Steroid Response Research Articles

THU-396 - Determinants of steroid responsiveness in patients with severe acute hepatitis of indeterminate, autoimmune hepatitis and drug induced aetiologies

THU-396 - Determinants of steroid responsiveness in patients with severe acute hepatitis of indeterminate, autoimmune hepatitis and drug induced aetiologies

Systems Genomics Reveals microRNA Regulation of ICS Response in Childhood Asthma.

Asthmatic patients' responses to inhaled corticosteroids (ICS) are variable and difficult to quantify. We have previously defined a Cross-sectional Asthma STEroid Response (CASTER) measure of ICS response. MicroRNAs (miRNAs) have shown strong effects on asthma and inflammatory processes. The purpose of this study was to identify key associations between circulating miRNAs and ICS response in childhood asthma. Small RNA sequencing in peripheral blood serum from 580 children with asthma on ICS treatment from The Genetics of Asthma in Costa Rica Study (GACRS) was used to identify miRNAs associated with ICS response using generalized linear models. Replication was conducted in children on ICS from the Childhood Asthma Management Program (CAMP) cohort. The association between replicated miRNAs and the transcriptome of lymphoblastoid cell lines in response to a glucocorticoid was assessed. The association study on the GACRS cohort identified 36 miRNAs associated with ICS response at 10% false discovery rate (FDR), three of which (miR-28-5p, miR-339-3p, and miR-432-5p) were in the same direction of effect and significant in the CAMP replication cohort. In addition, in vitro steroid response lymphoblastoid gene expression analysis revealed 22 dexamethasone responsive genes were significantly associated with three replicated miRNAs. Furthermore, Weighted Gene Co-expression Network Analysis (WGCNA) revealed a significant association between miR-339-3p and two modules (black and magenta) of genes associated with immune response and inflammation pathways. This study highlighted significant association between circulating miRNAs miR-28-5p, miR-339-3p, and miR-432-5p and ICS response. miR-339-3p may be involved in immune dysregulation, which leads to a poor response to ICS treatment.

A very early steroid responder after cataract surgery: a case report

BackgroundIncreased intraocular pressure (IOP), a side effect of corticosteroid eye drops, typically develops during the first few weeks of administration, and steroid response is not generally considered a cause of increased IOP immediately after cataract surgery.Case presentationHere, I report a rare case of increased IOP due to steroid eye drops immediately after surgery. A man in his 80s presented with vision loss. Bilateral cataracts and pseudoexfoliation syndrome were confirmed. Postoperative eye drops including steroid eye drops were started immediately after cataract surgery in the right eye. High IOP was observed at the next and subsequent morning visits, but IOP normalized when steroid eye drops were discontinued. After surgery on the left eye, steroids were not administered postoperatively, and no increase in IOP was observed.ConclusionThis case report highlights that a very early steroid response may be potential cause of elevated IOP immediately after cataract surgery.

Primary nephrotic syndrome in children in Cape Town, South Africa

Background. Histopathological patterns of childhood primary nephrotic syndrome (PNS) and clinical response to steroids have beenassociated with certain race groups in parts of South Africa. However, there are no recent studies of childhood PNS in Cape Town.Objectives. To describe the demographics, histological subtypes and steroid response of patients with PNS who underwent kidney biopsiesat Red Cross War Memorial Children’s Hospital (RCWMCH) over a 10-year period.Methods. Details of patients with PNS who underwent kidney biopsies in the Paediatric Nephrology Department at RCWMCH between2006 and 2015 were retrospectively recorded.Results. A total of 103 patients were included in the study. Most patients were either of mixed race (42%) or black (36%), with a mean age of6.8 years and a male-to-female ratio of 1.19:1. The most identified histopathological subtype was mesangioproliferative glomerulonephritis(MesPGN; 60% (n/N=62/103)). Of the patients with focal segmental glomerulosclerosis (FSGS), MesPGN and minimal change disease(MCD) 45% (n/N=43/95) were steroid-resistant, and 54% (n/N=51/95) were steroid-sensitive. There was no significant associationbetween any race group and steroid response. Patients with FSGS were more likely to be black, while MCD was more common in mixed-race patients (p=0.04). There was no difference in the likelihood of being mixed race or black between patients with FSGS and MesPGN(p=0.472).Conclusion. MesPGN was the most common histopathological subtype found in our study. There was no significant association betweenrace and steroid response. Patients with FSGS were more likely to be black than mixed race when compared with MCD patients. Race wasnot otherwise significantly associated with any histopathological subtype

Primary sclerosing cholangitis with partial steroid responsiveness: a case report.

A 69-year-old woman suspected to have IgG4-related sclerosing cholangitis causing bile duct stenosis was transferred from another hospital after diarrhea, eosinophilia, and eosinophilic infiltration were detected and prednisolone was prescribed. Additional biliary imaging suggested primary sclerosing cholangitis, but the IgG4 level and inferior bile duct stenosis were alleviated by steroid therapy, suggesting IgG4-related sclerosing cholangitis. Therefore, prednisolone was continued. Bile duct biopsy findings suggesting adenocarcinoma led to a diagnosis of pancreatoduodenectomy. The latter specimen only displayed evidence of primary sclerosing cholangitis, and prednisolone was discontinued. Intractable cholangitis necessitated left hepatectomy, after which serum alkaline phosphatase levels increased and eosinophilic colitis recurred. The reintroduction of prednisolone effectively managed the diarrhea but only temporarily reversed the alkaline phosphatase elevation. When histologic sections from resection specimens were compared, the hepatectomy specimen exhibited greater eosinophil infiltration than the earlier pancreatoduodenectomy specimen, suggesting eosinophilic cholangiopathy superimposed on primary sclerosing cholangitis.

Abstract #1385480: Goiter and Abdominal Mass: A Rare Presentation of Riedel’s Thyroiditis

Riedel’s thyroiditis (RT), also known as fibrous thyroiditis, is a rare inflammatory autoimmune disease that is often associated with various forms of systemic fibrosis such as sclerosing mesenteritis (SM). A 38-year-old female with a past medical history of hypertension presented with a painful growing goiter and a mesenteric mass, which was complicated by biliary obstruction and hydronephrosis. Physical exam showed tenderness on the abdomen and a diffusely enlarged firm thyroid gland, with no palpable nodules. Initial labs revealed C-reactive protein of 115 mg/L, TSH 180 mIU/L; Free T4: 0.79 ng/dL, positive Thyroid Peroxidase (>1051 IU/mL); normal IgG1 and IgG4. CT abdomen/pelvis demonstrated a mesenteric mass that encased multiple mesenteric vessels and the right ureter without bowel obstruction. Thyroid ultrasound showed an enlarged heterogeneous thyroid without a discrete nodule consistent with autoimmune thyroiditis. Thyroid fine needle aspiration (FNA) was non-diagnostic. Thyroid biopsy showed mostly fibrosis with scattered lymphoplasmacytic aggregates, with no evidence of carcinoma, lymphoma, IgG4-related disease, and no Hürthle cell presence. Interestingly, the mesenteric mass biopsy revealed the same pattern. Peripheral flow cytometry and infectious workup were negative. Diagnosis of RT and SM were made. The patient was treated with steroids and improved clinically. The hallmark of RT is the extension of fibrosis beyond the thyroid. This patient exhibited common features of RT such as neck pressure, and pain; female gender, elevated inflammatory markers, nondiagnostic FNA (scant cellularity due to fibrosis), and a positive steroid response. Moreover, intense infiltrative fibrosis mixed with lymphocytes and plasma cells instead of an extensive lymphocytic infiltrate with the germinal center formation on histology supports Riedel’s thyroiditis rather than Hashimoto's. Similarly, SM is a rare, non-neoplastic inflammatory and fibrotic disease that affects the integrity of mesenteric vessels causing common bile duct and ureter obstruction. Negative flow cytometry, the presence of sclerosis, and the absence of bowel/liver lesions involvement make other common causes of a mesenteric mass (lymphoma, desmoid tumor, carcinoid) less likely, supporting the diagnosis of SM. The concurrent timing of her thyroid enlargement and the mesenteric mass as well as the similarity in histology (dense fibrosis with patchy lymphoplasmacytic aggregates) suggests an association between RT and SM. Overall, the case highlights the challenges in diagnosing RT given its extreme rarity and emphasizes the importance of early treatment to prevent systemic involvement.

Correlation between Toll-like Receptor Gene Polymorphisms and Idiopathic Nephrotic Syndrome in Chinese Children.

Idiopathic nephrotic syndrome (INS) is the most common glomerular disease in children. Toll-like receptors (TLRs) have been reported to be associated with response to steroid treatment in children with INS. Nevertheless, the correlation between TLR genes and the progression of INS has not yet been clarified. The present study aimed to investigate the association of single-nucleotide polymorphisms (SNPs) in TLR2, TLR4, and TLR9 with susceptibility to INS as well as the clinical phenotyping of steroid responsiveness in Chinese children with INS. A total of 183 pediatric inpatients with INS were included and given standard steroid therapy. Based on their clinical response to steroids, the patients were classified into three groups: steroid-sensitive nephrotic syndrome (SSNS), steroid-dependent nephrotic syndrome (SDNS), and steroid-resistant nephrotic syndrome (SRNS). A total of 100 healthy children were employed as controls. The blood genome DNA was extracted from each participant. Six SNPs (rs11536889, rs1927914, rs7869402, rs11536891, rs352140, and rs3804099) in TLR2, TLR4, and TLR9 were selected and detected by multiplex polymerase chain reaction with next-generation sequencing to assess TLR gene polymorphisms. Among the 183 patients with INS, 89 (48.6%) had SSNS, 73 (39.9%) had SDNS, and 21 (11.5%) had SRNS. No significant difference was found in the genotype distribution between healthy children and patients with INS. However, the genotype and allele frequencies of TLR4 rs7869402 were significantly different between SRNS and SSNS. Compared with patients with the C allele and CC genotype, patients with the T allele and CT genotype had an increased risk of SRNS. TLR4 rs7869402 affected the steroid response in Chinese children with INS. It might be a predictor for the early detection of SRNS in this population.

Association between Thyroid autoimmunity and Fibromyalgia: Single center retrospective study (P9-6.004)

<h3>Objective:</h3> The objective of this study was to describe the prevalence of anti TPO ab among FM patients, their thyroid status and to evaluate clinical response to corticosteroids. <h3>Background:</h3> Fibromyalgia (FM) is a disorder characterized by widespread musculoskeletal pain and other somatic symptoms. Studies have shown that there is a high prevalence of anti TPO ab (Thyroid peroxidase antibody) positivity among FM patients. It is unknown if thyroid autoimmunity is a predisposing factor for FM. <h3>Design/Methods:</h3> We included 107 patients who were diagnosed with FM based on 2010 American College of Rheumatology Criteria who attended our neurology clinic at Appusami Hospital, India between July 2019 and 2022. We recorded data including age, gender, thyroid profile, anti TPO titer [Negative (&lt;15), positive (15 to 500), strongly positive(&gt;500)] and calculated age adjusted odds ratio for steroid responsiveness. <h3>Results:</h3> Mean age of the study group was 48.29 and 78.5% were females. In our series, 75.7% of FM patients had positive anti TPO ab (Positive- 41.12%;strongly positive-35.51%). 51.40% were euthyroid, 38.32% were hypothyroid and 10.28% were hyperthyroid. Overall 56.8% responded well to steroids. (80.85% of strongly positive;19.15% of positive patients). Age-adjusted odds of steroid response in patients with higher anti TPO ab is 5.2 times that of the one with low ab (p&lt;0.001) (95%CI 3.03;9.04) <h3>Conclusions:</h3> Thyroid autoimmunity is frequently associated with middle aged women with FM. Higher anti TPO ab titers strongly correlated with steroid responsiveness in our study and we recommend a short course of steroids for this subset of patients. These findings need to be confirmed with a larger prospective study. Further research should focus on understanding the pathophysiology of FM and it9s the causal relationship with thyroid autoimmunity. <b>Disclosure:</b> Dr. Eswaradass has nothing to disclose. C Eswaradass, 303 has nothing to disclose. Dr. Thermalingem has nothing to disclose. Dr. Thirunavukkarasu has nothing to disclose. Dr. Gurunathan has nothing to disclose.

Early Post Radiation Neuropathy: Complex Pathogenesis Including Microvasculitis and Tumor Spread (P14-8.001)

<h3>Objective:</h3> To describe patients with early radiation-induced peripheral nerve injury and investigate potential pathogenic mechanism(s). <h3>Background:</h3> Radiation-induced neuropathy typically occurs up to decades after radiation from neural fibrosis with insidious, painless progressive weakness. Reports of early radiation-associated neuropathies are lacking. <h3>Design/Methods:</h3> Patient cases labeled as “radiation neuropathy” were electronically retrieved from our electromyography (EMG) and Mayo Data Explorer databases between January 2014 to August 2022. Inclusion criteria included neural deficits within 6 months of radiation, EMG testing, and available follow-up nerve imaging. <h3>Results:</h3> Twenty-two patients (9 female, mean age 63 years [range 34–84]) were identified with a history of squamous (n=6), prostate (n=5), breast (n=3), rectal (n=2), hematologic (n=2), and other (n=4) cancers. Average radiation dose was 4491 cGy (range 1000–7208). Time to symptom onset averaged 1.9 months (range 0–4). Pre-radiation chemotherapy occurred in most (n=16). All neuropathies occurred in the same radiation territory, but most neuropathies (n=17) occurred distal to the radiation site. EMG-confirmed neuropathies included radiculopathies (n=10), brachial and lumbosacral plexopathies (n=10), and mononeuropathies (n=2). EMG myokymia was seen in few (n=6). Patients reported primarily painful paresthesias (n=18) and weakness (n=18). Clinical courses were monophasic (n=8), progressive (n=8), static (n=2), and unclear without follow-up (n=4). Follow-up neural MRI did not suggest infiltrative disease (n=21), but based on tumor location and progressive course, microscopic infiltration was suspected. Two patients had nerve biopsies showing prominent inflammation around epineural microvessels with vessel wall injury (microvasculitis). One biopsy revealed neoplastic spread of rectal squamous cell cancer. Steroid burst therapy was attempted in 6 patients; 5 reported benefits, and 4 had monophasic courses. <h3>Conclusions:</h3> Early-onset post radiation neuropathies having pain and monophasic courses are supported by steroid response and biopsy-confirmed microvasculitis to have an inflammatory-immune mechanism. Exclusion of infiltrative cancer and an idiosyncratic radiation injury with progressive course are important to consider. <b>Disclosure:</b> Dr. Skolka has nothing to disclose. Dr. Uhm has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Zai Lab. Dr. Ma has nothing to disclose. Dr. Santilli has nothing to disclose. Mr. Meiling has nothing to disclose. Dr. Sandroni has nothing to disclose. Dr. Staff has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Stem Cell Research &amp; Therapy. Dr. Pinto has nothing to disclose. Dr. Dyck has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Akcea/Ionis. Dr. Klein has a non-compensated relationship as a Klein with Neurology Journal that is relevant to AAN interests or activities.

Investigating the Electro-Optic Response of Steroid Doped Liquid Crystal Devices

Nature is highly efficient at producing chiral compounds that are enantiomerically pure. The inherent chirality of naturally occurring biomolecules means that many have the potential to be used as chiral dopants for cholesteric liquid crystal (CLC) systems. Though many biomolecules have been identified as chiral dopants, many remain yet to be probed for their ability to function as chiral dopants. Here, 10 naturally occurring biomolecules comprised of steroids and bile acids were tested as chiral dopants for CLCs. Progesterone was identified as having high miscibility with nematic liquid crystals and was used in responsive liquid crystal devices. Progesterone-doped CLC devices were fabricated to exhibit either normal mode or reverse mode switchable behavior. Polymer stabilized CLCs (PSCLC) devices exhibiting dynamic electro-optic red- and blue-tuning behaviors were also fabricated. Furthermore, immiscible lithocholic acid was synthetically modified to afford two derivatives that were miscible at 10 wt. % in nematic liquid crystals. The two lithocholic acid derivatives were used as chiral dopants and incorporated into polymer stabilized CLCs which exhibited blue tuning behavior.

CD44 staining in parietal epithelial cells and early steroid response in patients with minimal change disease.

CD44 staining in parietal epithelial cells and early steroid response in patients with minimal change disease.

Differential protein expression in endothelial cells exposed to serum from patients with acute graft-vs-host disease, depending on steroid response.

Graft-versus-host disease (GVHD) is a complication of allogeneic haematopoietic cell transplantation. Endothelial injury is crucial as pathophysiological substrate for GVHD. GVHD first-line treatment is high-dose corticosteroids, although some patients are steroid-refractory. Through the present study, we compared the endothelial proteomic profiles in response to serum from steroid-refractory acute GVHD (SR-aGVHD) and steroid-sensitive acute GVHD (SS-aGVHD) patients. Blood samples from SR-aGVHD (n= 4) and SS-aGVHD (n= 8) patients were collected at aGVHD diagnosis. Endothelial cell cultures were exposed (48 h) to patients' serum. Protein extraction and proteomic analysis were performed. Differences were statistically evaluated by multivariate analysis. Forty-four proteins contributed to separate all samples into the two study groups, among which 15 participated significantly (p< 0.05), 10 exhibiting a fold change >1.2. Differentially expressed proteins were mainly associated with oxidative phosphorylation (Cytochrome C oxidase subunit 6B1, CX6B1), inflammation and angiogenesis (Apolipoprotein D, APOD), cell survival (Rapamycin-insensitive companion of mTOR, RICTR), and oxidative stress (Riboflavin kinase, RIFK). This pilot study used a novel approach to distinguish the aGVHD response to steroid treatment. The proteins differentially expressed could constitute potential biomarkers for steroid-treatment response. These findings signify a step forward to identify the mechanisms of response to steroids, of high clinical relevance considering the SR-aGVHD elevated mortality.

Establishment and validation of clinical prediction model for steroid-resistant nephrotic syndrome in children

Objective: To identify the clinically relevant factors of steroid-resistant nephrotic syndrome (SSNS) in children and establish a predictive model followed by verifying its feasibility. Methods: A retrospective analysis was performed in a total of 111 children with nephrotic syndrome admitted to Children's Hospital of ShanXi from January 2016 to December 2021. The clinical data of general conditions, manifestations, laboratory tests, treatment, and prognosis were collected. According to the steroid response, patients were divided into SSNS and steroid resistant nephrotic syndrome (SRNS) group. Single factor Logistic regression analysis was used for comparison between the 2 groups, and variables with statistically significant differences were included in multivariate Logistic regression analysis. The multivariate Logistic regression analysis was used to identify the related variables of children with SRNS. The area under the receiver operating characteristic curve (ROC), the calibration curve and the clinical decision curve were used to evaluate its effectiveness of the variables. Results: Totally 111 children with nephrotic syndrome was composed of 66 boys and 45 girls, aged 3.2 (2.0, 6.6) years. There were 65 patients in the SSNS group and 46 in the SRNS group.Univariate Logistic regression analysis showed that the 6 variables, including erythrocyte sedimentation rate, 25-hydroxyvitamin D, suppressor T cells, D-dimer, fibrin degradation products, β2-microglobulin, had statistically significant differences between SSNS and SRNS groups (85 (52, 104) vs. 105 (85, 120) mm/1 h, 18 (12, 39) vs. 16 (12, 25) nmol/L, 0.23 (0.19, 0.27) vs. 0.25 (0.20, 0.31), 0.7 (0.6, 1.1) vs. 1.1 (0.9, 1.7) g/L, 3.1 (2.3, 4.1) vs. 3.3 (2.7, 5.8) g/L, 2.3 (1.9,2.8) vs. 3.0 (2.5, 3.7) g/L, χ2=3.73, -2.42, 2.24, 3.38, 2.24,3.93,all P<0.05), were included in the multivariate Logistic regression analysis. Finally, we found that 4 variables including erythrocyte sedimentation rate, suppressor T cells, D-dimer and β2-microglobulin (OR=1.02, 1.12, 25.61, 3.38, 95%CI 1.00-1.04, 1.03-1.22, 1.92-341.04, 1.65-6.94, all P<0.05) had significant correlation with SRNS. The optimal prediction model was selected. The ROC curve cut-off=0.38, with the sensitivity of 0.83, the specificity of 0.77 and area under curve of 0.87. The calibration curve showed that the predicted probability of SRNS group occurrence was in good agreement with the actual occurrence probability, χ2=9.12, P=0.426. The clinical decision curve showed good clinical applicability. The net benefit is up to 0.2. Make the nomogram. Conclusions: The prediction model based on the 4 identified risk factors including erythrocyte sedimentation rate, suppressor T cells, D-dimer and β2-microglobulin was suitable for the early diagnosis and prediction of SRNS in children. The prediction effect was promising in clinical application.

Rapamycin Restores Different Patterns of Cytokine Expression to Dexamethasone Treatment on CD14++CD16+ Monocytes from Steroid-Resistant Asthma Patients.

We aimed to investigate the differences in interleukin (IL)-10, IL-1β, IL-6, and tumor necrosis factor (TNF)-α expression in lipopolysaccharide (LPS)-stimulated CD14++CD16+ monocytes obtained from asthmatics after dexamethasone or dexamethasone plus rapamycin treatments between clinical steroid responders (R) and non-responders (NR). Cytokine expressions in LPS-stimulated CD14++CD16+ p-mammalian target of rapamycin (mTOR) monocytes from R and NR were determined using flow cytometry. IL-10high CD14++CD16+ p-mTOR population following LPS stimulation increased in the R group although decreased in the NR group with dexamethasone treatment. IL-1βhigh population decreased in the R group although increased in the NR group. Rapamycin treatment after LPS and dexamethasone resulted in a significant increase in the IL-10high population and a significant decrease in the IL-1βhigh population in the NR group. Dexamethasone treatment resulted in different patterns of change in cytokine expressions in LPS-stimulated CD14++CD16+ p-mTOR monocytes between the R and NR. mTOR inhibition can restore steroid responsiveness involving IL-10 and IL-1β in CD14++CD16+ p-mTOR monocytes.

Modeling the Effects of Cypermethrin Toxicity on Ovalbumin-Induced Allergic Pneumonitis Rats: Macrophage Phenotype Differentiation and p38/STAT6 Signaling Are Candidate Targets of Pirfenidone Treatment

Although the classic form of asthma is characterized by chronic pneumonitis with eosinophil infiltration and steroid responsivity, asthma has multifactorial pathogenesis and various clinical phenotypes. Previous studies strongly suggested that chemical exposure could influence the severity and course of asthma and reduce its steroid responsiveness. Cypermethrin (CYP), a common pesticide used in agriculture, was investigated for the possible aggravation of the ovalbumin (OVA)-induced allergic pneumonitis and the possible induction of steroid resistance in rats. Additionally, it was investigated whether pirfenidone (PFD) could substitute dexamethasone, as an alternative treatment option, for the induced steroid resistance. Fifty-six male Wistar albino rats were randomly divided into seven groups: control, PFD alone, allergic pneumonitis, CYP alone, allergic pneumonitis/CYP-exposed, allergic pneumonitis/CYP/dexamethasone (Dex), and allergic pneumonitis/CYP/PFD-treated groups. Allergic pneumonitis was induced by three intraperitoneal OVA injections administered once a week, followed by an intranasal OVA instillation challenge. CYP (25 mg/kg/d), Dex (1 mg/kg/d), and PFD (100 mg/kg/d) were administered orally from day 15 to the end of the experiment. Bronchoalveolar lavage fluid (BALF) was analyzed for cytokine levels. Hematoxylin and eosin (H&E) and periodic acid Schiff (PAS)-stained lung sections were prepared. Immunohistochemical identification of p38 MAPK and lung macrophages was performed. The inflammatory/oxidative status of the lung and PCR-quantification of the STAT6, p38 MAPK, MUC5AC, and IL-13 genes were carried out. The allergic pneumonitis-only group showed eosinophil-mediated inflammation (p < 0.05). Further CYP exposure aggravated lung inflammation and showed steroid-resistant changes, p38 activation, neutrophil-mediated, M1 macrophage-related inflammation (p < 0.05). All changes were reversed (p < 0.05) by PFD, meanwhile not by dexamethasone treatment. Pirfenidone could replace dexamethasone treatment in the current rat model of CYP-induced severe steroid-resistant asthma via inhibiting the M1 macrophage differentiation through modulation of the STAT6/p38 MAPK pathway.

A242 DELAYED STEROID TAPER MAY REDUCE RISK OF RELAPSE IN PATIENTS WITH IMMUNE CHECKPOINT INHIBITOR ASSOCIATED HEPATOTOXICIT

Abstract Background Immune checkpoint inhibitors (ICI) have become the cornerstone of treatment of certain malignancies. However, they can result in systemic toxicities including hepatitis. Societal guidelines recommend initial management with high dose steroids, then a slow taper as hepatitis resolves. However, there is significant variation in steroid response with some patients experiencing a relapse of hepatitis as steroid doses are tapered (“steroid relapse”). Purpose Identify clinical features that predict relapse, and to explore variations in steroid management, in patients with ICI hepatotoxicity. Method Patients receiving ICI in early phase clinical trials at Princess Margaret Cancer Centre, or treated at the Toronto Centre for Liver Disease for ICI hepatotoxicity, were included. Patients with CTCAE Grade (G)3 ICI hepatotoxicity (ALT &amp;gt;5 x ULN) were identified and clinical records reviewed for management and outcomes. Patients with an alternate cause for ALT elevation; who did not receive corticosteroids; or with HCC or viral hepatitis, were excluded. Result(s) Between August 2012 and December 2021, 36 patients with G3 ICI hepatotoxicity were identified. Most (23; 64%) had metastatic melanoma. Thirteen received anti-CTLA-4/PD-1; 18 anti-PD-1 or anti-PD-L1, and 5 anti-CTLA-4 monotherapy. All patients initially received corticosteroids (1-2mg/kg/day methylprednisone equivalent). Thirteen patients (36%) were steroid relapsers. Consistent steroid response was seen in 18 (50%). Age, sex, liver metastases, prior ICI exposure, peak ALT or starting dose of steroids (≤1.5 vs &amp;gt;1.5mg/kg/day methylprednisolone equivalents) did not predict relapse, although relapsers were more likely to have been treated with combination anti-CTLA-4/PD-1 (7 (54%) relapsers, vs 3 (16%) responders, p = 0.02). Relapse occurred after a median of 14.5 days (range 8-111), and after taper to median 54% (5-100) of initial steroid dose. In responders, ALT normalisation occurred after median 14 days (range 3-56). In 27 patients where sufficient data were available, societal guidelines on ALT thresholds to initiate steroid taper were followed in 13 (48%; 6 relapsers and 7 responders). However, initiation of steroid taper was delayed in responders compared to relapsers (after median 7 days (2-15) in responders vs 4 days (range 2-9) in relapsers, p = 0.04). Overall, 5 relapsers responded to re-escalation of steroids. Eight required additional treatment with MMF, and 4 required 3rd line therapy with Tacrolimus. Ultimately, hepatitis resolved in all patients. Conclusion(s) In patients with ICI hepatotoxicity, combination ICI therapy confers a higher risk of steroid relapse than monotherapy. There is significant heterogeneity in management of steroid dosing in patients with ICI hepatotoxicity. Delayed initiation of steroid taper may be associated with a reduced risk of relapse and warrants prospective evaluation as part of a standardised management algorithm. Please acknowledge all funding agencies by checking the applicable boxes below None Disclosure of Interest None Declared

A205 EVALUATING THE ASSOCIATION BETWEEN PERIPHERAL BLOOD EOSINOPHILS AND DRUG RESPONSE IN CROHN'S DISEASE: CONTINUING ANALYSIS

Abstract Background Th2 cytokines, IL-5 and IL-13 enhance peripheral and mucosal eosinophil survival, recruitment and degranulation, facilitating inflammation in Crohn's Disease. In a preliminary analysis, peripheral eosinophilia (PBE) is seen to have an association with rates of steroid response and anti-TNF response in CD patients. Participants with high PBE (&amp;gt; 200 cells/μL) appear to be more steroid-responsive but less responsive to Th1-targeting anti-TNF therapies. We hypothesize the pattern of PBE at CD diagnosis can help identify distinct subsets within a larger CD population and correlate with response to treatments such as prednisone or anti-TNFs. Purpose We aim to evaluate the pattern of PBE of CD patients at time of diagnosis (prior to drug exposure) and with each subsequent treatment; and if baseline PBE or any changes seen with drug exposures are predictive of treatment response. Method A retrospective cohort study is ongoing with CD patients exposed to glucocorticoids and an anti-TNF seen at 3 hospitals affiliated with University of Western Ontario. Patients were identified using administrative databases and reviewed for biochemical data (complete blood count) and disease activity (Harvey Bradshaw Index) at baseline, before and after each drug exposure. Participants were classified as having high PBE (eosinophils&amp;gt;200 cells/μL) versus low PBE (eosinophils &amp;lt;200 cells/μL). To date, 350 patients have been screened. Subgroup analyses of PBE &amp;gt; 300 cells/μL, and differences between female and male patients will be carried out. Result(s) 46 of 200 CD patients are included in the continuing analysis with a mean age of 45 years. 26 had PBE &amp;gt;200 cells/μL at baseline and 20 did not. The median number therapies used was 4 (IQR=0.75). All received glucocorticoids followed by an anti-TNF. There was no difference in the occurrence of hospitalization or surgery between the two groups. Overall 50% participants with high PBE &amp;gt;200 and &amp;gt;300 cells/μL had clinical response to glucocorticoid exposure, seen as a 3-point decrease in HBI compared to 45%, 47% in the low PBE cohort (n=13/26 vs. n=9/20 p=0.77; n=6/12 vs. n=16/34 p=1.0 respectively). With subsequent anti-TNF exposure, PBE rebounded in 7 participants. 36% patients in the high PBE group required anti-TNF dose escalation versus 24% in the low PBE group (n=9/25 vs. n=5/21, p=0.52). The proportion of patients with anti-TNF discontinuation was similar in both groups (high PBE 19.2%, n=5/26 vs. low PBE 15%, n=3/20, p=1.0). Men had higher steroid response rates compared to women in both high and low PBE groups (n=6/8 vs. n=8/18 p=0.21; n=4/9 vs. 4/11 p=1.0 respectively). Conclusion(s) Peripheral eosinophilia is seen in varying degrees in CD patients. Participants with high PBE are more steroid-responsive. High PBE patients overall were less responsive to anti-TNF therapies, requiring more dose-escalation and discontinued anti-TNF treatment. Completion of this study will help clarify the association between PBE in CD and treatment response. Please acknowledge all funding agencies by checking the applicable boxes below None Disclosure of Interest None Declared

Commentary: Consensual ophthalmotonic reaction.

Intraocular pressure (IOP) change in the untreated fellow eye accompanied by a corresponding IOP reduction in the operated eye has been identified as the “consensual ophthalmotonic reaction” (COR), and the terminology was coined by Weekers in 1924.[1] This response was initially observed after contusion, ocular compression, tonography, and cauterization of the sclera.[2] In 1927, Wilmer published the first report on COR after a fistulating surgery in experimental animals.[3] After that, multiple studies have reported the possibility of IOP variation in the fellow eye following unilateral glaucoma surgery, including not only trabeculectomy, but glaucoma drainage device implantations, filtering canaloplasty, and microshunt implantations as well.[4] However, whether there is an IOP increase, decrease, or no change in the fellow eye after glaucoma surgery is still controversial. These contrasting results could be due to differences in the type of glaucoma, preoperative IOP, surgical technique, antimetabolite dosage and duration, time point of observation, and outflow facility of the untreated fellow eye. The postulated mechanisms behind COR include neuronal, hormonal, and cytokine regulation of aqueous flow dynamics.[5] Nevertheless, the exact mechanism is yet to be elucidated. A decrease in IOP in the fellow eye could be associated with improved patient compliance to the antiglaucoma therapy or the effect of systemic absorption of the medications. Also, it could result from a “regression to the mean” effect, as trabeculectomy is often planned when the IOP is high on the variation curve.[6] Regarding COR with topical medications, Newman et al.[7] observed that the IOP reduction in contralateral eyes was found to be associated with timolol only and not prostaglandins or carbonic anhydrase inhibitors. A similar decrease in IOP in the fellow eye has also been reported after laser trabeculoplasty, which might be due to the effects of the systemic release of humoral agents, such as matrix metalloproteinase, and improved medication compliance.[8] An increase in the fellow eye IOP following glaucoma surgery has been observed in the present study. We have also observed an IOP rise in a significant number of patients in the unoperated eye in the early postoperative period after unilateral trabeculectomy, though we do not have published data. Different theories have been postulated that may explain this finding. Weekers[1] explained the possible existence of COR in which activation of the nervous system increased the fellow eye aqueous production. Diestelhorst and Krieglstein[5] also postulated that unilateral filtration surgery triggers a central nervous system-mediated reflective increase in aqueous flow in the unoperated fellow eye to maintain physiological stability. In an animal experiment, a supraoptic controlling pathway has been suggested to lead to an IOP rise in response to water drinking after unilateral optic nerve sections.[9] A few studies described that underperfusion of the trabecular meshwork by aqueous humor in the operated eye and increased extracellular trabecular meshwork material deposition induces a reflex mechanism mediated by specialized cells in the scleral spur that can lead to decreased outflow in the fellow eye.[10] Another hypothesis was an increase in the prostaglandin level in response to the inflammation in the operated eye.[11] Other possible explanations include a postoperative presumed steroid response or withdrawal of antiglaucoma medications.[12] No studies have attributed the increase in IOP in the fellow eye to one factor. In the literature, post-surgical COR is found to occur at an earlier time frame than post-laser COR, which might suggest the role of mechanical triggers rather than chemical triggers in post-surgical COR. The predominance of one mechanism occurring due to a particular intervention may guide the IOP varia tion in the contralateral eye. Further prospective studies and a much more detailed macroscopic overview are needed to delineate the underlying mechanisms and the exact biological role of post-surgical COR. The take-home message is that the fellow eye needs to be carefully monitored after unilateral glaucoma surgery. The fellow eye may be the only eye with vision or the better eye of the two. Also, fellow eyes may be already glaucomatous, that failure to monitor and recognize IOP rise may delay appropriate management leading to glaucoma progression. It is recommended to inform the patient about the possibility of IOP variation in the other eye after glaucoma surgery and the need for multiple visits, especially in the early postoperative period. Another relevant message is that the fellow eyes should not be preferably used as a control in studies assessing the IOP outcomes of a particular treatment or intervention.

Circumferential (360°) trabeculotomy for steroid-induced glaucoma in adults

PurposeTo evaluate the safety and efficacy of 360° circumferential trabeculotomy (TO) for steroid induced glaucoma (SIG) of short duration.MethodsRetrospective analysis of surgical results of 46 eyes of 35 patients undergoing microcatheter-assisted TO. All eyes had high intraocular pressure for at most about 3 years due to steroid use. Follow-up was between 2.63 and 47.9 months (mean 23.9, median 25.6).ResultsIntraocular pressure (IOP) before surgery was 30.8 ± 8.3 mm Hg, with 3.8 ± 1.0 pressure-lowering medications. After 1 to 2 years, mean IOP was 11.2 ± 2.6 mm Hg (n = 28); mean number of IOP-lowering medications was 0.9 ± 1.3. At their last follow-up, 45 eyes had an IOP < 21 mm Hg, and 39 eyes had an IOP < 18 mm Hg with or without medication. After 2 years, the estimated probability of having an IOP below 18 mm Hg (with or without medication) was 85 ± 6%, and the estimated probability of not using medication was 56 ± 7%. Steroid response was no longer present in all eyes receiving steroids after surgery. Minor complications consisted of hyphema, transient hypotony, or hypertony. One eye proceeded to receiving a glaucoma drainage implant.ConclusionTO is particularly effective in SIG with relative short duration. This concurs with the pathophysiology of the outflow system. This procedure seems particularly suited for eyes for which target pressures in the mid-teens are acceptable, particularly when chronic use of steroids is necessary.

Enhanced oxidative stress is associated with tissue neutrophilia and poor steroid response in chronic rhinosinusitis with nasal polyps.

To analyze the oxidative stress status and its association with tissue neutrophilia and oral steroid response in chronic rhinosinusitis with nasal polyps (CRSwNP) patients. The levels of total oxidant status (TOS) were detected in the sinonasal tissues by using specific assay kits. Tissue neutrophil was examined by immunohistochemical staining, and oxidant status index (OSI) was evaluated in polyps tissues, and the messenger RNA(mRNA) levels of superoxide dismutase 2(SOD2), aldehyde dehydrogenase 1(ALDH1A1), and microsomal glutathione S-transferase 1 (MGST1) were examined using quantitative real-time polymerase chain reactionin the sinonasal tissues. The receiver operating characteristics (ROCs) curve of ALDH1A1, MGST1, and SOD2 mRNA levels were evaluated to determine the steroid response of CRSwNP patients. The levels of TOS and OSI were significantly higher in CRSwNP and CRSsNP than in normal controls, and OSI in polyps tissues was positively associated with tissue neutrophilia and poor steroid response. The ALDH1A1, MGST1, and SOD2 mRNA levels showed comparable accuracy as predictors of poor steroid response indicated by thearea under the curve. These findings provided evidence that the increased level of oxidative stress contributes to enhanced tissue neutrophilia and poor steroid response in CRSwNP patients.