the in utero maladaptive state.NEW & NOTEWORTHY Dexamethasone (DEX) is frequently used in preterm infants dependent on ventilator support. Differences in vascular structure and function that may have developed prenatally arising from the chronic intrauterine hypoxemia in FGR infants may adversely affect responsiveness. The clinical efficacy of DEX was significantly less in FGR (birth weight < 10th centile) infants, compared with appropriate for gestational age (AGA) infants. Echocardiography showed significantly less improvement in pulmonary vascular resistance in FGR, compared with AGA infants.

Risk of flare and damage accrual after tapering glucocorticoids in modified serologically active clinically quiescent patients with systemic lupus erythematosus: a multinational observational cohort study.

OBJECTIVES: To assess the risk of flare and damage accrual after tapering glucocorticoids (GCs) in modified serologically active clinically quiescent (mSACQ) patients with systemic lupus erythematosus (SLE). METHODS: Data from a 12-country longitudinal SLE cohort, collected prospectively between 2013 and 2020, were analysed. SLE patients with mSACQ defined as the state with serological activity (increased anti-dsDNA and/or hypocomplementemia) but without clinical activity, treated with ≤7.5 mg/day of prednisolone-equivalent GCs and not-considering duration, were studied. The risk of subsequent flare or damage accrual per 1 mg decrease of prednisolone was assessed using Cox proportional hazard models while adjusting for confounders. Observation periods were 2 years and censored if each event occurred. RESULTS: Data from 1850 mSACQ patients were analysed: 742, 271 and 180 patients experienced overall flare, severe flare and damage accrual, respectively. Tapering GCs by 1 mg/day of prednisolone was not associated with increased risk of overall or severe flare: adjusted HRs 1.02 (95% CI, 0.99 to 1.05) and 0.98 (95% CI, 0.96 to 1.004), respectively. Antimalarial use was associated with decreased flare risk. Tapering GCs was associated with decreased risk of damage accrual (adjusted HR 0.96, 95% CI, 0.93 to 0.99) in the patients whose initial prednisolone dosages were >5 mg/day. CONCLUSIONS: In mSACQ patients, tapering GCs was not associated with increased flare risk. Antimalarial use was associated with decreased flare risk. Tapering GCs protected mSACQ patients treated with >5 mg/day of prednisolone against damage accrual. These findings suggest that cautious GC tapering is feasible and can reduce GC use in mSACQ patients.

Improvement in Echocardiographic and Diagnostic Biomarkers after Systemic Glucocorticoid Therapy in Infants with Pulmonary Hypertension.

OBJECTIVE: To assess the effect of treating pulmonary hypertension (PH) in infants younger than 1 year of age with systemic glucocorticoids while using echocardiographic and diagnostic biomarkers as measures of efficacy. STUDY DESIGN: A retrospective chart review was performed on 17 hospitalized infants younger than 1 year of age at St Louis Children's Hospital who received a 5- to 7-day course of systemic glucocorticoid treatment followed by a 3-week taper with no significant intracardiac shunts from January 1, 2017, to December 31, 2021. Quantitative echocardiographic indices for PH, N-terminal pro b-type natriuretic peptide, and/or b-type natriuretic peptide levels were collected before glucocorticoid treatment, after the glucocorticoid burst, and after the 21-day taper. RESULTS: Mean (±SD) gestational age was 32.1 (±5.8) weeks, 5 infants were (29%) concomitantly treated with sildenafil, and 8 were male. Twelve were classified as World Health Organization group 3 PH (71%) and 5 as World Health Organization group 1 PH. There were significant improvements 30 days after glucocorticoid initiation in b-type natriuretic peptide levels (P = .008), PCO2 (P = .03), eccentricity index (P = .005), right ventricular ejection time (P = .04), pulmonary artery acceleration time (P = .002), and pulmonary artery acceleration time-to-right ventricular ejection time ratio (P = .02). Tricuspid regurgitation velocity was not able to be assessed. There were no mortalities during the study timeline. CONCLUSIONS: In our retrospective study, systemic glucocorticoid therapy was well tolerated and appeared to be associated with significant improvement in cardiopulmonary function in infants with PH. Further prospective study in a larger sample is warranted.

Effectiveness of intravenous methylprednisolone pulse in patients with severe microscopic polyangiitis and granulomatosis with polyangiitis.

OBJECTIVES: To evaluate the effectiveness and safety of two different intravenous methylprednisolone (IVMP) pulse doses in patients with severe microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA). METHODS: We emulated a target trial using observational data from the nationwide registry in Japan. Patients with severe glomerulonephritis or diffuse alveolar haemorrhage were selected and pseudo-randomized into three groups using propensity score-based overlap weighting as follows: non-IVMP, IVMP 0.5 g/day and IVMP 1.0 g/day. The primary outcome was all-cause mortality, and the secondary outcomes were composite all-cause mortality and kidney failure, severe relapse and serious infection from 2 to 48 weeks after treatment initiation. To estimate the treatment effects, the Cox proportional hazard model and Fine-Gray subdistribution hazard model were used. RESULTS: In this emulated target trial, of 201 eligible patients (MPA, 175; GPA, 26), 6 (3%) died, 4 (2.0%) had kidney failure, 11 (5.5%) had severe relapse, and 40 (19.9%) had severe infections. Hazard ratios (HR) for IVMP 0.5 g/day and IVMP 1.0 g/day pulse groups compared with non-IVMP pulse were as follows: all-cause mortality 0.46 (95% CI: 0.07, 2.81) and 0.07 (95% CI: 0.01, 0.41), respectively; all-cause mortality/kidney failure 1.18 (95% CI: 0.26, 5.31) and 0.59 (95% CI: 0.08, 4.52), respectively; subdistribution HRs for severe relapse were 1.26 (95% CI: 0.12, 13.70) and 3.36 (95% CI: 0.49, 23.29), respectively; and for serious infection 1.88 (95% CI: 0.76, 4.65) and 0.94 (95% CI: 0.28, 3.13), respectively. CONCLUSION: IVMP 1.0 g/day pulse may improve 48-week mortality in patients with severe MPA/GPA.

Triamcinolone Acetonide Subconjunctival Injection as Stand-alone Inflammation Prophylaxis after Phacoemulsification Cataract Surgery.

PURPOSE: To compare the effectiveness and safety of a single injection of subconjunctival triamcinolone acetonide (TA) with that of postoperative topical prednisolone acetate (PA) with and without nonsteroidal anti-inflammatory drugs (NSAIDs) for cataract surgery prophylaxis. DESIGN: Retrospective, comparative effectiveness cohort study. PARTICIPANTS: Patients at Kaiser Permanente Northern California from 2018 through 2021. INTERVENTION: Exposure groups included topical PA with or without NSAID and subconjunctival injection of TA (Kenalog; Bristol-Myers-Squibb) 10 mg/ml or 40 mg/ml in a low dose (1.0-3.0 mg) or high dose (3.1-5.0 mg). MAIN OUTCOME MEASURES: The adjusted odds ratio (OR) and 95% confidence interval (CI) for the association of postoperative macular edema (ME) and iritis diagnoses 15 to 120 days after surgery (effectiveness measures) and a glaucoma-related event (safety measure) between 15 days and 1 year after surgery. RESULTS: Of 69 832 eligible patient-eyes, postoperative ME, iritis, and a glaucoma-related event occurred on average in 1.3%, 0.8%, and 3.4% of eyes in the topical groups and 0.8%, 0.5%, and 2.8% of eyes in the injection groups, respectively. In multivariable analysis, compared with the PA reference group, the PA plus NSAID group had a lower OR of ME (OR, 0.88; 95% CI, 0.74-1.04; P = 0.135). and all injection groups had even lower odds, with the high-dose TA 10-mg/ml group reaching statistical significance (OR, 0.64; 95% CI, 0.43-0.97; P = 0.033). A trend of lower odds of a postoperative iritis diagnosis was noted in the high-strength (40 mg/ml) groups. For postoperative glaucoma-related events, compared with PA, the TA 10-mg/ml low-dose group showed lower odds (OR, 0.69; 95% CI, 0.55-0.86; P = 0.001), the TA 10-mg/ml high-dose group showed similar odds (OR, 0.90; 95% CI, 0.70-1.15; P = 0.40), and the TA 40-mg/ml low-dose and high-dose groups showed higher odds of an event occurring (OR, 1.46 [95% CI, 0.98-2.18; P = 0.062] and OR, 2.14 [95% CI, 1.36-3.37; P = 0.001], respectively). CONCLUSIONS: The TA 10-mg/ml high-dose (4 mg) group was associated with a lower risk of postoperative ME and a similar risk of glaucoma-related events compared with the topical groups. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Dexamethasone Intracanalicular Insert for Clinically Significant Aqueous-Deficient Dry Eye: A Randomized Controlled Trial.

PURPOSE: To evaluate a commercially available dexamethasone intracanalicular insert to treat dry eye. DESIGN: Single-center, double-masked randomized controlled trial. PARTICIPANTS: Patients with clinically significant aqueous-deficient dry eye (combined ocular surface staining score, ≥ 3 [0-12]; corneal fluorescein staining score, ≥ 2 [0-6]; and Schirmer's wetting, < 10 mm at 5 minutes in both eyes) with symptoms (dryness, eye discomfort, or visual fatigue, ≥ 30 [0-100]) despite treatment with at least 1 prescription drop and deemed candidates for topical steroid therapy. METHODS: Seventy-five adult patients were enrolled. A 1:1 randomization sequence was used to determine which eye of each patient would receive the treatment (dexamethasone 0.4-mg intracanalicular insert with 30-day elution time) or sham (collagen plug). The fellow eye received the opposite treatment. Patients were masked to treatment assignment. Follow-up visits (at weeks 2, 4, and 6) were performed by a masked investigator. MAIN OUTCOME MEASURES: Dry eye parameters and patient symptoms were used for efficacy, and intraocular pressure (IOP) was used for safety assessment. RESULTS: The severity of dry eye was comparable between the treatment arms (fellow eyes) at baseline. Eyes that received the dexamethasone insert showed significantly less corneal staining at week 4 (mean difference [MD], -0.55; 95% confidence interval [CI], -0.91 to -0.19) and conjunctival staining at week 4 (MD, -0.68; 95% CI, -1.05 to -0.30) and week 6 (MD, -0.34; 95% CI, -0.65 to -0.02). Schirmer's wetting was comparable between the two treatment arms. Although the patients reported less dryness in eyes that received the insert at week 4 (MD, -5.5; 95% CI, -11.4 to 0.4), no statistically significant differences were found in any patient-reported symptoms. At week 4, dexamethasone-treated eyes were more likely to show an IOP increase (by 5-10 mmHg; 9 eyes vs. 1 eye; relative risk, 9.00; 95% CI, 1.14-71.0). All cases of increased IOP were managed with short-term topical ß-blockers and subsided. CONCLUSIONS: The dexamethasone intracanalicular insert may be considered a dropless dual treatment for clinically significant aqueous-deficient dry eye when topical steroid treatment is deemed appropriate. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Treatment of Noninfectious Uveitic Macular Edema with Periocular and Intraocular Corticosteroid Therapies: A Report by the American Academy of Ophthalmology.

PURPOSE: To review the evidence on the effectiveness and complications of periocular and intraocular corticosteroid therapies for noninfectious uveitic macular edema. METHODS: A literature search of the PubMed database was conducted last in December 2021 and a post-assessment search was conducted in March 2023. The searches were limited to articles published in English and no date restrictions were imposed. The combined searches yielded 739 citations; 53 articles were selected for inclusion because the studies (1) evaluated periocular corticosteroid injection, intraocular corticosteroid injection or implant, suprachoroidal corticosteroid injection, or a combination thereof for uveitic macular edema; (2) had outcomes that included visual acuity (VA) or macular edema assessed clinically or imaged by OCT or fluorescein angiography; and (3) included more than 20 patients. RESULTS: This assessment reviewed 23 articles that provided level I or level II evidence from 18 studies on the use of periocular, suprachoroidal, and intravitreal triamcinolone acetonide injections and intravitreal dexamethasone and fluocinolone acetonide implants or inserts in noninfectious uveitic macular edema. These reports consistently demonstrated that all investigated periocular and intraocular corticosteroid therapies improved VA, macular structure, or both. One comparative study showed that intravitreal triamcinolone acetonide injection and the dexamethasone intravitreal implant had effectiveness superior to that of periocular triamcinolone acetonide injection for these outcomes. As a group, the studies highlighted the potential for these therapies to elevate intraocular pressure and to accelerate cataract formation. CONCLUSIONS: The published literature provides high-quality evidence that periocular and intraocular corticosteroid therapies are effective and safe for the treatment of noninfectious uveitic macular edema. However, information on the relative effectiveness and complication rates across the different therapies is limited. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Low-dose glucocorticoid increase the risk of fracture in postmenopausal women with low bone mass: a retrospective cohort study.

Long-term glucocorticoids (GCs) treatment is associated with osteoporosis and fractures. We investigated whether low-dose GC treatment also increased the risk of osteoporotic fractures, and the results showed that even low-dose GC treatment increased the risk of osteoporotic fractures, especially spine fractures. PURPOSE: The effect of low-dose glucocorticoid (GC) therapy on the fracture risk in postmenopausal women with low bone mass was investigated. METHODS: 119,790 66-year-old postmenopausal women with low bone mass based on bone mineral density (BMD) results were included. GC group consisted of patients who had been prescribed oral GCs within 6 months of BMD testing. In GC group, GCs dosage was calculated by a defined daily dose (DDD), and divided into five groups according to GC usage (Group 1[G1]; < 11.25 DDDs, G2; ≥ 11.25, < 22.5 DDDs, G3; ≥ 22.5, < 45 DDDs, G4; ≥ 45, < 90 DDDs, G5; ≥ 90 DDDs). The risk of major osteoporotic fractures (MOF) and non-MOF was analyzed and compared with that of the control group during the 1-year follow-up. RESULTS: The risk of total fracture was higher in G3-G5 than in the control group (G3, hazard ratio (HR) 1.25, 95% confidence interval [CI] 1.07-1.46; G4, 1.37 [1.13-1.66]; G5 1.45 [1.08-1.94]). The risk of MOF was higher in all groups except G2 than in the control group (G1, 1.23 [1.05-1.45]; G3, 1.37 [1.11-1.68]; G4, 1.41 [1.09-1.83]; G5, 1.66 [1.14-2.42]). The risk of spine fracture was significantly higher in all GC groups except G2 than in the control group. The risk of non-MOF was higher only in G4 than in the control group (G4, 1.48 [1.13-1.94]). CONCLUSION: Low-dose GC therapy can increase the risk of osteoporotic fractures, particularly spine fractures, in postmenopausal women with low bone mass.