Glucocorticoid Regimens Research Articles

Clinical Analysis of Acute Myeloid Leukemia Patients with Hemophagocytic Syndrome

To investigate the clinical features of acute myeloid leukemia patients with hemophagocytic syndrome. The clinical data of 2 patients with acute myeloid leukemia complicated with hemophagocytic syndrome were collected, and the clinical characteristics and treatment outcomes were analyzed. There were two patients with acute myeloid leukemia, including 1 male and 1 female，aged for 67 and 40 years old，respectively. Hemophagocytic syndrome occurred in one patient after induction therapy for acute myeloid leukemia and one patient after consolidation therapy. Both of the patients with hemophagocytic syndrome showed fever, hemocytopenia, high ferritin, high titer sCD25 levels and hemophagocytes in bone marrow. After achieved anti-infection, glucocorticoid, human immunoglobulin and etoposide regimens treatment, hemophagocytic syndrome was controlled in both of the two patients. One patient failed to induce acute myeloid leukemia and one patient achieved complete remission. Acute myeloid leukemia complicated with hemophagocytic syndrome is rare. Early identification, early anti-infection combined with HLH94 regimen can control hemophagocytosis and improve prognosis.

Clinical and Genetic Characteristics in Young, Glucocorticoid-Naive Boys With Duchenne Muscular Dystrophy.

Duchenne muscular dystrophy (DMD) is a pediatric neuromuscular disorder caused by mutations in the dystrophin gene. Genotype-phenotype associations have been examined in glucocorticoid-treated boys, but there are few data on the young glucocorticoid-naive DMD population. A sample of young glucocorticoid-naive DMD boys is described, and genotype-phenotype associations are investigated. Screening and baseline data were collected for all the participants in the Finding the Optimum Corticosteroid Regime for Duchenne Muscular Dystrophy (FOR-DMD) study, an international, multicenter, randomized, double-blind, clinical trial comparing 3 glucocorticoid regimens in glucocorticoid-naive, genetically confirmed boys with DMD between 4 and <8 years of age. One hundred ninety-six boys were recruited. The mean ± SD age at randomization was 5.8 ± 1.0 years. The predominant mutation type was out-of-frame deletions (67.4%, 130 of 193), of which 68.5% (89 of 130) were amenable to exon skipping. The most frequent mutations were deletions amenable to exon 51 skipping (13.0%, 25 of 193). Stop codon mutations accounted for 10.4% (20 of 193). The mean age at first parental concerns was 29.8 ± 18.7 months; the mean age at genetic diagnosis was 53.9 ± 21.9 months; and the mean diagnostic delay was 25.9 ± 18.2 months. The mean diagnostic delay for boys diagnosed after an incidental finding of isolated hyperCKemia (n = 19) was 6.4 ± 7.4 months. The mean ages at independent walking and talking in sentences were 17.1 ± 4.2 and 29.0 ± 10.7 months, respectively. Median height percentiles were below the 25th percentile regardless of age group. No genotype-phenotype associations were identified expect for boys with exon 8 skippable deletions, who had better performance on time to walk/run 10 m (p = 0.02) compared to boys with deletions not amenable to skipping. This study describes clinical and genetic characteristics of a sample of young glucocorticoid-naive boys with DMD. A low threshold for creatine kinase testing can lead to an earlier diagnosis. Motor and speech delays were common presenting symptoms. The effects of low pretreatment height on growth and adult height require further study. These findings may promote earlier recognition of DMD and inform study design for future clinical trials. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT01603407.

Vexas: A new syndrome not always associated with hemopathy.

A 63-year-old male presented with polyarthralgia and a purpuric rash on the lower extremities associated with fatigue and weight loss. Clinically, we noticed a subcutaneous nodule on his left arm, and its biopsy revealed a septal panniculitis with dermo-hypodermic vasculitis consistent with a polyarteritis nodosa. Biopsy of the petechial purpura was also performed, and it revealed leukocytoclastic vasculitis. A glucocorticoid regimen was started.

Use of Unique Glucocorticoid Regimens to Improve Fecundity in Patients With Congenital Adrenal Hyperplasia: A Case Series

Decreased fecundity among women with congenital adrenal hyperplasia (CAH) and non-classical CAH (NCAH) is due, in part, to excess adrenal androgen and progesterone production. This inhibits follicular phase endometrial growth leading to impairment of embryo implantation. We present 3 cases of women with CAH or NCAH who were able to become pregnant after switching to glucocorticoid regimens with longer half-lives.

RITUXIMAB AND IMMUNOSUPPRESSANTS IN PATIENTS WITH SYSTEMIC SCLERODERMA WITH INTERSTITIAL LUNG DISEASE: A COMPARISON OF EFFICACY AND SAFETY

TOPIC: Pulmonary Manifestations of Systemic Disease TYPE: Original Investigations PURPOSE: To compare the impact of Immunosupressants (IS) and Rituximab (RTM) a single-agent therapy on SSc clinical manifestation and activity, and the safety of these agents in the open-label prospective non-randomized study. METHODS: 116 patients with the confirmed SSc diagnosis and ILD evidence based on MSCT findings were enrolled into the study. All patients received low and moderate-dose glucocorticoids regimens. Group A(n=35) received RTM as a single therapy agent for 13.3±2.3 months at total dose 1.35±0,5g (the patient’s average age was 45.0±15 years, with female proportion 80%; SSc duration 6.3±2.3 years; diffused/localized forms 1.3/1). Group B (n=36) received parenteral CyP for 12±6 months at total dose 10.6±5 g (the average age 47±12 years, females 92%, SSc duration 5.0±4.8 years, diffused/localized forms 1.6/1).Group C (n=45) received MMF for 12±6 months at a dose of 2 grams per day (the average age 49±13 years, females 91%, SSc duration 7.1±5 years, diffused/localized forms 1/1.3). The time courses of FVC, modified skin count(mRss, points), activity index (EScSG, points) were assessed into the study. RESULTS: In Groups A, B and C the therapy was associated with significant decrease in mRss (11.5±9.5 vs 8.2±6.2,р=0.02;11.2±7.9 vs 7.9±6.8, p=0.008; 7.5±6.9 vs 4.8±3.9, p=0.007, respectively) and EScSG(2.8±1.4 vs 1.4±1.2, р=0.00017; 3.2±1.9 vs 1.4±1.2, p=0.000165, 1.9±1.5 vs 1.2±0.9, p=0.01, respectively).Evaluation of FVC time course revealed significant FVC increase only in Groups A(78.7±20.0 vs 84.2±20.0, р= 0.002) and B ( 80.5±20.1 vs 85.8±20.4, p=0.034), with median increment about 5%.In Groups A and B 10% FVC increase was found in 26% and 31%, respectively, thus exceeding respective parameter twice in Group C -13% (р=0.15 and 0.008, respectively). The patient percentage with FVC decrease by≥10% did not differ significantly between groups.The therapy was better tolerated in RTM-treated group: during RTM therapy adverse reactions emerged in lower proportion of the patients (4/11%) compared with CyP (19/53%, p=0.0000) and MMF-treated group (12/27%,р=0,5). CONCLUSIONS: All agents effectively alleviated skin induration and EScSG, but only RTM and CyP significantly improved FVC. The RTM single therapy was better tolerated compared to IS. The study findings substantiate potential use an RTM single therapy both as a first-line agent for ILD treatment in the patients with a progressive course of ILD damage SSc, and in the event of CyP inefficacy of poor tolerability. The MMF use is more preferable in patients with less pronounced ILD. CLINICAL IMPLICATIONS: The obtained data substantiate the need for differentiated pharmacotherapy prescribing depending on the severity of ILD. DISCLOSURES: No relevant relationships by Lidia Ananyeva, source=Web Response No relevant relationships by Oxana Desinova, source=Web Response No relevant relationships by Liudmila Garzanova, source=Web Response No relevant relationships by Olga Koneva, source=Web Response No relevant relationships by Olga Ovsynnikova, source=Web Response No relevant relationships by Mayya Starovoytova, source=Web Response

DMD/BMD - GENETICS: EP.116 Establishing clinical and genetic characteristics in young, glucocorticoid-naïve boys with Duchenne muscular dystrophy: the FOR DMD study

We describe the clinical characteristics and genetic profile of a large sample of young glucocorticoid-naïve boys with Duchenne muscular dystrophy (DMD). Screening and baseline data were collected for participants in the FOR-DMD study, an international, multi-centre, randomized, double-blind clinical trial comparing 3 commonly prescribed glucocorticoid regimens in untreated DMD boys with a confirmed genetic diagnosis of DMD between 4 and < 8 years of age. One hundred ninety-six boys were recruited in the study. The mean age at randomization was 5.9 (standard deviation, SD 1 year). The most frequent mutation type was out of frame deletions (130/193, 67.3%) of which 68.5% (89/130) were amenable to exon skipping. Mutations amenable to exon 51 skipping were the most frequent (n=25). Stop codon mutations were reported in 19/193 boys (10%). The mean age of parental concern was 29.8 months (SD 18.7); the mean age of genetic diagnosis was 50.3 months (SD 23.8). The mean ages at independent walking and talking in sentences were 17.1 (SD 4.2) and 29.0 (SD 10.7) months, respectively. Pre-steroid median height and weight were below the 50th percentiles regardless of age group. Boys with exon 8 skippable deletions performed better in time to walk/run 10 meters compared to boys carrying other out of frame deletions not amenable to skipping (4.8±0.7 vs 6.3±4 seconds, p 0.001). Boys with exon 53 skippable deletions showed a lower baseline performance in the 6-minute walk test compared to boys with other out of frame deletions not amenable to skipping (308.9±61 vs 342±46 metres, p 0.003). In conclusion, this study describes clinical, genetic, and anthropometric characteristics of a sample of young glucocorticoid-naïve boys with DMD. Some genotype-phenotype associations were identified. These findings characterise a baseline pre-steroid cohort and, with the longitudinal data to follow, will help to inform eligibility criteria and outcome measures for future clinical trials in DMD.

Glucocorticoid dosing and relapses in giant cell arteritis-a single centre cohort study.

To investigate the relationship between real life glucocorticoid (GC) dosing and relapse rates in patients with new onset GCA in a single centre. Complete clinical data taken from the inpatient and outpatient records of consecutive GCA patients followed beyond stopping GC were retrospectively analysed for GC doses, other immunomodulatory agents and relapses. We included 54 patients with GCA confirmed by biopsy or imaging and followed over their complete GC course. In the 25% dose percentile, patients who needed no pulse therapy at onset reached a dose of 15 mg prednisolone or lower at day 40, of 7.5 mg prednisolone or lower on day 169 (after 24 weeks), and were off prednisolone on day 496 (70 weeks). They were below British Society for Rheumatology recommended doses between week 4 and week 12 and above these after week 14. The cumulative prednisolone dose reached in this 25% quartile was 3.74 g. Of the 54 patients, 24 (44%) relapsed, only four of whom had stopped GC clearly (17-58 weeks) earlier than the 25% dose quartile and one was distinctly (>10%) below the 25% GC percentile. MTX treatment was not significantly associated with fewer relapses (P = 0.178). Despite a long-term GC regimen with slow rates of reduction in the low dose range and high cumulative prednisolone doses, 44% of the patients relapsed. Only five (21%) of these relapses may have been prevented by adhering to the recommended GC regimen.

Dexamethasone use in metastatic castration-resistant prostate cancer patients treated with abiraterone acetate: this "cort" is not out of order!

In the recent issue of Asian Journal of Andrology, Ni et al.1 explore a therapeutic reflex that we as clinicians have developed over the years when treating patients with metastatic castration-resistant prostate cancer (mCRPC) with abiraterone acetate (AA). With the first signs of progression, usually, this is a rising prostate-specific antigen (PSA) level; we often continue AA but switch corticoid from prednisone to 0.5 mg of dexamethasone daily. In a subset of patients, this causes a temporary PSA decline lasting several months to occasionally over a year. It is a very cheap, well-tolerated, and safe option, although evidence for a long-term oncological benefit, such as an overall survival (OS) increase, is lacking.1 The true underlying mechanism of this corticoid switch remains unclear, but there are two possible theories: dexamethasone might counter tumor resistance to AA or dexamethasone might have a direct antitumor effect itself. This latter theory seems to be the more plausible. Historical phase II trials, performed before AA entered clinical practice, demonstrated that dexamethasone monotherapy may induce a PSA response (≥50% decline) in up to 61% of mCRPC patients.2 One phase II trial randomized 82 chemotherapy-naive mCRPC patients to either 0.5 mg of dexamethasone once daily or 5 mg of prednisone twice daily. PSA response rate was 47% versus 24%, respectively (P = 0.05).3 Interestingly, this 23% difference between both groups is almost equal to the 24.8% of patients who had a PSA response following switch from prednisone to dexamethasone in the study of Ni et al.1 Compared to prednisone, dexamethasone more potently activates the glucocorticoid receptor. It has an antiangiogenic effect through inhibition of interleukin-6 and vascular endothelial growth factor. It also decreases the production of insulin-like growth factor-1, which is known as an antiapoptotic molecule.4 Instead of performing a corticoid switch, would it not be better to start patients with AA+dexamethasone in the first place? There is some evidence to support this. Attard et al.5 performed a randomized phase II safety study on mCRPC with AA and four different glucocorticoid regimens: prednisone 5 mg twice or once daily, 2.5 mg twice daily, or dexamethasone 0.5 mg once daily. Prednisone 5 mg twice daily and dexamethasone were the only regimens that showed no increased mineralocorticoid excess. Dexamethasone was associated with a higher PSA response rate (88% vs 60%–78%) and longer radiographic progression-free survival (26.6 months vs 12.8–18.5 months), although the study was not powered to demonstrate oncological superiority. However, compared to prednisone, dexamethasone was associated with increased insulin resistance and decreased bone mineral density.5 Which patients under AA+prednisone are the best candidates for a switch to dexamethasone? The proposed models by Ni et al.1 estimate biochemical relapse-free survival (based on serum alkaline phosphatase [ALP] and AKR1C3 expression) and OS (based on serum ALP and PSA). These are, however, not predictive but prognostic models. They can be informative for clinicians and patients to estimate survival but are not predictive for PSA response following corticoid switch. However, previous observational studies (summarized in Supplementary Table 1 by Ni et al.1) and common sense give us some indications. Metastatic prostate cancer patients who responded to AA+prednisone and experienced biochemical progression in the absence of gross radiographical and clinical progression tend to be ideal candidates for corticoid switching. On the other hand, for heavily pretreated mCRPC patients who did not respond to AA or who have a limited life expectancy, earlier exploration of life-prolonging drugs could be better suited. Finally, a corticoid switch also is a viable option in patients who have no further life-prolonging treatments available. COMPETING INTERESTS All authors declare no competing interests.

Voclosporin: a novel calcineurin inhibitor for the management of lupus nephritis

ABSTRACT Introduction Kidney survival rates in lupus nephritis (LN) remain suboptimal, with 10–20% of patients progressing to end-stage kidney disease by 10–20 years. Recently, the landscape of LN management has changed with the advent of new molecules that have demonstrated safety and efficacy in clinical trials. Areas covered In this review, we approach the current state of LN management, the unmet therapeutic needs, and deep dive into voclosporin, a novel calcineurin inhibitor (CNI) that has demonstrated improved efficacy when added to a mycophenolate mofetil (MMF) and glucocorticoid regimen, without an increase in adverse events. We focus on the characteristics of this new CNI and the studies that led to its approval by the US FDA. Expert opinion Voclosporin adds to therapeutic options for LN. This drug offers potential advantages over other CNIs. The addition of voclosporin to a standard-of-care regimen of MMF/glucocorticoids demonstrated higher and faster response rates. As other regimens, a combination of CNI, MMF, and glucocorticoids must be individualized and is not appropriate for all patients. Some questions remain to be answered for this regimen, such as the length of treatment, the tapering schedule, and its long-term safety and efficacy for preserving kidney function.

Favorable outcomes with reduced steroid use in juvenile dermatomyositis

BackgroundHigh-intensity glucocorticoid regimens are commonly used to induce and maintain remission in Juvenile Dermatomyositis but are associated with several adverse side-effects. Evidence-based treatment guidelines from North American and European pediatric rheumatology research societies both advocate induction with intravenous pulse steroids followed by high dose oral steroids (2 mg/kg/day), which are then tapered. This study reports the time to disease control with reduced glucocorticoid dosing.MethodsWe retrospectively reviewed the records at a single tertiary-care children’s hospital of patients diagnosed with Juvenile Dermatomyositis between 2000 and 2014 who had a minimum of 2 years of follow-up. The primary outcome measure was time to control of muscle and skin disease. Additional outcome measures included glucocorticoid dosing, effect of treatment on height, frequency of calcinosis, and complications from treatment.ResultsOf the 69 patients followed during the study period, 31 fulfilled inclusion criteria. Median length of follow-up was 4.58 years, (IQR 3–7.5). Myositis control was achieved in a median of 7.1 months (IQR 0.9–63.4). Cutaneous disease control was achieved in a median of 16.7 months (IQR 4.3–89.5). The median starting dose of glucocorticoids was 0.85 mg/kg/day, (IQR 0.5–1.74). The median duration of steroid treatment was 9.1 months, (IQR 4.7–17.4), while the median duration of any pharmacotherapy was 29.2 months (IQR 10.4 to 121.3). Sustained disease control off medications was achieved in 21/31 (68%) patients by the end of review. Persistent calcinosis was identified in only one patient (3%).ConclusionCurrent accepted treatment paradigms for Juvenile Dermatomyositis include oral glucocorticoids beginning at 2 mg/kg/day and reduced over a prolonged time period. However, our results suggest that treatment using reduced doses and duration with early use of steroid-sparing agents is comparably effective in achieving favorable outcomes in Juvenile Dermatomyositis.

Peri-operative steroid management in the paediatric population.

Patients with adrenal insufficiency are at risk of adrenal crisis, a potentially life-threatening emergency in the peri-operative period due to their attenuated ability to mount a cortisol response. There is a lack of standardization regarding peri-operative stress-dose glucocorticoids in paediatric clinical practice with the absence of agreed protocols. For the individual patient, the risk of adrenal crisis must be weighed against the potential adverse clinical outcomes associated with unnecessary or supra-physiologic glucocorticoid dosing in susceptible patients. Specific clinical concerns in the paediatric population include osteopenia, growth restriction and increased risk of cardiovascular disease in adulthood. This review aimed to identify and evaluate available literature in the field of peri-operative stress-dose glucocorticoids. A comprehensive literature search was conducted to construct a narrative review. The outcome of this review identified that paediatric patients, unlike adults, do not show a graded response to surgical stress with implications for glucocorticoid stress dose regimens for general anaesthesia and less invasive surgical procedures. The studies highlight a lack of information on physiological steroid responses to stress situations and differences in the approach to glucocorticoid replacement strategies in the paediatric population. The review identified there is a lack of high-quality paediatric-specific studies evaluating appropriate stress-dose glucocorticoid regimens in paediatric patients with or at risk of adrenal insufficiency. Further research is needed to establish clear evidence-based clinical guidelines for paediatric peri-operative practice regarding steroid stress dosing in adrenal insufficiency. Current knowledge would suggest that a balanced view of risks and benefits should be taken appropriate to the clinical context, to dictate peri-operative stress-dose glucocorticoids use that permits safe perioperative management.

Efficacy and Safety of Different Intravenous Glucocorticoid Regimens in the Treatment of Graves' Ophthalmopathy: A Meta-Analysis.

Purpose The intravenous glucocorticoid (iv GC) represents the mainstay of therapy for Graves' ophthalmopathy (GO), but uncertainty remains concerning the optimal regimen. Although the European Group on Graves' Orbitopathy (EUGOGO) regimen has been commonly employed, evidence for its superiority to other regimens is still lacking. The aim of this meta-analysis was to compare the efficacy and safety of the EUGOGO regimen with higher-dose regimens in the management of GO. Methods A systematic review and meta-analysis of randomized controlled trials (RCTs) and cohort studies comparing the EUGOGO regimen with higher-dose regimens was conducted. PubMed, Embase, and Web of Science databases were searched for relevant studies. The efficacy outcomes were response rate, change in clinical activity score (CAS), rate of proptosis improvement, and retreatment rate. The safety outcome was the incidence of adverse events. Results In the five included eligible trials, 136 participants in the EUGOGO regimen and 177 participants in higher-dose regimens were evaluated. Compared with the EUGOGO regimen, higher-dose regimens had no beneficial effect on the response rate, change of CAS, rate of proptosis improvement, and retreatment rate (OR: 1.3; 95% CI: 0.36–4.65; SMD: –0.04; 95% CI: –0.54, 0.45; OR: 0.79; 95% CI: 0.44–1.44; OR: 0.87; 95% CI: 0.27–2.77). For the incidence of adverse events, the results also showed no significant difference between the 2 groups (OR: 1.14; 95% CI: 0.62–2.09). Conclusion The current evidence showed that the efficacy of the EUGOGO regimen was comparable with higher-dose regimens. Since there was no significant difference in the incidence of adverse events between the two regimens, appropriate selection of patients and careful monitoring were required in both regimens. More well-designed, large-scale, and longer follow-up period studies were needed to further verify the finding of this analysis.

Effect of Reduced-Dose vs High-Dose Glucocorticoids Added to Rituximab on Remission Induction in ANCA-Associated Vasculitis

The current standard induction therapy for antineutrophil cytoplasm antibody (ANCA)-associated vasculitis is the combination of high-dose glucocorticoids and cyclophosphamide or rituximab. Although these regimens have high remission rates, they are associated with considerable adverse events presumably due to high-dose glucocorticoids. To compare efficacy and adverse events between a reduced-dose glucocorticoid plus rituximab regimen and the standard high-dose glucocorticoid plus rituximab regimen in remission induction of ANCA-associated vasculitis. This was a phase 4, multicenter, open-label, randomized, noninferiority trial. A total of 140 patients with newly diagnosed ANCA-associated vasculitis without severe glomerulonephritis or alveolar hemorrhage were enrolled between November 2014 and June 2019 at 21 hospitals in Japan. Follow-up ended in December 2019. Patients were randomized to receive reduced-dose prednisolone (0.5 mg/kg/d) plus rituximab (375 mg/m2/wk, 4 doses) (n = 70) or high-dose prednisolone (1 mg/kg/d) plus rituximab (n = 70). The primary end point was the remission rate at 6 months, and the prespecified noninferiority margin was -20 percentage points. There were 8 secondary efficacy outcomes and 6 secondary safety outcomes, including serious adverse events and infections. Among 140 patients who were randomized (median age, 73 years; 81 women [57.8%]), 134 (95.7%) completed the trial. At 6 months, 49 of 69 patients (71.0%) in the reduced-dose group and 45 of 65 patients (69.2%) in the high-dose group achieved remission with the protocolized treatments. The treatment difference of 1.8 percentage points (1-sided 97.5% CI, -13.7 to ∞) between the groups met the noninferiority criterion (P = .003 for noninferiority). Twenty-one serious adverse events occurred in 13 patients in the reduced-dose group (18.8%), while 41 occurred in 24 patients in the high-dose group (36.9%) (difference, -18.1% [95% CI, -33.0% to -3.2%]; P = .02). Seven serious infections occurred in 5 patients in the reduced-dose group (7.2%), while 20 occurred in 13 patients in the high-dose group (20.0%) (difference, -12.8% [95% CI, -24.2% to -1.3%]; P = .04). Among patients with newly diagnosed ANCA-associated vasculitis without severe glomerulonephritis or alveolar hemorrhage, a reduced-dose glucocorticoid plus rituximab regimen was noninferior to a high-dose glucocorticoid plus rituximab regimen with regard to induction of disease remission at 6 months. ClinicalTrials.gov Identifier: NCT02198248.

The changes in pyroptosis-related inflammatory factors in the peripheral blood of patients with Henoch-Schonlein purpura.

Henoch-Schonlein purpura (HSP) is a common capillary allergic bleeding disease. To explore the variation of pyroptosis-related inflammatory factors level in the peripheral blood of patients with HSP. A total of 87 HSP patients treated in our hospital from June 2020 to March 2021 were selected and divided into the renal impairment group (n=29) and the non-renal impairment group (n=58) according to the presence of hematuria and proteinuria. A total of 50 healthy individuals from the hospital were selected as the control group. The renal impairment and non-renal impairment groups were treated with a regular regimen of compound glycyrrhizin tablets and glucocorticoids, respectively. Serum interleukin (IL)-18, IL-1β, and peripheral caspase-1-positive cells were compared pre- and post-treatment among the three groups. The pre-treatment serum IL-1β levels in the renal impairment and non-renal impairment groups were significantly higher than that in the control group (P<0.01). After treatment, the IL-1β level in the non-renal impairment group was not significantly different from that in the control group (P>0.05). However, the IL-1β level in the renal impairment group post-treatment was significantly higher than that in the other two groups (P<0.01). The positive rate of caspase-1 expression in peripheral blood before treatment in the renal impairment group and non-renal impairment group was significantly higher than that in the control group (P<0.01). After treatment, the positive rate of caspase-1 expression in the non-renal impairment group was comparable to that in the control group (P>0.05), whereas the rate in the renal impairment group was significantly higher than that in the other two groups (P<0.01). After treatment, the serum IL-1β levels and caspase-1 positive rate in HSP patients who were responsive to treatment (as assessed by hematuria or proteinuria levels after treatment) were lower than that in patients who were unresponsive to treatment P<0.001), but not significantly different to the control group (P>0.05). The levels of serum IL-1β and caspase-1 changed in response to alterations in the disease condition and treatment response in HSP patients, which suggested that pyroptosis-related inflammatory factors may have potential application value in predicting disease progression and efficacy of hormone therapy.

FC 035VOCLOSPORIN INCREASES RENAL RESPONSE AT COMMONLY USED UPCR THRESHOLDS IN PATIENTS WITH LUPUS NEPHRITIS

Abstract Background and Aims Voclosporin is a novel calcineurin inhibitor with a favorable metabolic profile and a consistent dose-concentration relationship, potentially eliminating the need for therapeutic drug monitoring. We have previously reported the primary endpoint of the Phase 3 AURORA trial showing the addition of voclosporin to mycophenolate mofetil (MMF) and a low-dose glucocorticoid regimen results in significantly higher renal response (RR) rates at one year of treatment compared to MMF and low-dose glucocorticoids alone in patients with lupus nephritis (LN). For the primary endpoint, RR was defined as ≤0.5 mg/mg UPCR with stable renal function in the presence of low-dose glucocorticoids and no use of rescue medication. Several studies have demonstrated that proteinuria represents the best single predictor for long-term renal outcomes.1,2 Given the efficacy of voclosporin in terms of proteinuria reduction, we conducted a sensitivity analysis evaluating RR with additional UPCR targets. Method A total of 179 participants in the voclosporin (23.7 mg BID) arm and 178 participants in the control arm from the AURORA trial were included in this analysis. All participants received MMF (target 1 g BID) and low-dose oral glucocorticoids (initiated at 20-25 mg/day and tapered to 2.5 mg/day at 16 weeks). For this post hoc analysis, the UPCR component of RR was revised to include UPCR targets at 0.2 mg/mg intervals above and below the original ≤0.5 target used for the primary endpoint in AURORA (i.e., ≤0.7 mg/mg or ≤0.3 mg/mg, respectively). Odds ratios for RR at six months and one year of treatment were analyzed using a logistic regression model with terms for treatment, baseline UPCR, biopsy class, and MMF use at baseline and region. Results RR with UPCR ≤0.7 mg/mg was achieved by 46.9% of participants in the voclosporin arm vs 32.0% of participants in the control arm at one year of treatment (OR 2.07, p&amp;lt;0.0014) and 39.1% of participants in the voclosporin arm vs 24.7% of participants in the control arm at six months of treatment (OR 2.10, p=0.0020). RR with UPCR ≤0.3 mg/mg was achieved by 28.5% of participants in the voclosporin arm vs 15.7% of participants in the control arm at one year (OR 2.27, p=0.0023 and 22.9% of participants in the voclosporin arm vs 14.0% of participants in the control arm at six months of treatment (OR 1.90, p=0.0238; Table 1). Conclusion Participants treated with voclosporin in addition to MMF and low-dose glucocorticoids achieved statistically significantly increased renal response rates regardless of the level of UPCR used, including at an even more stringent ≤0.3 mg/mg target. This analysis further supports the efficacy observed with voclosporin in the Phase 3 AURORA and the prior Phase 2 AURA-LV global trials.

Novel Therapies for ANCA-associated Vasculitis.

The purpose of this review is to discuss the most recent evidence on the treatment innovations and future prospective in the management of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAVs). In AAV, a growing body of research is available on novel treatment options for remission induction and to clarify some uncertainties concerning the optimal use of available drugs. Efforts are being made to reduce the toxicity associated with high-dose, prolonged glucocorticoids (GC) regimens. Despite major advances in the prognosis of AAV, relapses are still common and the intensity and duration of remission treatment constitute a great challenge in the management of these chronic conditions. A paradigm shift in practice in the management of AAV is being supported by recent evidence suggesting the comparable efficacy and improved safety profile of schemes with a reduced dose of GC for the induction and maintenance of remission in patients with severe granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA). Moreover, recent appraisal of pathogenetic mechanisms, including complement activation pathways, has introduced the revolutionary concept of an alternative to GC, such as avacopan. Plasma exchange failed to prevent end-stage renal disease and mortality in patients with severe renal involvement or pulmonary haemorrhage according to a large multicentre randomised trial. Intensified immunosuppressive strategies for patients with life-threatening manifestations, including the combination of rituximab (RTX) with cyclophosphamide (CYC) have revealed promising preliminary data. New evidence for the use of alternative immunosuppressive agents (e.g. mycophenolate mofetil or abatacept) for the induction of remission in patients with non-severe disease is emerging. Several studies have been recently published, or are ongoing, to assess the optimal strategy and duration of maintenance of remission with the available treatment options (GC, azathioprine, and RTX). Preliminary evidence supports the superiority of a more prolonged course of maintenance treatment. The management of refractory or relapsing eosinophilic granulomatosis with polyangiitis (EGPA) has been improved by the recent demonstration of efficacy and safety of an interleukin-5 inhibitor, mepolizumab. Ongoing randomised studies will clarify the role of RTX in patients with severe manifestations of EGPA.

Early Pulse Glucocorticoid Therapy and Improved Hormonal Outcomes in Primary Hypophysitis

Introduction: The role of glucocorticoids in primary autoimmune hypophysitis (PAH) has been fraught with variability in regimens, leading to inconsistent outcomes in terms of anterior pituitary (AP) hormonal recovery. Hence, we aimed to compare the clinical, hormonal, and radiological outcomes of a standardized high-dose glucocorticoid therapy group (GTG) in PAH with a matched clinical observation group (COG). Methods: Thirty-nine retrospective patients with PAH evaluated and treated at a single center in western India from 1999 to 2019 with a median follow-up duration of 48 months were subdivided into the GTG (n = 18) and COG (n = 21) and compared for the outcomes. Results: Baseline demographic, hormonal, and radiological features matched between the groups, except pituitary height, which was significantly higher in GTG. Cortisol, thyroid, and gonadal axes were affected in 25 (64%), 22 (56%), and 21 (54%) patients, respectively, and central diabetes insipidus was seen in 7 (18%) patients. Panhypophysitis (PH) was the most common radiological subtype (n = 33, 84.6%). Resolution of mass effects was similar in both groups. Overall and complete AP hormonal recovery was significantly higher in the GTG than in the COG (12/14 [85.7%) vs. 6/14 [42.8%], p = 0.02; 10/14 [71.4%] vs. 1/14 [7.7%], p = 0.0007, respectively). Proportion of cases with empty sella were significantly higher in the COG (9/20 [45%] vs 1/17 [5.9%], p = 0.001). Among PH patients in the GTG (n = 17), we found duration from symptoms onset to treatment as the predictor of recovery. Conclusion: In a PH subtype-predominant PAH cohort, a standardized high-dose glucocorticoid regimen resulted in higher overall and complete AP hormonal recovery than that in the COG. Initiation of glucocorticoids in the early disease course may have been contributory.

Effectiveness of glucocorticoids in patients hospitalized for severe SARS-CoV-2 pneumonia

BackgroundSeveral studies have reported the beneficial effect of glucocorticoids in the treatment of cytokine storm that occurs in patients with severe COVID-19. Various glucocorticoids regimens have been proposed. MethodsRetrospective observational study that includes patients with severe SARS-CoV-2 pneumonia and compares admission to an Intensive Care Unit (ICU) or death during hospitalization in three groups of patients: no glucocorticoids treatment, use of glucocorticoids doses equivalent to less than 250 mg of prednisone daily and use of equivalent doses greater than or equal to 250 mg of prednisone daily. Multivariate analysis was performed using logistic regression, using the propensity index as a covariant. ResultsOf the 259 patients enrolled in the study, 67 (25.9%) had an unfavorable evolution, dying or requiring ICU admission. Comparative analyzes between different glucocorticoids treatments and the association with ICU admission or death were: glucocorticoids treatment (any dose) versus no glucocorticoids treatment (OR: 0.71 [0.30–1.66]), treatment with glucocorticoids (≥250 mg prednisone daily) versus no glucocorticoids treatment (OR: 0.35 [0.11–1.08]) and glucocorticoids treatment (≥250 mg prednisone daily) versus patients with glucocorticoids doses <250 mg prednisone daily or without glucocorticoids treatment (OR: 0.30 [0.10–0.88]). ConclusionThe results of this study show that patients with severe SARS-CoV-2 pneumonia treated with glucocorticoids pulses with equivalent doses of prednisone greater than or equal to 250 mg have a more favorable evolution (less mortality and less admission to ICU).

Impaired attention in patients with adrenal insufficiency – Impact of unphysiological therapy

Patients with adrenal insufficiency (AI) are treated with glucocorticoid (GC) replacement therapy. Although current GC regimens aim to mimic the physiological circadian rhythm of cortisol secretion, temporary phases of hypo- and hypercortisolism are common undesired effects. Both conditions may lead to impairment in cognitive functioning. At present, little is known about cognitive functioning in patients with AI, especially regarding the effects of dosage and duration of glucocorticoid replacement therapy. There is also little data available comparing the effects of GC therapy on patients with primary (PAI) and secondary (SAI) forms of AI.In this study 40 adults with AI (21 PAI, 19 SAI) substituted with hydrocortisone (HC) and 20 matched healthy controls underwent 10 different neuropsychological tests evaluating memory, executive functioning, attention, psychomotricity and general intellectual ability. Furthermore demographic data, dosage of HC, duration of therapy and co-medication were evaluated. Patients were compared in groups with regard to diagnosis, dosage and duration of therapy.Patients showed worse performance than controls in attention, though patients with PAI and SAI seemed to be equally impaired. There were no limitations in intellectual abilities or memory function.High dosage of HC was found to impair attention, visual-motoric skills and executive functioning while the duration of therapy showed no significant impact on cognitive functions.In conclusion, our study showed that AI patients on HC replacement therapy reveal significant cognitive deficits concerning attention. There was no difference between patients with PAI and SAI. Furthermore, high dosage seems to have a negative impact especially on executive functioning.

Efectividad de los glucocorticoides en pacientes hospitalizados por neumonía grave por SARS-CoV-2

IntroductionSeveral studies have reported the beneficial effect of glucocorticoids in the treatment of cytokine storm that occurs in patients with severe COVID-19. Various glucocorticoids regimens have been proposed. MethodsRetrospective observational study that includes patients with severe SARS-CoV-2 pneumonia and compares admission to an Intensive Care Unit (ICU) or death during hospitalization in three groups of patients: no glucocorticoids treatment, use of glucocorticoids doses equivalent to less than 250mg of prednisone daily and use of equivalent doses greater than or equal to 250mg of prednisone daily. Multivariate analysis was performed using logistic regression, using the propensity index as a covariant. ResultsOf the 259 patients enrolled in the study, 67 (25.9%) had an unfavorable evolution, dying or requiring ICU admission. Comparative analyzes between different glucocorticoids treatments and the association with ICU admission or death were: glucocorticoids treatment (any dose) versus no glucocorticoids treatment (OR: 0.71 [0.30-1.66]), treatment with glucocorticoids (≥250mg prednisone daily) versus no glucocorticoids treatment (OR: 0.35 [0.11-1.08]) and glucocorticoids treatment (≥250mg prednisone daily) versus patients with glucocorticoids doses <250mg prednisone daily or without glucocorticoids treatment (OR: 0.30 [0.10-0.88]). ConclusionThe results of this study show that patients with severe SARS-CoV-2 pneumonia treated with glucocorticoids pulses with equivalent doses of prednisone greater than or equal to 250mg have a more favorable evolution (less mortality and less admission to ICU).