Cumulative Steroid Research Articles

The Impact of FDA-Approved Novel Agents for Steroid-Refractory Chronic Graft vs. Host Disease on Treatment Patterns and Outcomes—A Single-Center Longitudinal Cohort Analysis

Objectives—chronic graft vs. host disease (cGVHD) is associated with substantial morbidity and mortality. We aimed to analyze advances in treatment strategy and outcomes during the last decade due to the incorporation of novel immunosuppressive therapy (IST) drugs in the armamentarium. Methods—we retrospectively analyzed all patients > 18 years with cGVHD after their first hematopoietic cell transplantation (HCT) between 2012 and 2020 (n = 91), divided into three treatment periods: 2012–2014, 2015–2017, and 2018–2020 (groups 1, 2, and 3, respectively). Results—mean cumulative steroid dose and dose/total cGVHD-treatment days was lower in groups 2–3 compared to 1 (p = 0.008 and p = 0.042, respectively). The median IST-free survival was 79 (95%CI54–94) months, with more patients in group 3 (47% (95%CI 25–54%) discontinuing IST at 3 years, p = 0.1). Groups 2–3 compared to 1 had better glycemic control (p < 0.01), higher bone density (p = 0.06), and fewer cardiovascular events. The number of admissions/patient dropped from 0.7/year in group 1 to 0.24/year and 0.36/year in groups 2–3, respectively (p = 0.36). Employment reintegration was higher in groups 2–3 compared with 1 (p = 0.05) and so was earlier return to work (p = 0.01). There were no differences in survival outcomes. Conclusions—the incorporation of novel agents appears to be associated with reduced overall steroid burden, improved cGVHD control, and fewer long-term side effects.

Short term effectiveness of ustekinumab versus vedolizumab in Crohn's disease after failure of anti-TNF agents: An observational comparative study design with a Bayesian analysis.

Crohn's disease (CD) is a debilitating gastrointestinal disease with complex etiology. Although effective, recipients of anti-tumor necrosis factor (TNF) agents may experience primary or secondary nonresponse, necessitating alternative treatments. This study is intended to compare the short-term effectiveness of ustekinumab and vedolizumab in treating CD after failure of multiple lines of anti-TNF therapy using real-world data. A retrospective study was conducted at a tertiary hospital in Dammam, Saudi Arabia, including adults (≥18 years old) with CD who did not respond to anti-TNF therapy. Primary endpoints were clinical improvement per the Harvey-Bradshaw Index (HBI) scores and remission at 12 weeks on an ordinal outcome scale. Secondary endpoints included clinical, biochemical, and endoscopic remission; clinical response; corticosteroid-free days; and cumulative steroid dose. Proportional odds and logistic regression Bayesian models were used to analyze outcomes, and the probability of treatment effectiveness was calculated from the posterior distribution. The study included 101 patients (ustekinumab, n = 71 and vedolizumab, n = 30) with a median age of 32 years (IQR: 26.0-38.0); 54.4% were male. At 12 weeks, the HBI endpoint showed an adjusted odds ratio (aOR) = 0.60 (95% confidence interval [CI]: 0.25-1.31), favoring ustekinumab, with a 75% probability of treatment effectiveness over vedolizumab. The clinical ordinal scale had an aOR = 0.61 (95% CI: 0.26-1.35) with a 73% probability of effectiveness for ustekinumab. Ustekinumab was also associated with favorable outcomes in secondary endpoints, reaching up to a 90% probability of effectiveness. In CD patients with anti-TNF failure, ustekinumab was more effective than vedolizumab in the short term. These real-world insights contribute to understanding CD management but require validation in larger prospective studies and randomized controlled trials.

DIPG-42. PHASE 1/2 CLINICAL TRIAL OF OMBIPEPIMUT-S IN JAPANESE PEDIATRIC PATIENTS WITH RECURRENT/REFRACTORY DIFFUSE INTRINSIC PONTINE GLIOMA, GLIOBLASTOMA, OR HIGH-GRADE GLIOMA

Abstract BACKGROUND Pediatric patients with recurred/relapsed diffuse intrinsic pontine glioma (DIPG), glioblastoma, or high-grade gliomas (HGGs) have a dismal prognosis. The present study investigated the impacts of 1) the absolute count of Wilms tumor 1 (WT1)-specific cytotoxic T cells (CTLs) at the initiation of WT-1 specific peptide vaccine (Ombipepimut-S) consisting of a killer peptide—adegramotide, a helper peptide—nelatimotide, and adjuvant MontanideTM ISA 51 VG and of 2) cumulative steroid dose on patients’ survival. We aimed to explore the optimal timing for initiating this cancer immunotherapy for them. METHODS The absolute counts of WT1-specific CTLs and lymphocytes were examined at the initiation of vaccination. This first-in-child phase 1/2 study investigated survival (overall survival [OS] and progression-free survival [PFS]), as well as cumulative steroid dose until day 28 after vaccination initiation and immune responses according to the Kaplan-Meier method and receiver-operating curve (ROC) analysis, respectively. RESULTS 18 patients (median age: 8.9 years [range: 2.8–18.7]), 11 (61.1%), 5 (27.8%), and 2 (11.1%) had DIPG, glioblastoma, and HGG, respectively) were intradermally injected with ombipepimut-S. WT1-specific immune responders accounted for 70.6% of patients. Median OS was significantly longer (P = 0.024) in WT1-specific immune responders (9.9 months [6.0−33.4]) than in nonresponders (4.9 months [2.2−16.5]). Under a low cumulative steroid dose (< 0.66 mg/kg body weight), ombipepimut-S significantly extended both OS (P=0.0015) and PFS (P=0.007). Immune responders tended to show the higher absolute counts of WT1-specific CTLs (P=0.091) and lymphocytes (P=0.087) at the initiation of vaccination. CONCLUSIONS Ombipepimut-S exhibited antitumor activity, and this cancer immunotherapy appeared to be preferably initiated when the patient’s immunity is relatively preserved immediately after the completion of standard therapy for primary disease or before the tumor recurs or relapses.

Daily compared with alternate-day levamisole in pediatric nephrotic syndrome: an open-label randomized controlled study.

Levamisole is less expensive and has a better toxicity profile compared to other steroid sparing agents used in nephrotic syndrome. It has a plasma half-life of 2.0 to 5.6hours, but is conventionally administered on alternate days. We aimed to assess whether daily levamisole is safe and more effective than standard alternate-day therapy in maintaining remission in children with frequently relapsing or steroid-dependent nephrotic syndrome (FR/SDNS). An open-label randomized controlled trial was conducted in children with FR/SDNS. Group A received daily while Group B received alternate-day levamisole (2-3mg/kg/dose) for 12months. Prednisolone was tapered off by 3months. Patients were monitored for relapses, further steroid requirement, and adverse effects. A total of 190 children with FR/SDNS (94 in Group A and 96 in Group B) were analyzed. Sustained remission for 12months was observed in 36% of Group A and 27% of Group B patients (p = 0.18). Numbers completing 12months in the study were 67% in Group A and 56% in Group B (p = 0.13). Time to first relapse, persistent FR/SDNS, and withdrawal due to poor compliance were statistically similar in both groups, while relapse rate and cumulative steroid dosage were significantly lower in Group A compared to Group B (p = 0.03 and p = 0.02, respectively). The incidence of adverse effects was comparable in both groups, with reversible leucopenia and hepatic transaminitis being the commonest. Daily levamisole therapy was not superior to alternate-day therapy in maintaining sustained remission over 12months. Nevertheless, relapse rate and cumulative steroid dosage were significantly lower without increased adverse effects.

#2045 Epigenetic data can predict initial treatment response in nephrotic syndrome

Abstract Background and Aims The majority of children with idiopathic nephrotic syndrome (INS) and adults with Focal Segmental Glomerulosclerosis (FSGS) and Minimal Change Disease (MCD) receive glucocorticoid treatment at diagnosis. Only those with a high likelihood of having monogenic disease or a contraindication to steroids might avoid this treatment. About 10% overall will not respond to steroids and we have no reliable way of prospectively identifying these patients. Therefore, some patients will receive a futile treatment which is accompanied by significant side effects. DNA methylation (DNAm) is an epigenetic mechanism meaning that it can induce stable but reversible changes in gene expression without any change in underlying DNA sequence. DNAm has shown great potential as a treatment stratification tool, for example, DNAm data is used in oncology to identify which patients are likely to benefit from alkylating chemotherapy. We investigated whether DNAm can predict initial response to steroids in children and young adults with nephrotic syndrome. Method Three hundred and seventeen patients with INS were selected from the NephroS and NURTuRE cohorts. All patients were diagnosed with INS ≤ 30 years of age and those who underwent a renal biopsy had a histological diagnosis of either FSGS or MCD. Peripheral blood DNAm measurements were generated using the Illumina MethylationEPIC Beadchip (>850, 000 CpG sites). Clinical data was used to label patients by their initial response to steroids (sensitive, n = 156, or resistant, n = 161). Machine learning models were created to predict steroid response from the DNAm data. Models were generated using elastic net following feature filtering, and model hyperparameters were tuned and performance measured within the context of cross validation. To exclude whether cumulative steroid exposure prior to sample collection had impacted our results, the CpG sites in the final model were compared to those identified in a published study examining steroid exposure and DNAm (4). Results The 317 INS patients had a median age at diagnosis of 5 years (IQR 2-10) and a median time between diagnosis and DNAm sample collection of 4 years (IQR 1-10). The steroid resistant group were made up of patients with known monogenic disease (n = 75, 24%) and those without pathogenic variants (n = 86, 27%). Initial response to steroid treatment could be predicted with 65% accuracy and an area under the curve (AUC) of 0.75, (sensitivity 0.65, specificity of 0.66, see Fig. 1) using DNAm levels at 14 CpG sites. There was no overlap between the 14 CpG sites in our prediction model and those that are known to alter with steroid treatment. Conclusion We have demonstrated that peripheral blood cell DNAm profiles are a promising predictor of steroid response in INS. Further work to incorporate genetic data into the prediction models is underway and external validation of the results in a separate cohort of patients is required.

#2623 Homeostatic Model Assessment (HOMA) in pediatric patients with nephrotic syndrome receiving tacrolimus

Abstract Background and Aims Children with nephrotic syndrome (NS) receive diabetogenic drugs like tacrolimus (TAC) and steroids. TAC is toxic to pancreatic β-cells and suppresses insulin production in a time and dose dependent manner. This is well documented in renal transplant patients who develop post-transplant diabetes mellitus (PTDM). Although overt diabetes is uncommon in children receiving TAC for NS, the subclinical effect on β cell function has not been studied. Our aim was to study pancreatic beta cell function as assessed by homeostasis model assessment (HOMA) indices in children with NS who received TAC therapy for at least 1 year duration. Method We performed a prospective descriptive study where we followed children (1-18 years) with NS who received TAC therapy for at least 1 year. We noted patient demographics, clinical and histologic pattern of NS, cumulative steroid dose (mg/kg/day) received 90 days prior and TAC C0 levels. Fasting insulin, blood sugar to calculate HOMA indices for IR (insulin resistance), HOMA % β for beta cell function, HOMA-IS (insulin sensitivity), C-peptide and HbA1C were done once at study inclusion and yearly intervals when required. Statistical analysis included Pearson's correlation, paired t test and regression analysis. Results We performed HOMA indices in 37 children (19 males, 18 females) between September 2021-February 2023. Six patients had 2 measurements during the study period. The mean age of onset of NS was 28 months (95% CI [20; 36]) and mean age at HOMA indices measurement was 69 months (95% CI [59; 79]). Of the 37 patients, 54% (20/37) had late steroid resistance, 32% (12/37) had early steroid resistance, 8% (3/37) had steroid dependent NS, 6% (2/37) had frequently relapsing NS. Kidney biopsy performed in 36 children showed minimal change disease in 55.5% (20/36) and focal segmental glomerulosclerosis in 44.5% (16/36). The mean TAC duration, TAC Co level and mean cumulative steroid dose received in last 90 days were 27 months (95% CI [22;32]), 4.54 ng/ml (95% CI [4.12;4.97]) and 0.36 mg/kg/d (95% CI [0.28;0.44]) respectively. Eleven (30%) patients had cutaneous signs of insulin resistance like acanthosis nigricans and 9 (24%) patients had fasting blood sugar of >100 mg/dl. In Pearson's correlation analysis we found positive correlation between TAC Co level, HOMA IR (r = 0.4, P = 0.008) and TAC Co, HOMA %β (r = 0.44, P = 0.003) and cumulative steroid dose, fasting blood glucose (r = 0.3, P = 0.46). There was negative correlation between TAC Co level, HOMA IS (r = −0.4, P = 0.007). In regression analysis, only TAC Co level significantly influenced all HOMA indices including insulin resistance, insulin sensitivity and beta cell function. A HbA1C of > 5.7 (pre-diabetes range) was found in 32.4% (12/37) patients which warrants further monitoring. C-peptide levels were significantly higher after 12 months of TAC therapy in 6 patients who had two measurements (p = 0.032). Conclusion Tacrolimus therapy for nephrotic syndrome in children can affect pancreatic beta cell function as assessed by HOMA indices. Long term monitoring of pancreatic beta cell function in children with NS on TAC is needed to assess the full extent of these subclinical alterations.

COVID-19 Associated Mucormycosis and Risk Factors: A Case-Control Study from Turkey

Background: Mucormycosis, a fatal fungal infection, has increased during the COVID-19 pandemic and posed significant challenges for clinicians. Objectives: Our research focused on identifying the clinical traits of patients with COVID-19-associated mucormycosis (CAM), comparing them with a control group, and identifying risk factors for the development of CAM. Methods: Our study was conducted on 39 CAM patients and 78 control patients from September 2020 to October 2022 at a tertiary education center and regional hospital. The control group was selected blindly in a 1:2 ratio among patients who did not develop mucormycosis, were hospitalized due to COVID-19, and were either discharged or deceased. The control group was matched to the case group regarding age and hospitalization date. To test potential risk factors for CAM, we performed a binary logistic regression analysis. The variables included in the multivariate binary logistic regression model were gender, diabetes, cumulative steroid dose (dexamethasone equivalent), duration of steroid treatment, and tocilizumab/anakinra treatment. Results: In our study, 39 patients were diagnosed with CAM. The average age of the patients was 66 ± 11.5 years. Of the patients, 54.7% (n = 64) were male, with a statistically significantly higher proportion of men in the CAM group (74.4% vs. 44.9%, P = 0.003). The diabetes rate was 51.3% (n = 60) among all patients, and it was higher in the CAM group (69.2% vs. 42.3%, P = 0.006). Regarding in-hospital mortality, the rate was higher in the CAM group (56.4% vs. 14.1%, P < 0.001). The median length of stay in the hospital was 37 days for the CAM group and 10 days for the control group (P < 0.001). The cumulative steroid dose was elevated in the CAM group compared to the control group (191 ± 61.4 mg vs. 117 ± 69.8 mg, P < 0.001). The duration of steroid treatment was 16.5 ± 6.2 days in the CAM group, compared to 9.8 ± 4.7 days in the control group (P < 0.001). Among CAM cases, paranasal involvement was the most common (56.4%), followed by rhino-orbital involvement (33.3%). In binary logistic regression analysis, male gender (OR, 3.9; 95% CI, 1.4 – 11.3), diabetes mellitus (OR, 4.4; 95% CI, 1.5 – 12.4), more than ten days of steroid use (OR, 5.5; 95% CI, 1.3 – 22.4), and tocilizumab/anakinra use (OR, 0.23; 95% CI, 0.06 – 0.8) were identified as risk factors for the development of CAM (p values 0.011, 0.005, 0.019, and 0.020, respectively). Conclusions: Male gender, diabetes mellitus, and steroid use for more than ten days were identified as positive risk factors, while tocilizumab/anakinra use was identified as a negative risk factor for the development of CAM.

Growth in children with nephrotic syndrome: a post hoc analysis of the NEPTUNE study.

Steroids, the mainstay of treatment for nephrotic syndrome in children, have multiple adverse effects including growth suppression. Anthropometric measurements in children < 18years enrolled in the Nephrotic Syndrome Study Network (NEPTUNE) were collected. The longitudinal association of medication exposure and nephrotic syndrome characteristics with height z-score and growth velocity was determined using adjusted Generalized Estimating Equation regression and linear regression. A total of 318 children (57.2% males) with a baseline age of 7.64 ± 5.04years were analyzed. The cumulative steroid dose was 216.4 (IQR 61.5, 652.7) mg/kg (N = 233). Overall, height z-scores were not significantly different at the last follow-up compared to baseline (- 0.13 ± 1.21 vs. - 0.23 ± 1.71, p = 0.21). In models adjusted for age, sex, and eGFR, greater cumulative steroid exposure (β - 7.5 × 10-6, CI - 1.2 × 10-5, - 3 × 10-6, p = 0.001) and incident cases of NS (vs. prevalent) (β - 1.1, CI - 2.22, - 0.11, p = 0.03) were significantly associated with lower height z-scores over time. Rituximab exposure was associated with higher height z-scores (β 0.16, CI 0.04, 0.29, p = 0.01) over time. Steroid dose was associated with lower height z-score, while rituximab use was associated with higher height z-score.

Rituximab versus tacrolimus as corticosteroid-sparing therapy for children with steroid-dependent nephrotic syndrome: A systematic review and meta-analysis of randomized and nonrandomized controlled trials.

Prolonged use of corticosteroids induced complicated course in children with steroid-dependent nephrotic syndrome (SDNS), and the use of tacrolimus, a first-line alternative calcineurin inhibitor (CNI) agent was related to some unwanted adverse effects. Rituximab, a second alternative treatment has been proven to reliably reduce the number of relapses within 12 months with minimal adverse effects. Our review follows Preferred Reporting Items for Systematic Review and Meta-analysis guidelines. All the databases were derived from MEDLINE, Proquest, EBSCOhost, Wiley, and Google Scholar within the past 11 years. The risk of bias was evaluated using the Revised Cochrane Risk of Bias Tool for Randomized Trials (RoB 2) and Risk of Bias in Non-Randomized Studies of Interventions. Meta-analysis used Review Manager (version 5.4) with a random effect model to obtain a pooled mean difference (MD) and odds ratio with 95% confidence intervals (CIs). Four studies were included based on our eligibility criteria, and only three were included in the quantitative analysis. Three studies had low and one study had a moderate risk of bias. Pooled data results indicated that Rituximab was superior to tacrolimus in reducing the number of patients with 1-2 relapses (MD = 0.44, [95% CI: 0.21-0.91]) and had higher eGFR values (MD = 6.67; [CI - 2.92-10.61]). However, Rituximab showed insignificant superiority compared to tacrolimus in reducing the number of patients with 3 relapses, sustained remission, cumulative steroid use, serum cholesterol, and serum albumin concentrations. Rituximab exhibits more advantages in treating SDNS compared to tacrolimus, although the treatment options are highly individualized. Both regimens must also be weighed against their potential side effects to achieve a better overall health status.

CAR19 monitoring by peripheral blood immunophenotyping reveals histology-specific expansion and toxicity

AbstractChimeric antigen receptor (CAR) T cells directed against CD19 (CAR19) are a revolutionary treatment for B-cell lymphomas (BCLs). CAR19 cell expansion is necessary for CAR19 function but is also associated with toxicity. To define the impact of CAR19 expansion on patient outcomes, we prospectively followed a cohort of 236 patients treated with CAR19 (brexucabtagene autoleucel or axicabtagene ciloleucel) for mantle cell lymphoma (MCL), follicular lymphoma, and large BCL (LBCL) over the course of 5 years and obtained CAR19 expansion data using peripheral blood immunophenotyping for 188 of these patients. CAR19 expansion was higher in patients with MCL than other lymphoma histologic subtypes. Notably, patients with MCL had increased toxicity and required fourfold higher cumulative steroid doses than patients with LBCL. CAR19 expansion was associated with the development of cytokine release syndrome, immune effector cell–associated neurotoxicity syndrome, and the requirement for granulocyte colony-stimulating factor 14 days after infusion. Younger patients and those with elevated lactate dehydrogenase (LDH) had significantly higher CAR19 expansion. In general, no association between CAR19 expansion and LBCL treatment response was observed. However, when controlling for tumor burden, we found that lower CAR19 expansion in conjunction with low LDH was associated with improved outcomes in LBCL. In sum, this study finds CAR19 expansion principally associates with CAR-related toxicity. Additionally, CAR19 expansion as measured by peripheral blood immunophenotyping may be dispensable to favorable outcomes in LBCL.

The association of an elevated Th/Ts ratio and lupus anticoagulant with symptomatic osteonecrosis in systemic lupus erythematosus patients.

This study aimed to assess the risk factors for symptomatic osteonecrosis (ON) in systemic lupus erythematosus (SLE) and identify clinical characteristics and laboratory markers for predicting symptomatic ON occurrence in SLE patients. Seventy (6.0%) of 1175 SLE patients diagnosed with symptomatic ON were included in this study. An equal number of SLE patients without symptomatic ON, matched in terms of age and gender, were enrolled in the control group. Clinical symptoms, routine laboratory examinations, lymphocyte subsets, and treatments of these patients were retrospectively reviewed and compared between the two groups. Logistic regression analysis was employed to identify risk factors associated with symptomatic ON in SLE. Among the 70 cases in the symptomatic ON group, 62 (88.6%) patients experienced femoral head necrosis, with bilateral involvement observed in 58 patients. Bone pain was reported in 32 cases (51.6%), and 19 cases (30.6%) presented with multiple symptoms. Univariate analysis revealed significant differences between the two groups in various factors, including disease duration (months), cumulative steroid exposure time, history of thrombosis, neurological involvement, the number of affected organs, myalgia/myasthenia, and the use of medications such as glucocorticoids, immunosuppressants, aspirin, and statins (P<0.05). Moreover, lupus anticoagulant (LA) levels were significantly higher in the symptomatic ON group than in the control group (P<0.05). Furthermore, notable distinctions were observed in peripheral blood immune cells, including an elevated white blood cell count (WBC), a decreased percentage of Ts cells (CD3+CD8+), and an elevated Th/Ts ratio. Logistic regression analysis revealed that a history of thrombosis, LA positivity, and an elevated Th/Ts ratio remained positive factors associated with symptomatic ON (P<0.05). Decreased Ts cells and changes in the T lymphocyte subset play an important regulatory role in the development of symptomatic ON. A history of thrombosis and LA are associated with an increased probability of symptomatic ON in SLE and may serve as potential predictors.

Insights into future management of lupus nephritis

Lupus nephritis (LN) is a common and serious manifestation of systemic lupus erythematosus and is a major cause of mortality and morbidity. The current standard-of-care treatment for LN include conventional immunosuppressive treatments such as mycophenolate mofetil, cyclophosphamide, or azathioprine, combined with glucocorticoids. However, this treatment approach has several unmet needs, such as achieving only modest remission rates, potential toxicities, and prolonged cumulative steroid exposure, resulting in suboptimal patient outcomes. The LN treatment landscape is evolving rapidly to meet these unmet needs, with belimumab and voclosporin being the first drugs approved specifically for treatment of LN in 2020 and 2021, respectively. Here, we review the likely roles in LN therapy for several targeted therapies, including select therapies under investigation, and interventions in early development such as therapies targeting B cells (obinutuzumab, atacicept, ianalumab, and CD19 chimeric antigen T-cell therapy), inflammatory cytokines (secukinumab and anifrolumab), and the immunoproteasome (zetomipzomib); we also review treatment strategies designed to minimize steroid exposure. Treatments in development have demonstrated encouraging short- and long-term efficacy and steroid-sparing potential, potentially paving the way for improved treatment regimens and patient outcomes in LN.

Ocular complications in pediatric nephrotic syndrome treated with corticosteroids

Background Posterior subcapsular cataracts (PSC) and raised intraocular pressure (IOP) are the most common ocular complications of oral steroid administration, particularly following long-term use or treatment with high doses.&#x0D; Objective To evaluate the association between cumulative steroid dose and duration of treatment with the occurrence of PSC and raised IOP, as well as its associated factors in children with idiopatic nephrotic syndrome (INS).&#x0D; Methods This cross-sectional study included children aged 4–18 years with INS who received oral steroid therapy for at least six consecutive months. Patients underwent complete eye examinations by an ophthalmologist to evaluate their visual acuity as well as the occurrence of PSC and/or raised IOP. Results Of 92 subjects, 19.6% had PSC, 12% had raised IOP, and one had a best corrected visual acuity (BCVA) of &lt;6/20. The median cumulative steroid dose was 12,161 (range 1,795–81,398) mg and median treatment duration was 23 (range 6–84) months. There were significant positive associations between cumulative steroid dose as well as treatment duration and the occurrence of PSC, with cut-off points of 11,475 mg and 24 months, respectively, as determined by receiver operator characteristic (ROC) curves. Females were four times more likely to have PSC compared to males (PR 4; 95%CI 1.57 to 13.38; P=0.001). Cumulative steroid dose and duration of treatment were not associated with raised IOP.&#x0D; Conclusion Cumulative steroid dose of 11,475 mg or higher and/or duration of steroid therapy of 24 months of more were significantly associated with the occurrence of PSC, but not with raised IOP.

Clinical features of neurotoxicity after CD19 CAR T-cell therapy in mantle cell lymphoma

AbstractCD19 chimeric antigen receptor (CAR) T-cell therapy has proven highly effective for treating relapsed/refractory mantle cell lymphoma (MCL). However, immune effector cell–associated neurotoxicity syndrome (ICANS) remains a significant concern. This study aimed to evaluate the clinical, radiological, and laboratory correlatives associated with ICANS development after CD19 CAR T-cell therapy in patients with MCL. All patients (N = 26) who received standard-of-care brexucabtagene autoleucel until July 2022 at our institution were evaluated. Laboratory and radiographic correlatives including brain magnetic resonance imaging (MRI) and electroencephalogram (EEG) were evaluated to determine the clinical impact of ICANS. Seventeen (65%) patients experienced ICANS after treatment, with a median onset on day 6. Ten (38%) patients experienced severe (grade ≥3) ICANS. All patients with ICANS had antecedent cytokine release syndrome (CRS), but no correlation was observed between ICANS severity and CRS grade. Overall, 92% of EEGs revealed interictal changes; no patients experienced frank seizures because of ICANS. In total, 86% of patients with severe ICANS with postinfusion brain MRIs demonstrated acute neuroimaging findings not seen on pretreatment MRI. Severe ICANS was also associated with higher rates of cytopenia, coagulopathy, increased cumulative steroid exposure, and prolonged hospitalization. However, severe ICANS did not affect treatment outcomes of patients with MCL. Severe ICANS is frequently associated with a range of postinfusion brain MRI changes and abnormal EEG findings. Longer hospitalization was observed in patients with severe ICANS, especially those with abnormal acute MRI or EEG findings, but there was no discernible impact on overall treatment response and survival.

P688 Comparative Effectiveness of Ustekinumab Versus Vedolizumab in Treating Crohn’s Disease After Failure of Anti-TNF Agents: Real-World Evidence

Abstract Background Despite effective anti-TNF agents in treating Crohn’s disease (CD), some recipients experience primary or secondary non-responses, requiring alternative options. Ustekinumab and vedolizumab have not been compared in randomized controlled trials (RCTs) among CD population. Thus, we used real-world data to compare ustekinumab and vedolizumab at 12 weeks after failure of TNF inhibitors. Methods A retrospective study was conducted at a tertiary hospital in Dammam, Saudi Arabia. Patients with CD who had not responded to anti-TNF agents and had never been exposed to vedolizumab and/or ustekinumab were included. Children ≤ 18 years of age, naïve CD patients, CD patients using only anti-TNF agents, and patients who lost follow up were excluded. Primary endpoints were clinical improvements, which were measured by Harvey-Bradshaw Index scores at 12 weeks, and clinical remission, which was measured as an ordinal outcome. Remission clinically, biochemically, and endoscopically; clinical response; cumulative steroid dose; and corticosteroid-free days were secondary endpoints. Using probabilistic Bayesian models and proportional odds models, we analyzed outcomes, and the posterior distribution was used to calculate the probability of treatment effectiveness. A national institutional review board approved the study. Results Five hundred forty-six patients received biological agents for inflammatory bowel disease, of whom 101 received biological agents for CD; 71 patients received ustekinumab, and 30 patients received vedolizumab. The baseline characteristics were similar except for perianal disease, which was frequently reported in ustekinumab arm (P = 0.006). Most of the patients were male (54.5%), with a median age of 32 (IQR: 26.0-38.0). Most patients (51.5%) had stricturing disease in the Ileocolonic site (70.3%). For ustekinumab, the median HBI score was 5 (IQR: 3.0 -8.0) whereas for vedolizumab, it was 5 (IQR: 4.0 -7.0). In table 1, a Bayesian multivariable proportional odds model revealed a 40% reduction in median HBI scores at 12 weeks favoring ustekinumab, with an aOR of 0.60 (95% CI: 0.25 to 1.31) and a probability of effectiveness of 75% for ustekinumab. At 12 weeks, the ordinal outcome scale was 39% lower for ustekinumab arm, with an aOR of 0.61 (95% CI: 0.26 to 1.35) and a probability of effectiveness of 73% for ustekinumab arm. Secondary endpoints showed favorable results for ustekinumab reaching up to a 90% probability of effectiveness. Conclusion Among CD patients who failed anti-TNF therapies, ustekinumab was more effective than vedolizumab. To validate these results and determine these treatments’ relative efficacy in managing CD, further investigations, including prospective studies and RCTs, are essential.

P777 Is the long-term Budesonide use have any influence on Bone Mineral Density in Inflammatory Bowel Diseases?

Abstract Background Systemic steroid use, and IBD itself, both have negative effect on bone mineral density. Budesonide is a synthetic steroid with high topical glucocorticoid activity and low systemic bioavailability. When compared to systemic steroids, the frequency of side effects of budesonide appears to be quite low, however, there is no documented report about the long term budesonide use on BMD in IBD patients. We also do not know other potential side effects of long term budesonide use. In this study, we aimed to evaluate the long term budesonide use on BMD and its’ other potential side effects, in IBD patients. Methods We retrospectively reviewed the files of the patients who had been using budesonide for ≥24 months and had DEXA measurements during the follow-up period (Budesonide group). Patients in the budesonide group were matched 1:1 with patients without a history of budesonide use, in relation to pre or post registry number of each index case under budesonide. Matching between groups has been done, in terms of gender, age, type of IBD, history of resection, concomitant medications, and comorbidities. For the exact matching, move on for the next or further next available patient, pre or post of each index case, was taken as a choice. (Control group). At the initiation and completion of budesonide treatment, DEXA scans were taken, and biochemical parameters and bone fractures were recorded. We also recorded other causes of secondary osteoporosis in patients (such as comorbidities, medications, alcohol, and cigarette use), as well as cumulative steroid doses and durations in those using conventional corticosteroids. Results A total of 104 patients were included in the study, with 52 in the budesonide group and 52 in the control group. The mean duration of budesonide use was 46.13 ± 15.4 months (range: 25-94 months), and the mean cumulative budesonide usage dose was found to be 34.9 ± 11.8 g (range: 14-64.8 g) in the budesonide group. Table 1a presents the comparison of the two groups. None of the patients in the budesonide group showed deterioration in BMD during the follow-up (Table 1b and 1c). No other prominent long term side effects, valued for the file recording, was found. Conclusion Budesonide treatment seems to be safe in consideration for maintaining long term remission in IBD. Relatively low number of patients, not considering the first two year’s follow up and dropping of the cases with earlier side effects, missed for the long-term judgement under budesonide, may explain the lacking of the other potential side effects (indicated in the literature).

Adrenocortical suppression in children with nephrotic syndrome treated with corticosteroids.

Children with nephrotic syndrome are exposed to alternate day steroids for prolonged periods and this poses the need for evaluation of adrenocortical suppression using the adrenocorticotropic hormone (ACTH) stimulation test. This cross-sectional study enrolled children (2-18years) both with steroid sensitive nephroticsyndrome (SSNS) (n = 27) and steroid resistant (SRNS) (n = 25); those on daily prednisolone or having serious bacterial infections or hospitalized were excluded. The primary objective was to determine prevalence of adrenocortical suppression in those on low dose alternate day steroids for more than 8weeks or having received > 2mg/kg/d for > 2weeks in the past 1year and currently in remission. A baseline morning fasting sample of serum cortisol was taken and 25IU of ACTH (Acton Prolongatum*) injected intramuscularly and repeat serum cortisol sample taken after 1h. All patients with 1h post ACTH cortisol < 18.0 µgm/dl were diagnosed with adrenal insufficiency. Receiver operating characteristic curve was drawn to predict the prednisolone dose for adrenal insufficiency. Fifty-two (33 males) children were enrolled (mean age 9.4years); proportion of adrenal insufficiency was 50% and 64% using baseline and post stimulation cutoffs. The total cumulative annual dose of prednisolone 0.22mg/kg/day predicted adrenocortical suppression with AUC 0.76 (95% CI 0.63-0.89), with sensitivity of 63.9% and specificity of 81.3%. A significant proportion of children with nephrotic syndrome were detected with adrenal insufficiency on ACTH stimulation test. A cumulative steroid intake of > 0.22mg/kg/day on an alternate day basis emerged as a risk factor for predicting adrenocortical suppression.

Steroid induced ocular complications in idiopathic nephrotic syndrome: a cross sectional single center study.

To screen children receiving steroids to identify ocular complications and their prevalence. The cross-sectional study was conducted at the Paediatric Nephrology and Ophthalmology departments of the Sindh Institute of Urology and Transplantation, Karachi, from May to October 2022, and comprised patients who received at least 1500mg cumulative steroid dose for a minimum of 3 months. They were screened for steroidsensitive or steroid-resistant nephrotic syndrome. Ocular examinations, including visual acuity, intraocular pressure, slit-lamp biomicroscopy, lens examination and fundus evaluation, were performed. Data was analysed using SPSS 22. Of the 124 subjects with mean age 8.15±2.03 years (range: 6-12 years), 64(51.6%) were boys. Steroidsensitive nephrotic syndrome was present in 97(78%) cases. The mean cumulative steroid dose was 3999.31±1564.22mg. Overall, 36(29%) children developed ocular complications. Blood pressure, number of relapses and the duration of treatment were significantly associated (p<0.05). Refractive errors were the most frequent side effects/complication seen among children with nephrotic syndrome who received prolonged corticosteroids.

Association Between Initial Corticosteroid Regimen and Treatment Response Time in Acetylcholine Receptor Antibody–Positive Myasthenia Gravis

Background: Corticosteroids remain the cornerstone in the management of myasthenia gravis (MG). Initiation of corticosteroid treatment at a high dose and subsequently decreasing the dose or gradual escalation from a low dose is recommended. We aimed to investigate the association between the initial corticosteroid regimen and treatment response.Methods: A retrospective study was conducted on 234 acetylcholine receptor (AChR) antibody (Ab)–positive MG patients who visited our institution between January 2010 and February 2023. Patients were grouped based on prednisolone dosages received: initial high (IH, ≥50 mg/day) or initial low (IL, ≤20 mg/day). Time to initial improvement and the achievement of minimal manifestation (MM) status were the main outcomes.Results: Of the 234 patients, 135 were classified as IH and 99 as IL group. The IH group demonstrated a faster onset of improvement compared with the IL group (20.0 [16.0–29.0] vs. 40.0 [27.0–84.0] days), with the IH group being a significant prognostic factor for initial improvement (HR, 2.44; 95% CI, 1.76–3.39). However, the IH group had a higher incidence of steroid‐induced exacerbation (51.9% vs. 2.0%, p &lt; 0.001). No significant difference between the IH and IL groups was found in terms of the proportion of patients achieving MM or the time to achieve MM within the first year after treatment initiation.Conclusion: While an initial high dose of corticosteroid treatment accelerated the onset of therapeutic responses in patients with AChR Ab–positive MG, it was associated with a higher cumulative steroid dose and an increased risk of steroid‐induced exacerbations.

Polymyalgia rheumatica - an up-to-date review on diagnosis and management

Polymyalgia rheumatica (PMR) is the most common inflammatory rheumatic disease in those over the age of 50 years. Previously it was considered to be a benign clinical syndrome characterised by subacute onset bilateral shoulder and pelvic girdle pain and stiffness, with a corresponding rise in acute phase reactants, and distinctive rapid resolution of symptoms with the instigation of moderate doses of glucocorticoids. However, over the past decade, with the advancements and, indeed, wider application of imaging modalities in PMR, we have garnered an increased understanding of the anatomic predilection of inflammation and, subsequently, disease pathogenesis. Moreover, our appreciation of the relationship between PMR and giant cell arteritis (GCA) has strengthened. Glucocorticoids have formed the cornerstone of the management of PMR for decades, with often protracted treatment durations and associated high cumulative steroid burden and adverse effects. However, we are now on the cusp of a new era in the management of PMR, with our therapeutic armamentarium expanding with the recent FDA approval of the interleukin -6 antagonist sarilumab for the management of refractory disease. It is an exciting time for PMR, and this review aims to explore the recent advancements in both diagnosis and management, while also providing an updated perspective on the relationship between PMR and GCA.