The effect of glucocorticoids on major kidney outcomes and adverse events in IgA nephropathy has been uncertain.
To evaluate the efficacy and adverse effects of methylprednisolone in patients with ...IgA nephropathy at high risk of kidney function decline.
An international, multicenter, double-blind, randomized clinical trial that enrolled 503 participants with IgA nephropathy, proteinuria greater than or equal to 1 g per day, and estimated glomerular filtration rate (eGFR) of 20 to 120 mL/min/1.73 m2 after at least 3 months of optimized background care from 67 centers in Australia, Canada, China, India, and Malaysia between May 2012 and November 2019, with follow-up until June 2021.
Participants were randomized in a 1:1 ratio to receive oral methylprednisolone (initially 0.6-0.8 mg/kg/d, maximum 48 mg/d, weaning by 8 mg/d/mo; n = 136) or placebo (n = 126). After 262 participants were randomized, an excess of serious infections was identified, leading to dose reduction (0.4 mg/kg/d, maximum 32 mg/d, weaning by 4 mg/d/mo) and addition of antibiotic prophylaxis for pneumocystis pneumonia for subsequent participants (121 in the oral methylprednisolone group and 120 in the placebo group).
The primary end point was a composite of 40% decline in eGFR, kidney failure (dialysis, transplant), or death due to kidney disease. There were 11 secondary outcomes, including kidney failure.
Among 503 randomized patients (mean age, 38 years; 198 39% women; mean eGFR, 61.5 mL/min/1.73 m2; mean proteinuria, 2.46 g/d), 493 (98%) completed the trial. Over a mean of 4.2 years of follow-up, the primary outcome occurred in 74 participants (28.8%) in the methylprednisolone group compared with 106 (43.1%) in the placebo group (hazard ratio HR, 0.53 95% CI, 0.39-0.72; P < .001; absolute annual event rate difference, -4.8% per year 95% CI, -8.0% to -1.6%). The effect on the primary outcome was seen across each dose compared with the relevant participants in the placebo group recruited to each regimen (P for heterogeneity = .11): full-dose HR, 0.58 (95% CI, 0.41-0.81); reduced-dose HR, 0.27 (95% CI, 0.11-0.65). Of the 11 prespecified secondary end points, 9 showed significant differences in favor of the intervention, including kidney failure (50 19.5% vs 67 27.2%; HR, 0.59 95% CI, 0.40-0.87; P = .008; annual event rate difference, -2.9% per year 95% CI, -5.4% to -0.3%). Serious adverse events were more frequent with methylprednisolone vs placebo (28 10.9% vs 7 2.8% patients with serious adverse events), primarily with full-dose therapy compared with its matching placebo (22 16.2% vs 4 3.2%).
Among patients with IgA nephropathy at high risk of progression, treatment with oral methylprednisolone for 6 to 9 months, compared with placebo, significantly reduced the risk of the composite outcome of kidney function decline, kidney failure, or death due to kidney disease. However, the incidence of serious adverse events was increased with oral methylprednisolone, mainly with high-dose therapy.
ClinicalTrials.gov Identifier: NCT01560052.
Previous trials have suggested that vasopressin and methylprednisolone administered during in-hospital cardiac arrest might improve outcomes.
To determine whether the combination of vasopressin and ...methylprednisolone administered during in-hospital cardiac arrest improves return of spontaneous circulation.
Multicenter, randomized, double-blind, placebo-controlled trial conducted at 10 hospitals in Denmark. A total of 512 adult patients with in-hospital cardiac arrest were included between October 15, 2018, and January 21, 2021. The last 90-day follow-up was on April 21, 2021.
Patients were randomized to receive a combination of vasopressin and methylprednisolone (n = 245) or placebo (n = 267). The first dose of vasopressin (20 IU) and methylprednisolone (40 mg), or corresponding placebo, was administered after the first dose of epinephrine. Additional doses of vasopressin or corresponding placebo were administered after each additional dose of epinephrine for a maximum of 4 doses.
The primary outcome was return of spontaneous circulation. Secondary outcomes included survival and favorable neurologic outcome at 30 days (Cerebral Performance Category score of 1 or 2).
Among 512 patients who were randomized, 501 met all inclusion and no exclusion criteria and were included in the analysis (mean SD age, 71 13 years; 322 men 64%). One hundred of 237 patients (42%) in the vasopressin and methylprednisolone group and 86 of 264 patients (33%) in the placebo group achieved return of spontaneous circulation (risk ratio, 1.30 95% CI, 1.03-1.63; risk difference, 9.6% 95% CI, 1.1%-18.0%; P = .03). At 30 days, 23 patients (9.7%) in the intervention group and 31 patients (12%) in the placebo group were alive (risk ratio, 0.83 95% CI, 0.50-1.37; risk difference: -2.0% 95% CI, -7.5% to 3.5%; P = .48). A favorable neurologic outcome was observed in 18 patients (7.6%) in the intervention group and 20 patients (7.6%) in the placebo group at 30 days (risk ratio, 1.00 95% CI, 0.55-1.83; risk difference, 0.0% 95% CI, -4.7% to 4.9%; P > .99). In patients with return of spontaneous circulation, hyperglycemia occurred in 77 (77%) in the intervention group and 63 (73%) in the placebo group. Hypernatremia occurred in 28 (28%) and 27 (31%), in the intervention and placebo groups, respectively.
Among patients with in-hospital cardiac arrest, administration of vasopressin and methylprednisolone, compared with placebo, significantly increased the likelihood of return of spontaneous circulation. However, there is uncertainty whether this treatment results in benefit or harm for long-term survival.
ClinicalTrials.gov Identifier: NCT03640949.
Guidelines recommend corticosteroids in patients with IgA nephropathy and persistent proteinuria, but the effects remain uncertain.
To evaluate the efficacy and safety of corticosteroids in patients ...with IgA nephropathy at risk of progression.
The Therapeutic Evaluation of Steroids in IgA Nephropathy Global (TESTING) study was a multicenter, double-blind, randomized clinical trial designed to recruit 750 participants with IgA nephropathy (proteinuria greater than 1 g/d and estimated glomerular filtration rate eGFR of 20 to 120 mL/min/1.73 m2 after at least 3 months of blood pressure control with renin-angiotensin system blockade and to provide follow-up until 335 primary outcomes occurred.
Patients were randomized 1:1 to oral methylprednisolone (0.6-0.8 mg/kg/d; maximum, 48 mg/d) (n = 136) or matching placebo (n = 126) for 2 months, with subsequent weaning over 4 to 6 months.
The primary composite outcome was end-stage kidney disease, death due to kidney failure, or a 40% decrease in eGFR. Predefined safety outcomes were serious infection, new diabetes, gastrointestinal hemorrhage, fracture/osteonecrosis, and cardiovascular events. The mean required follow-up was estimated to be 5 years.
After randomization of 262 participants (mean age, 38.6 SD, 11.1 years; 96 37% women; eGFR, 59.4 mL/min/1.73 m2; urine protein excretion, 2.40 g/d) and 2.1 years' median follow-up, recruitment was discontinued because of excess serious adverse events. Serious events occurred in 20 participants (14.7%) in the methylprednisolone group vs 4 (3.2%) in the placebo group (P = .001; risk difference, 11.5% 95% CI, 4.8%-18.2%), mostly due to excess serious infections (11 8.1% vs 0; risk difference, 8.1% 95% CI, 3.5%-13.9%; P < .001), including 2 deaths. The primary renal outcome occurred in 8 participants (5.9%) in the methylprednisolone group vs 20 (15.9%) in the placebo group (hazard ratio, 0.37 95% CI, 0.17-0.85; risk difference, 10.0% 95% CI, 2.5%-17.9%; P = .02).
Among patients with IgA nephropathy and proteinuria of 1 g/d or greater, oral methylprednisolone was associated with an increased risk of serious adverse events, primarily infections. Although the results were consistent with potential renal benefit, definitive conclusions about treatment benefit cannot be made, owing to early termination of the trial.
clinicaltrials.gov Identifier: NCT01560052.
The objective of this study was to improve the therapeutic efficacy of methylprednisolone acetate (MPA) in the treatment of rheumatoid arthritis (RA) by incorporating the drug into the hydroxyapatite ...(HAp) nanoparticles. The nanoparticles were synthesized using a chemical precipitation technique and their size and morphology were evaluated by dynamic light scattering and scanning electron microscopy (SEM). The solid-state behavior of the nanoparticles was also characterized by operating X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and Fourier-transform infrared spectroscopy (FTIR). The Brunauer–Emmett–Teller and Barrett–Joyner–Halenda N2 adsorption/desorption analyses were also performed to determine the surface area, Vm (the volume of the N2 adsorbed on the one gram of the HAp when the monolayer is complete) and the pore size of the samples. Furthermore, the therapeutic efficacy of the prepared nanoformulation on the adjuvant induced arthritic rats was assessed. HAp mesoporous nanoparticles with a particle size of 70.45nm, pore size of 2.71nm and drug loading of 44.53% were obtained. The specific surface area of HAp as well as the Vm values were decreased after the drug loading process. The nanoformulation revealed the slower drug release profile compared to the pure drug. The MTT assay indicated that the MPA-loaded nanoparticles had a lower cytotoxic effect on NIH-3T3 and CAOV-4 cell lines compared to the pure drug. Interestingly, the in vivo study confirmed that the drug-loaded nanoparticles could considerably decrease the paw volume and normalize the hematological abnormalities in the arthritic rats.
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To analyze the effects of a short course of methyl-prednisolone pulses (MP) during the second week of disease (week-2) in patients with severe coronavirus disease 2019 (COVID-19) pneumonia.
...Comparative observational study using data collected from routine care at Hospital Universitario Cruces, Barakaldo, Bizkaia, Spain in patients with COVID-19 pneumonia. We compared patients who received week-2-MP (125-250 mg/d x3) with those who did not, with the end-points time to death and time to death or endotracheal intubation.
We included 242 patients with COVID-19 pneumonia and elevated inflammatory markers at admission. Sixty-one patients (25%) received week-2-MP. Twenty-two patients (9%) died and 31 (12.8%) suffered death or intubation. The adjusted HRs for death and death or intubation for patients in the week-2-MP group were 0.35 (95%CI 0.11 to 1.06, p = 0.064) and 0.33 (95%CI 0.13 to 0.84, p = 0.020), respectively. These differences were specifically seen in the subcohort of patients with a SpO2/FiO2 at day 7 lower than 353 (adjusted HR 0.31, 95% CI 0.08 to 1.12, p = 0.073 and HR 0.34, 95%CI 0.12 to 0.94, p = 0.038, respectively) but not in patients with higher SpO2/FiO2. Patients receiving out-of-week-2-MP, non-pulse glucocorticoids or no glucocorticoids had an increased adjusted risk for both outcomes compared with week-2-MP group: HR 5.04 (95% CI 0.91-27.86), HR 10.09 (95% CI 2.14-47.50), HR 4.14 (95% CI 0.81-21.23), respectively, for death; HR 7.38 (95% CI 1.86-29.29), HR 13.71 (95% CI 3.76-50.07), HR 3.58 (95% CI 0.89-14.32), respectively, for death or intubation. These differences were significant only in the subgroup with low SpO2/FiO2.
Week-2-MP are effective in improving the prognosis of patients with COVID-19 pneumonia with features of inflammatory activity and respiratory deterioration entering the second week of disease. The recognition of this high-risk population should prompt early use of MP at this point.
We have studied the effect of two glucocorticoid hormones: hydrocortisone and its synthetic analogue methylprednisolone on regeneration activity of Girardia tigrina planarian tissues. The results ...indicate that both hormones influence the recovery rate of the regenerating tissue in either a stimulatory or inhibitory way depending on the hormone, its concentration and the regenerating body part of the worm. We suggest that exogenous glucocorticoids can influence endogenous mechanisms of endocrine regeneration, including hormone-receptor interaction. The revealed features of the effects of hydrocortisone and methylprednisolone may be associated with the formation of specific hormone-receptor complexes with each of them, as well as with the dependence of the effects of methylprednisolone on the type of interaction with hydrocortisone receptors i.e., as an agonist or as an antagonist. We have studied the effect of two glucocorticoid hormones: hydrocortisone and its synthetic analogue methylprednisolone on the regeneration activity of head and tail blastema of the Girardia tigrina planarian. The regeneration activity was studied in head and tail blastema formed after resection by means of lifetime computer morphometry and immunohistochemical labeling of neoblasts. The search for orthologous proteins-glucocorticoid receptors (hydrocortisone) was performed using the SmedGD database of the Schmidtea mediterranea planarian. The results indicate that both hormones influence the recovery rate of the regenerating head and tail blastema. The worms with regenerating tail blastema have less sensitivity to the hormones' treatment compared to the ones with regenerating head blastema. Hydrocortisone at a high concentration (10sup.−3 M) suppressed the regeneration rate, while stimulating it at lower concentrations (10sup.−4-10sup.−6 M). The same concentrations of methylprednisolone inhibited the regeneration of head blastema, but did not affect the tail blastema regeneration. The two hormones acted differently: while hydrocortisone stimulated the proliferation of neoblasts in the periwound region, methylprednisolone reduced the mitotic activity, mainly on the tail zone furthest from the wound surface. We suggest that exogenous glucocorticoids can influence endogenous mechanisms of hormone-dependent regeneration.
Due to the continuing debates on the utility of high-dose methylprednisolone (MP) early after acute spinal cord injury (ASCI), we aimed to evaluate the therapeutic and adverse effects of high-dose MP ...according to the second National Acute Spinal Cord Injury Study (NASCIS-2) dosing protocol in comparison to no steroids in patients with ASCI by performing a meta-analysis on the basis of the current available clinical trials.
We searched PubMed and Cochrane Library (to May 22, 2018) for studies comparing neurologic recoveries, adverse events, and in-hospital costs between ASCI patients who underwent high-dose MP treatment or not. Data were synthesized with corresponding statistical models according to the degree of heterogeneity.
We enrolled 16 studies (1,863 participants) including 3 randomized controlled trials (RCTs) and 13 observational studies. Pooled results indicated that MP was not associated with an increase in motor score improvement (RCTs:
= 0.84; observational studies:
= 0.44) and incidence of recovery by at least one grade on the American Spinal Injury Association Impairment Scale or Frankel (
= 0.53). Meanwhile, MP did not lead to better sensory recovery (
= 0.07). However, MP was associated with a significantly higher incidence of gastrointestinal hemorrhage (
= 0.04) and respiratory tract infection (
= 0.01). The difference in the overall in-hospital costs between MP and control groups was not statistically significant (
= 0.78).
Based on the current evidence, high-dose MP treatment, in comparison to controls, does not contribute to better neurologic recoveries but may increase the risk of adverse events in patients with ASCI. Therefore, we recommend against routine use of high-dose MP early after ASCI.
Multisystem inflammatory syndrome in children (MIS-C) is the most severe pediatric disease associated with severe acute respiratory syndrome coronavirus 2 infection, potentially life-threatening, but ...the optimal therapeutic strategy remains unknown.
To compare intravenous immunoglobulins (IVIG) plus methylprednisolone vs IVIG alone as initial therapy in MIS-C.
Retrospective cohort study drawn from a national surveillance system with propensity score-matched analysis. All cases with suspected MIS-C were reported to the French National Public Health Agency. Confirmed MIS-C cases fulfilling the World Health Organization definition were included. The study started on April 1, 2020, and follow-up ended on January 6, 2021.
IVIG and methylprednisolone vs IVIG alone.
The primary outcome was persistence of fever 2 days after the introduction of initial therapy or recrudescence of fever within 7 days, which defined treatment failure. Secondary outcomes included a second-line therapy, hemodynamic support, acute left ventricular dysfunction after first-line therapy, and length of stay in the pediatric intensive care unit. The primary analysis involved propensity score matching with a minimum caliper of 0.1.
Among 181 children with suspected MIS-C, 111 fulfilled the World Health Organization definition (58 females 52%; median age, 8.6 years interquartile range, 4.7 to 12.1). Five children did not receive either treatment. Overall, 3 of 34 children (9%) in the IVIG and methylprednisolone group and 37 of 72 (51%) in the IVIG alone group did not respond to treatment. Treatment with IVIG and methylprednisolone vs IVIG alone was associated with lower risk of treatment failure (absolute risk difference, -0.28 95% CI, -0.48 to -0.08; odds ratio OR, 0.25 95% CI, 0.09 to 0.70; P = .008). IVIG and methylprednisolone therapy vs IVIG alone was also significantly associated with lower risk of use of second-line therapy (absolute risk difference, -0.22 95% CI, -0.40 to -0.04; OR, 0.19 95% CI, 0.06 to 0.61; P = .004), hemodynamic support (absolute risk difference, -0.17 95% CI, -0.34 to -0.004; OR, 0.21 95% CI, 0.06 to 0.76), acute left ventricular dysfunction occurring after initial therapy (absolute risk difference, -0.18 95% CI, -0.35 to -0.01; OR, 0.20 95% CI, 0.06 to 0.66), and duration of stay in the pediatric intensive care unit (median, 4 vs 6 days; difference in days, -2.4 95% CI, -4.0 to -0.7).
Among children with MIS-C, treatment with IVIG and methylprednisolone vs IVIG alone was associated with a more favorable fever course. Study interpretation is limited by the observational design.
To our knowledge, the comparative effectiveness of commonly used conservative treatments for carpal tunnel syndrome has not been evaluated previously in primary care. We aimed to compare the clinical ...and cost-effectiveness of night splints with a corticosteroid injection with regards to reducing symptoms and improving hand function in patients with mild or moderate carpal tunnel syndrome.
We did this randomised, open-label, pragmatic trial in adults (≥18 years) with mild or moderate carpal tunnel syndrome recruited from 25 primary and community musculoskeletal clinics and services. Patients with a new episode of idiopathic mild or moderate carpal tunnel syndrome of at least 6 weeks' duration were eligible. We randomly assigned (1:1) patients (permutated blocks of two and four by site) with an online web or third party telephone service to receive either a single injection of 20 mg methylprednisolone acetate (from 40 mg/mL) or a night-resting splint to be worn for 6 weeks. Patients and clinicians could not be masked to the intervention. The primary outcome was the overall score of the Boston Carpal Tunnel Questionnaire (BCTQ) at 6 weeks. We used intention-to-treat analysis, with multiple imputation for missing data, which was concealed to treatment group allocation. The trial is registered with the European Clinical Trials Database, number 2013-001435-48, and ClinicalTrial.gov, number NCT02038452.
Between April 17, 2014, and Dec 31, 2016, 234 participants were randomly assigned (118 to the night splint group and 116 to the corticosteroid injection group), of whom 212 (91%) completed the BCTQ at 6 weeks. The BCTQ score was significantly better at 6 weeks in the corticosteroid injection group (mean 2·02 SD 0·81) than the night splint group (2·29 0·75; adjusted mean difference −0·32; 95% CI −0·48 to −0·16; p=0·0001). No adverse events were reported.
A single corticosteroid injection shows superior clinical effectiveness at 6 weeks compared with night-resting splints, making it the treatment of choice for rapid symptom response in mild or moderate carpal tunnel syndrome presenting in primary care.
Arthritis Research UK.
Osteoarthritis (OA) of the knee affects the aging population and has an associated influence on the health care system. Rigorous studies evaluating radiofrequency ablation for OA-related knee pain ...are lacking. This study compared long-term clinical safety and effectiveness of cooled radiofrequency ablation (CRFA) with intra-articular steroid (IAS) injection in managing OA-related knee pain.
This is a prospective, multicenter, randomized trial with 151 subjects with chronic (≥6 months) knee pain that was unresponsive to conservative modalities. Knee pain (Numeric Rating Scale NRS), Oxford Knee Score, overall treatment effect (Global Perceived Effect), analgesic drug use, and adverse events were compared between CRFA and IAS cohorts at 1, 3, and 6 months after intervention.
There were no differences in demographics between study groups. At 6 months, the CRFA group had more favorable outcomes in NRS: pain reduction 50% or greater: 74.1% versus 16.2%, P < 0.0001 (25.9% and 83.8% of these study cohorts, respectively, were nonresponders). Mean NRS score reduction was 4.9 ± 2.4 versus 1.3 ± 2.2, P < 0.0001; mean Oxford Knee Score was 35.7 ± 8.8 vs 22.4 ± 8.5, P < 0.0001; mean improved Global Perceived Effect was 91.4% vs 23.9%, P < 0.0001; and mean change in nonopioid medication use was CRFA > IAS (P = 0.02). There were no procedure-related serious adverse events.
This study demonstrates that CRFA is an effective long-term therapeutic option for managing pain and improving physical function and quality of life for patients with painful knee OA when compared with IAS injection.
ClinicalTrials.gov (NCT02343003).
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