Partial Clinical Remission Research Articles

Postoperative outcome of special primary aldosteronism undergoing surgery based on adrenal vein sampling results

To further demonstrate the gold standard role of adrenal vein sampling (AVS) in the subtyping diagnosis of primary aldosteronism (PA). In this study, 9 patients with special PA, whose functional advantages indicated by AVS were contrary to the results of CT examination, were selected. Laparoscopic adrenalectomy was performed based on AVS results, and the surgical outcome was followed up. Nine patients, aged[M(Q1, Q3)] 58.0 (52.0, 63.0) years, including 7 males and 2 females, were followed up for 12 (9, 12) months. CT revealed unilateral morphological abnormalities in 5 cases (the functional advantage side indicated by AVS was contrary to the results of CT examination), and bilateral abnormalities in 4 cases (AVS results confirmed unilateral abnormalities). During the follow-up, all 9 patients achieved complete biochemical remission, 4 patients achieved complete clinical remission, and 5 patients achieved partial clinical remission. The study indicates that compared with CT imaging, AVS has better accuracy in PA subtyping, and selecting surgical side based on AVS results is a reliable and effective strategy.

An online tool using clinical factors to estimate the probability of partial clinical remission of adult-onset Type 1 diabetes

A type 1 diabetes (T1D) diagnosis is often followed by a period of reduced exogenous insulin requirement, with acceptable glucose control, called partial clinical remission (pCR). Various criteria exist to define pCR, which is associated with better clinical outcomes.We aimed to develop formulae and a related online calculator to predict the probability of pCR at 3- and 12-months post-T1D diagnosis.We analysed data from 133 adults at their T1D diagnosis (mean ± SD age: 27 ± 6 yrs., HbA1c 11.1 ± 2.0 %, 98 ± 22 mmol/mol), 3- and 12-months later. All patients were enrolled in the prospective observational InLipoDiab1 study (NCT02306005). We compared four definitions of pCR: 1) stimulated C-peptide >300 pmol/l; 2) insulin dose-adjusted HbA1c ≤9 %; 3) insulin dose <0.3 IU/kg/24 h; and HbA1c ≤6.4 % (46 mmol/mol); and 4) insulin dose <0.5 IU/kg/24 h and HbA1c <7 % (53 mmol/mol). Using readily available demographics and clinical chemistry data exhaustive search methodology was used to model pCR probability.There was low concordance between pCR definitions (kappa 0.10). The combination of age, HbA1c, diastolic blood pressure, triglycerides and smoking at T1D onset predicted pCR at 12-months with an area under the curve (AUC) = 0.87. HbA1c, triglycerides and insulin dose 3-mths post-diagnosis had an AUC = 0.89. A related calculator for pCR in adult-onset T1D is available at http://www.bit.ly/T1D-partial-remission.

Partial Clinical Remission of Type 1 Diabetes in Swedish Children: A Longitudinal Study from the Swedish National Quality Register (SWEDIABKIDS) and the Better Diabetes Diagnosis (BDD) Study.

Aims/Hypotheses: To investigate the frequency and characteristics of partial remission in Swedish children with type 1 diabetes and whether the insulin delivery method, that is, continuous subcutaneous insulin infusion (CSII) or multiple daily injections (MDIs), affects incidence and duration of this period, 2007-2011. Factors that increase the proportion of subjects who enter partial remission and extend this period can improve long-term metabolic control and reduce the risk of severe hypoglycemia, improve quality of life, and, in the long run, reduce late complications. Methods: Longitudinal data from 2007 to 2020 were extracted from the Swedish National Quality Register (SWEDIABKIDS) with all reported newly diagnosed children. Data on C-peptide from the participants in the Better Diabetes Diagnosis study from 2007 to 2010 were used. The definition of partial remission was insulin dose-adjusted HbA1c: HbA1c (%) + [4 × total daily insulin dose (U/kg/day)] ≤9. Results: Of the 3887 patients, 56% were boys. More boys than girls were in partial remission throughout the follow-up period until 24 months after diabetes onset. Fewer children 0-6 years old had partial remission at 3 and 12 months but not at 24 months compared with older age-groups. A larger proportion of patients using CSII at 12 and 24 months remained in partial remission compared with those with MDI (37% vs. 33%, P = 0.02 and 31% vs. 27%, P = 0.01, respectively). The level of C-peptide was higher in the group with partial remission and mean HbA1c was lower (both P < 0.001). Partial remission at 12 months after diabetes onset was associated with CSII (odds ratio [OR]: 1.39, confidence interval [CI]:1.13, 1.71), shorter diabetes duration (OR: 0.80, CI: 0.76, 0.84), and male sex (OR: 1.23, CI: 1.04, 1.46). Conclusions/Interpretation: Insulin through MDI, longer duration of diabetes, and female sex were associated with lower frequency of partial remission. Use of CSII seems to contribute to longer partial remission among Swedish children with type 1 diabetes.

Evaluation of type 1 diabetes’ partial clinical remission after three years of heterologous adipose tissue derived stromal/stem cells transplantation associated with vitamin D supplementation

BackgroundMesenchymal stem cell infusion and vitamin D supplementation may have immunomodulatory actions that could prolong the preservation of residual insulin secretion in patients with type 1 diabetes (T1D). Intervention with these agents after onset of T1D could favor the development of a remission phase, with potential clinical impact. We aimed to compare the presence of clinical remission (CR), glycemic control and daily insulin requirement at 6, 12, 18, 24 and 36 months after the diagnosis of T1D using IDAA1c in patients who received therapy with adipose tissue-derived mesenchymal stem cell (ASC) infusion and vitamin D supplementation and a control group. Methods: This retrospective cohort study analyzed data from the medical records of patients with T1D diagnosed between 15 and 40 years. Partial CR was defined as an IDAA1c index < 9. Patients in the intervention group received an infusion of adipose tissued-derived mesenchymal stem cells (ASCs) within 3 months after diagnosis and supplementation with 2000 IU of cholecalciferol for 1 year, started on the day following the infusion. Partial CR was also determined using the ISPAD criteria, to assess its agreement with IDAA1c. Results: A total of 28 patients were evaluated: 7 in the intervention group (group 1) and 21 in the control group (group 2). All patients in group 1 evolved with partial CR while only 46.7% of patients in group 2 had this outcome. Group 1 had a higher frequency of CR when evaluated with IDAA1c and ISPAD criteria. The mean duration of CR varied between the two criteria. Although HbA1c was similar between groups during follow-up, group 1 had a lower total daily insulin requirement (p < 0.005) at all time points. At 36 months, group 1 used 49% of the total daily insulin dose used by group 2 with similar glycemic control. Conclusion: The intervention with infusion of ASC + vitamin D supplementation was associated with partial CR at 6 months. Although there were no differences in CR established by the IDAA1c and ISPAD criteria after three years of follow-up, patients who underwent intervention had nearly the half insulin requirement of controls with conventional treatment, with similar glycemic control.Trial Registration37001514.0.0000.5257.

#2875 Experience in the use of plasmapheresis as a therapeutic tool in acute pathologies in a tertiary level hospital

Abstract Background and Aims Apheresis is a therapeutic modality which purpose is the elimination from plasma of the pathogenic components of a disease or its clinical manifestations. Plasmapheresis is an apheresis technique used in the treatment of various diseases with varying degrees of proven clinical efficacy. The aim of our work is to describe the experience in the use of plasmapheresis in different acute pathologies in our center, and if there are factors that favor the clinical response to treatment. Method Retrospective cohort study. We included plasmapheresis performed in the years 2017-2022. Variables such as age, sex, etiology, type of replacement performed, number of sessions, and American Society for Apheresis (ASFA) classification, among others, were collected. We defined response to treatment as partial or total clinical remission. Results We included 72 patients who received plasmapheresis during 2017-2022. Mean age 54 ± 18 years. 56.9% male. Disease etiology was neurological in 56.9%, nephrological in 36.1% and hematological in 6.9%. Between 2017-2019, 39.7% of the plasmapheresis were performed, while the remaining 60.3% were between 2020-2022. The number of sessions was 5.3 ± 2. 59.6% were performed with albumin, 29.2% with fresh frozen plasma and 13.9% with albumin and fresh frozen plasma. The ASFA indication was category I in 68.1%. 23.6% presented some complication, the most frequent being febrile in 6.9%, systemic infection and allergic reaction in 5.6%. A response to treatment was observed in 75%. Antibodies were positive before starting plasmapheresis in 29.2%, decreasing to 16.7% 3 months after treatment. There was recurrence in 19.4%, 16.7% received more cycles of plasmapheresis and there was 11.1% mortality due to disease. In patients with response to treatment, a higher percentage of response was observed in those diseases of non-nephrological origin (70.4% vs. 29.6%, p 0.04), lower percentage of complications (16.7% vs. 83.3%, p 0.01) and lower mortality associated with the disease (3.7% vs. 96.3%, p 0.001). Conclusion Plasmapheresis is a therapeutic plasma exchange technique that is increasingly used in our hospital, with a greater increase in recent years. It is a therapeutic option that should be considered in many occasions as first line or adjuvant treatment, with a low rate of complications and clinical improvement in most patients. Despite this, studies with a larger number of patients are required to increase and consolidate the existing evidence on the use of these procedures.

#992 Protocol based on PLA2R1 epitope recognition is superior to standard protocol in achieving remission in PLA2R1-associated membranous nephropathy

Abstract Background and Aims Membranous nephropathy (MN) is a rare, but severe autoimmune disease affecting kidney glomeruli. Clinical evolution is variable, ranging from spontaneous remission to persistent nephrotic syndrome and kidney failure. The major autoantigen in MN is PLA2R1 protein associated with 50-70% of all cases. Patients may present antibodies against a single immunodominant CysR domain or may develop additional antibodies against CTLD1 and/or CTLD7 and/or CTLD8 domains of PLA2R1 defining a cascade immunization or epitope spreading. The mechanism of epitope spreading has been described in a variety of contexts: it can reinforce immune response to eliminate a pathogen, but can also be associated with the aggravation of autoantibody-mediated autoimmune pathologies. The value of this marker in the management of MN patients remains debated. Our initial study (confirmed on an independent cohort) has shown that the single domain recognition (non-spreader patients) is associated with a higher chance of spontaneous remission (45% vs 0.05% in GEMRITUX cohort) and a better response to treatment (100% of remission regardless of the dose of rituximab used). The patients with multi domain recognition (spreader patients) of CTLD1 and/or CTLD7 domains, on the other hand, have poor prognosis and are less likely to achieve remission requiring high doses of rituximab. Based on these studies we have proposed a personalized treatment protocol with either low or high dose Rituximab based on patients’ PLA2R1 epitope spreading status. The aim of this study was to evaluate the efficacy of this personalized treatment in comparison to the established GEMRITUX protocol. Method A multicenter, randomized, controlled, prospective clinical trial was conducted in 12 French hospitals. Sixty-four consecutive patients with PLA2R1-related MN were randomly assigned to either the control group following the GEMRITUX protocol (symptomatic treatment for 6 months, two 375 mg/m2 rituximab infusions at month-6 in case of persistent nephrotic syndrome (NS)) or the personalized treatment (PMMN) group (patients with no epitope spreading at month-0 were treated as per GEMRITUX protocol, while patients with epitope spreading at month-0 or month-6 with persistent NS were treated immediately with two 1 g rituximab infusions). The primary study outcome was the rate of clinical remission at month-12. The secondary outcomes were complete and partial remission, immunological remission, proteinuria, albuminuria, serum creatinine, and PLA2R1 antibody titer. Results From 64 patients included, three were excluded from final analyses due to loss to follow-up. There was no difference in age, gender, albumin, UPCR, anti-PLA2R1 titer and the rate of PLA2R1 epitope spreading at baseline between the two groups. At M12, 34% of patients from the GEMRITUX group and 69% of patients from PMMN group achieved partial clinical remission (P = .0105) defined as UPCR &amp;lt; 3.5 g/g with a decrease greater than 50% from baseline; improvement or normalization of serum albumin; and increase of serum creatinine lower than 20%. While there was no difference in remission rate between the GEMRITUX group and PMMN group for patients with single domain recognition (38% vs 50%, respectively, P = .7107), multi-domain recognizers (spreaders) were more likely to achieve remission with personalized protocol (36% vs. 87%, P = .0078). The rate of complete clinical remission between the two experimental groups, defined as UPCR &amp;lt;0.3 g/g and normal albumin, was close to statistical significance (0% vs 16%, P = .0538). Conclusion Personalized treatment protocol based on the stratification of patients with PLA2R1-related MN according to their epitope spreading status, is superior to the standard GEMRITUX protocol in achieving partial clinical remission at 12 months. Patients with multiple domain recognition should be treated immediately with high doses of rituximab to increase their chances of remission.

Unlocking the Long-Term Effectiveness of Benralizumab in Severe Eosinophilic Asthma: A Three-Year Real-Life Study.

Background: Benralizumab has been shown to restore good control of severe eosinophilic asthma (SEA). Robust data on benralizumab effectiveness over periods longer than 2 years are scarce. Methods: This retrospective multicentric study was conducted on 108 Italian SEA patients treated with benralizumab for up to 36 months. Partial and complete clinical remission (CR) were assessed. Data were analyzed with descriptive statistics or using linear, logistic, and negative binomial mixed-effect regression models. Results: At 36 months, benralizumab reduced the exacerbation rate by 89% and increased the forced expiratory volume in 1 second (FEV1) (+440 mL at 36 months, p < 0.0001). Benralizumab improved asthma control as well as sinonasal symptoms in patients with chronic rhinosinusitis with nasal polyposis (CRSwNP). Up to 93.33% of patients either reduced or discontinued OCS; benralizumab also decreased ICS use and other asthma medications. Overall, 84.31% of patients achieved partial or complete CR. Conclusions: Benralizumab improved asthma and sinonasal outcomes up to 36 months. These findings support the potential of benralizumab to induce CR, emphasizing its role as a disease-modifying anti-asthmatic drug for the management of SEA. Further research is warranted to expand these findings by minimizing data loss and assessing benralizumab's long-term safety.

Scoping review of end-of-life care for persons with anorexia nervosa.

End-of-life (EOL) care is the part of palliative care intended for persons nearing death. In anorexia nervosa (AN), providing EOL care instead of coercing life-sustaining measures is controversial. The existing literature has not been synthesized yet. To clearly delineate differing views and identify open questions as well as areas of possible consensus, we conducted the first-ever synthesis of the existing literature. We searched EMBASE, PubMed, PsycInfo, and Web of Science for scientific publications on forgoing coerced life-sustaining measures and/or providing EOL care for persons with AN who refuse life-sustaining measures, typically artificial nutrition. Palliative care outside of the EOL context and medical assistance in dying were not reviewed. As very little quantitative studies were identified, we qualitatively analyzed conceptual questions, ethical reasoning, legal aspects, stakeholder attitudes, practical aspects, stakeholder needs, and outcome. We identified 117 eligible publications from 1984 to 2023, mainly case reports (n=26 different cases) and ethical analyses. Conceptualizations of key terms such as terminality, futility, and decision-making capacity (DMC) in AN varied widely and were often value-laden and circular. Ethical reasoning centered on weighing the preservation of life versus quality of life in the context of uncertainty about DMC and likelihood of clinical remission. Studies on stakeholder attitudes reflected this challenge. In some cases, courts ruled against coerced life-sustaining measures and/or in favor of EOL care for persons with AN. While eligibility criteria were contested, recommendations for deliberating about and providing EOL care were consistent. We identified only one study on stakeholder needs and none on outcome. Case reports described quality of life under EOL care as good and death as the most frequent outcome but engagement in voluntary treatment and (partial) clinical remission in some. The debate around EOL care in AN needs consented, coherent terminology whose value base is reduced to a minimum and made transparent. While more empirical research into decision-making in AN and predictors of outcome might help reduce uncertainty, fundamental normative questions need to be addressed, for example regarding the ethico-legal significance of treatment refusals, the weighing of quantity versus quality of life and the appropriateness of diagnosis-based ethico-legal exceptionalism such as hard paternalism. More research is needed on outcome of and stakeholder needs in EOL care for persons with AN.

Approaches to Measuring Beta Cell Reserve and Defining Partial Clinical Remission in Paediatric Type 1 Diabetes.

Type 1 diabetes (T1D) results from the autoimmune T-cell mediated destruction of pancreatic beta cells leading to insufficient insulin secretion. At the time of diagnosis of T1D, there is residual beta cell function that declines over the subsequent months to years. Recent interventions have been approved to preserve beta cell function in evolving T1D. The aim of this review is to summarise the approaches used to assess residual beta cell function in evolving T1D, and to highlight potential future directions. Studies including subjects aged 0 to 18 years were included in this review. The following search terms were used; "(type 1 diabetes) and (partial remission)" and "(type 1 diabetes) and (honeymoon)". References of included studies were reviewed to determine if additional relevant studies were eligible. There are numerous approaches to quantifying beta cell reserve in evolving T1D. These include c-peptide measurement after a mixed meal or glucagon stimuli, fasting c-peptide, the urinary c-peptide/creatinine ratio, insulin dose-adjusted haemoglobin A1c, and other clinical models to estimate beta cell function. Other biomarkers may have a role, including the proinsulin/c-peptide ratio, cytokines, and microRNA. Studies using thresholds to determine if residual beta cell function is present often differ in values used to define remission. As interventions are approved to preserve beta cell function, it will become increasingly necessary to quantify residual beta cell function in research and clinical contexts. In this report, we have highlighted the strengths and limitations of the current approaches.

Muscle-to-fat ratio in children and adolescents with type 1 diabetes in predicting glycaemic control and partial clinical remission.

Advances in treatment could mitigate the expected adverse changes in the body composition of children and adolescents with type 1 diabetes (T1D). To examine the evolution of weight status and body composition and their association with glycaemic control and partial clinical remission in youth with T1D. Ninety-nine participants with T1D (median age 9.5 years [interquartile range 7.3, 12.9], 59.6% boys) were longitudinally followed for 3years since diagnosis. Data at seven pre-determined time points were extracted from medical files. Outcome measures included body mass index (BMI) z-scores, muscle-to-fat ratio (MFR) z-scores, haemoglobin A1c (HbA1c) levels, continuous glucose monitoring metrics, and insulin dose-adjusted HbA1c (IDAA1c) levels. The BMI z-scores increased significantly (p<0.001) for both sexes, with no significant change in MFR z-scores over time. The girls had higher BMI z-scores (p<0.001) and lower MFR z-scores than the boys (p=0.016). The mean HbA1c levels decreased during the first month and at 3months since diagnosis (p<0.001), then plateaued and achieved a median overall HbA1c of 7.1% for the entire cohort. At 12months, 37 participants (37.6%) were in partial clinical remission, as evidenced by IDAA1c≤9. The odds of partial clinical remission at 2years increased by 2.1-fold for each standard deviation increase in the MFR z-score (p<0.001). Higher MFR z-scores were associated with better metabolic control. Integration of body composition assessments could mitigate adverse body changes in paediatric patients with T1D.

A RANDOMIZED, PLACEBO-CONTROLLED TRIAL OF PSYLLIUM FIBER AND FECAL MICROBIOTA TRANSPLANTATION FOR MILD TO MODERATE ULCERATIVE COLITIS

Abstract BACKGROUND Emerging clinical data shows potential for fecal microbiota transplantation (FMT) in treating ulcerative colitis (UC), though factors affecting clinical response remain poorly defined. Pre-clinical data suggest the role of dietary fiber in enhancing microbial metabolites to mitigate colitis severity. This study aimed to evaluate the role of the prebiotic psyllium in improving the clinical outcomes of FMT for mild to moderate UC, with the long-term goal of enhancing FMT as a therapeutic strategy for UC. METHODS In a randomized, placebo-controlled clinical trial, 32 participants were screened, and 27 adults with mild to moderate UC were enrolled. Baseline fiber intake was assessed through a food frequency questionnaire. Subjects were randomly assigned to receive FMT alone, FMT with daily fiber (10g of psyllium), or a placebo with or without fiber. The primary endpoint was clinical response by Mayo score at week 8. Secondary endpoints included clinical response by partial Mayo (pMayo) score, endoscopic sub-score, and clinical remission. At week 8, participants underwent crossover treatment with clinical evaluation at week 12. The study ended early due to the manufacturer discontinuing fecal microbiota preparation supply. RESULTS Analysis of primary and secondary endpoints in "FMT alone" and "FMT with fiber" groups revealed no statistically significant differences in clinical response (55.56% alone, N=9 vs. 22.22% fiber, N=9, p=0.1686). Participants with low and high dietary fiber consumption had similar response rates, regardless of supplemental fiber. Consequently, we combined the "FMT" and "no FMT" groups, which showed a significantly higher proportion of subjects achieving clinical response in the FMT group as defined by the partial Mayo score (50.00% FMT group (N=18) and 11.1% in the no FMT group (N=9), p=0.0485). A similar trend was observed for clinical response as defined by the total Mayo score and endoscopic sub-score, where the FMT group outperformed the placebo (38.89% FMT, N=18, vs. 11.11% placebo, N=9, p=0.1362). Among the 9 subjects who received FMT at week 0 and exhibited clinical response defined by pMayo, 77.8% (n=7) maintained their response at week 12. Additionally, 2 patients who initially had no response at week 8 achieved a clinical response by week 12. CONCLUSION The results demonstrate a robust effect of single-dose FMT via colonoscopy in a mild to moderate UC cohort. Given the low cohort size, our results lack the statistical power to reveal the clinical impact of fiber supplementation in FMT. Notably, a substantial proportion of initially responsive FMT recipients maintained their clinical response at week 12, indicating the potential for sustained benefits. Microbiome and metabolomic analyses are currently underway to assess the functional impact of dietary fiber in shaping the effectiveness of FMT for UC.

P731 Relapse rate following withdrawal of anti-TNF therapy in patients with inflammatory bowel disease: A single-center experience

Abstract Background Discontinuation of anti–tumor necrosis factor alpha treatment (anti-TNFα) in patients with inflammatory bowel disease (IBD) poses a significant risk for relapse. The aim of this study is to analyze relapse rates and to possibly identify factors associated with relapse in IBD patients after treatment cessation with anti-TNFα. Methods This is a prospective study conducted at University Clinic of Gastroenterology in Albania from 2019-2022. IBD patients who discontinued biologic therapy with infliximab (IFX) or adalimumab (ADA) were included. All the patients discontinued therapy due to reimbursement issues. Demographic, clinical,laboratory and endoscopic data were collected for each patient. Relapse rates and predictors for relapse were studied using survival and Cox regression analysis. Results A total of 52 IBD patients, mean age 50.8±14.7 years (46 UC and 6 CD), 25(48%) males, were included in the study. Mean follow-up was 29 months. 47.4% were treated with ADA and 51.5 % with IFX. The mean period of biologic therapy was 33.3 months for all patients. Upon treatment cessation, 55.8% of patients were in complete clinical remission, and 30.8% were in partial clinical remission. Cumulative relapse rates at 6, 12, 24 and 36 months were 23.9%, 39.1%, 44.2% and 69.7% respectively for all UC patients while 66.7% of CD patients relapsed within 6 months. The mean time to relapse was 13 months for UC and 5 months for CD patients. Among all IBD patients in complete clinical remission at the time of treatment discontinuation, the cumulative relapse rates at 6, 12, 24 and 36 months, were: 6.9%, 24.8%, 57.7%, and 58% respectively. Significantly higher cumulative relapse rates were found in patients with partial remission, the at the same time points: 37.5%, 50%, 75%, and 81.2% respectively (p=0.01). Multivariable Cox analysis revealed that the only factor associated with lower risk of relapse was mucosal healing (vs nonmucosal healing: HR, 0.322; 95% CI, 1.26 to 6.677; p=0.012). Conclusion The majority of IBD patients relapsed within 3 years after anti TNFα discontinuation, Mucosal healing was the only factor associated with a lower risk of relapse. These results emphasise the crucial role of mucosal healing in guiding treatment decisions for IBD patients.

Clinical Remission in Patients Affected by Severe Eosinophilic Asthma on Dupilumab Therapy: A Long-Term Real-Life Study.

Background. Nowadays, highly selective biological drugs offer the possibility of treating severe type 2 asthma. However, in the real-life setting, it is crucial to confirm the validity of the chosen biological treatment by evaluating the achievement of clinical remission. Study purpose. The main aims of this real-life study were to evaluate the efficacy of dupilumab in terms of clinical, functional, and inflammatory outcomes at 6, 12, 18, and 24 months of treatment and to estimate the percentage of patients achieving partial or complete clinical remission at 12 and 24 months of treatment. In addition, we attempted to identify whether baseline clinical characteristics of patients could be associated with clinical remission at 24 months of treatment. Materials and methods. In this observational prospective study, 20 outpatients with severe uncontrolled eosinophilic asthma were prescribed dupilumab and followed-up after 6, 12, 18, and 24 months of treatment. At each patient visit, the need for oral corticosteroids (OCS) and corticosteroid required dose, number of exacerbations during the previous year or from the previous visit, asthma control test (ACT) score, pre-bronchodilator forced expiratory volume in the 1st second (FEV1), fractional exhaled nitric oxide at a flow rate of 50 mL/s (FeNO50), and blood eosinophil count were assessed. Results. The number of OCS-dependent patients was reduced from 10 (50%) at baseline to 5 (25%) at one year (T12) and 2 years (T24). The average dose of OCS required by patients demonstrated a significant reduction at T12 (12.5 ± 13.75 mg vs. 2.63 ± 3.94 mg, p = 0.015), remaining significant even at T24 (12.5 ± 13.75 mg vs. 2.63 ± 3.94 mg, p = 0.016). The number of exacerbators showed a statistically significant decrease at T24 (10 patients, 50% vs. 3 patients, 15%, p = 0.03). The mean number of exacerbations demonstrated a statistically significant reduction at T24 (1.45 ± 1.58 vs. 0.25 ± 0.43, p = 0.02). The ACT score improved in a statistically significant manner at T12 (15.30 ± 4.16 vs. 21.40 ± 2.35, p < 0.0001), improving further at T24 (15.30 ± 4.16 vs. 22.10 ± 2.59, p < 0.0001). The improvement in pre-bronchodilator FEV1 values reached statistical significance at T24 (79.5 ± 14.4 vs. 87.7 ± 13.8, p = 0.03). The reduction in flow at the level of the small airways (FEF25-75%) also demonstrated an improvement, although it did not reach statistical significance either at T12 or T24. A total of 11 patients (55%) showed clinical remission at T12 (6 complete + 5 partial) and 12 patients (60%) reached clinical remission at T24 (9 complete + 3 partial). Only obesity was associated with a negative odds ratio (OR) for achieving clinical remission at T24 (OR: 0.03, 95% CI: 0.002-0.41, p = 0.004). No other statistically significant differences in baseline characteristics emerged between patients who reached clinical remission at T24 and the group of patients who did not achieve this outcome. Conclusion. Dupilumab appears to be an effective drug in promoting achievement of clinical remission in patients with severe uncontrolled eosinophilic asthma. The achievement of clinical remission should be continuously evaluated during treatment. Further studies are needed to clarify whether certain baseline clinical characteristics can help predict dupilumab favorable outcomes.

Analiza učestalosti i dužine trajanja kliničke remisije u pacijenata sa novootkrivenim tipom 1 dijabetesa

Introduction: Clinical remission (CR) phase, in other words, euglycaemia, in the absence of insulin therapy (complete CR) or with a reduced daily dose of insulin (partial CR) can be achieved in some patients with new-onset type 1 diabetes (T1D) after the introduction of insulin therapy. Unfortunately, there is still not enough information about the factors influencing the induction and duration of remission. Material and methods: This research included 62 patients with the diagnosis of new-onset T1D, who were treated at the Clinic of Endocrinology, Diabetes and Metabolic Diseases, University Clinical Centre of Serbia in 2019 and 2020. Demographic, clinical and laboratory data were acquired from medical records. Descriptive statistical methods, Fisher's exact probability test, Pearson's chi-square test, Student's t test, Mann Whitney U test and Spearman's correlation coefficient were used for statistical analysis. Results: Clinical remission was inducted in 46.8% of patients and its average duration was 11.2 months. Patients with CR had remarkably lower HbA1c values (9.9 ± 2.8 vs 11.8 ± 2.4%; p=0.007) and lost less weight (4 vs 12 kg, p&lt;0.001) compared to patients without CR. Additionally, C peptide levels at the beginning and 6 minutes after the glucagon test were remarkably higher in patients with CR compared to patients without CR (p&lt;0.001). At the same time, remarkably more patients with CR had autoantibodies detected compared to those without CR (GAD 100% vs 72.4% i IA2-2A 81.8% vs 34.5%; p=0.001). The duration of CR was remarkably correlated with the level of C peptide at the beginning and 6 minutes after the glucagon test (p&lt;0.001). Conclusion: Patients with CR (46.8%) had better metabolic control, less weight loss, better endogenous insulin reserve capacity and less frequent presence of autoantibodies to beta cell antigens at disease onset. At the same time, the duration of CR was associated with an initially better, preserved, endogenous insulin reserve.

Better Cardiorespiratory Fitness Defined as VO2max Increases the Chance of Partial Clinical Remission and Prolongs Remission Duration in People with Newly Diagnosed Type 1 Diabetes.

An essential process affecting the course of type 1 diabetes (DM1) is the appearance and duration of clinical remission. One of the most important factors promoting the occurrence of remission is physical activity, due to increased activity of antioxidants, reduces insulin resistance and improves glucose transport. Maximal oxygen capacity (VO2max) is an objective measure of the body's aerobic capacity. To assess VO2max, oxygen uptake should be measured directly during the exercise test. The aim of the study was to evaluate the physical capacity in adults with DM1 and its relationship with the occurrence of partial clinical remission (pCR) during 2 years follow-up. The pCR was assessed by the following mathematical formula: A1c (%) + [4 × insulin dose (U/kg/d)]. The result ⩽9 indicates pCR. VO2max was assessed between 6th and 24th month of diabetes duration using an ergospirometer (COSMED K5 System), during an exercise test carried out on a cycloergometer (RAMP incremental exercise test). The study group consisted of 32 adults with DM1. People with pCR were proved to have higher VO2max level [36.0 (33.0-41.5) vs 30.9 (26.5-34.4) ml/min/kg, P = .009. Univariate and multivariate regression confirmed a significant association between VO2max and presence of pCR [AOR 1.26 (1.05-1.52), P = .015]. Duration of remission was longer among group with higher VO2max results [15 (9-24) vs 9 (0-12) months, P = .043]. The positive relationship was observed between diabetes duration and VO2max (rs = 0.484, P = .005). Multivariate linear regression confirms a significant association between remission duration and VO2max (ml/min/kg) (β = 0.595, P = .002). The higher VO2max, the better chance of partial clinical remission at 2 years of DM1 and longer duration of remission.

FRI593 Ergocalciferol And Pancreatic β-Cell Function In New-onset Type 1 Diabetes: A Randomized Controlled Trial

Abstract Disclosure: B.U. Nwosu: None. S. Parajuli: None. R. Sharma: None. B.A. Barton: None. A.F. Lee: None. Background: The impact of high-dose vitamin D (ergocalciferol) on pancreatic β-cell function in youth with newly diagnosed type 1 diabetes (T1D) is unclear. Objective: To determine the effect of ergocalciferol on residual pancreatic β-cell function (RBCF) in youth with newly diagnosed T1D. Hypothesis: Ergocalciferol supplementation increases RBCF and prolongs the partial clinical remission (PR) phase of T1D. Design, Setting, and Participants: This 12-month randomized, double-blind, placebo-controlled trial of youth aged 10-21 years with newly diagnosed T1D of &amp;lt;3mo was conducted at a single center in the US between October 19, 2017 through April 20, 2021. Interventions: Participants were randomized 1:1 to once weekly dose of 50,000 IU of ergocalciferol for 2 months, and then once every 2 weeks for 10 months, versus placebo. Main outcomes and measures: The primary outcome was the percentage change from baseline in the area under the curve (AUC) of stimulated C-peptide over 12 months. Results: Thirty-six subjects were randomized to either the ergocalciferol arm: n=18, mean age 13.3±SD2.8 years, with 10 male and 8 female subjects; or to the placebo arm: n=18, mean age 14.3±2.9 years, with 14 male and 4 female subjects. Ergocalciferol significantly reduced the temporal trends in both the A1c (p=0.04) and the insulin-dose adjusted A1c (IDAA1c) (p=0.02), and the overall group means for IDAA1c versus placebo (p=0.02). A random intercept model, adjusted for age, sex, and race, showed that the percentage change in AUC C-peptide from baseline through the 12-month study period declined in both arms of the study. Specifically, by 28.4 ± 6.2 (p&amp;lt;.0001) in the ergocalciferol arm and by 41.5 ± 5.9 (p&amp;lt;.0001) in the placebo arm, with the decline in the ergocalciferol arm being significantly slower than that in the placebo arm, p=0.029 for the difference in the slopes of the trends between the two arms. There were no adverse events. Conclusion: High-dose ergocalciferol significantly slowed the rate of decline in C-peptide compared to placebo in children and adolescents with T1D. Presentation: Friday, June 16, 2023

1282-P: Interactive Tool to Estimate Probability of Partial Clinical Remission in Adult-Onset Type 1 Diabetes

Introduction: Type 1 diabetes (T1D) diagnosis is often (in adults) followed by a (‘honeymoon’) period of reduced insulin need, also called partial clinical remission (pCR), which is associated with better outcomes. Various definitions of pCR exist. Aim: To create an online calculator to predict probability of pCR in adult-onset T1D 12-mths post-diagnosis. Methods: We analysed data from 133 adults at T1D diagnosis (mean±SD age: 27±6, HbA1c: 11.1±2.0%, BMI: 22.5±3.7 kg/m2), 3-mths and 12-mths later. All were enrolled in the prospective observational InLipODiab (NCT02306005) study. We used 4 definitions for pCR 12-mths post-diagnosis: 1) insulin dose-adjusted HbA1c≤9%; 2) insulin dose&amp;lt;0.3U/kg/24h and HbA1c≤6.4%; 3) insulin dose&amp;lt;0.5U/kg/24h and HbA1c&amp;lt;7%; 4) stimulated C-peptide &amp;gt;300pmol/L. Exhaustive search was used to find the best models (based on AIC) based on usually available data at diagnosis and 3-mths. Calculator (Figure 1) available at http://www.bit.ly/T1D-partial-remission. Results: There was low concordance between pCR definitions (Cohen’s weighted kappa 0.01-0.61.) Combination of age, HbA1c, diastolic BP, triglycerides and smoking at T1D onset predicted pCR (12-mths) with AUC=0.84. HbA1c, triglycerides and insulin dose 3-mths post-diagnosis had an AUC=0.89. Conclusion: A new online calculator can predict pCR in adult-onset T1D for clinical and research use. Disclosure A.Grzelka-wozniak: None. A.S.Januszewski: None. J.Flotynska: None. A.Jenkins: Advisory Panel; Insulet Corporation, Board Member; Insulin for Life, Research Support; Abbott Diabetes, Medtronic, Hemsley Charitable Trust, Juvenile Diabetes Research Foundation (JDRF), National Institutes of Health. D.Zozulinska-ziolkiewicz: Advisory Panel; Abbott, Lilly, Lilly, Novo Nordisk, Medtronic, Speaker's Bureau; Abbott, Ascensia Diabetes Care, Novo Nordisk, Medtronic, Boehringer-Ingelheim, AstraZeneca. A.Uruska: Other Relationship; Lilly, Boehringer-Ingelheim, AstraZeneca, Ascensia Diabetes Care, Sanofi.

Outcomes and experiences of families with children with type 1 diabetes on insulin pumps through subsidised pump access programs in Western Australia.

In Australia, access to insulin pump therapy for children with type 1 diabetes (T1D) is predominantly restricted to families with private health insurance. In an attempt to improve equity, additional subsidised pathways exist which provide pumps to families with reduced financial resources. We aimed to describe the outcomes and experiences of families with children commenced on pumps through these subsidised pathways in Western Australia (WA). Children with T1D in WA who did not have private health insurance and received pumps from the subsidised pump programs between January 2016 and December 2020 were included. Study 1 was designed to review glycaemic outcome. A retrospective analysis of HbA1c was conducted in the whole cohort and in children who commenced pump after the first year of diagnosis to exclude the impact of the partial clinical remission phase following diagnosis. HbA1c at baseline, and six, 12, 18 and 24 months after pump initiation were collected. Study 2 was designed to review experiences of families commenced on pumps through subsidised pathway. A questionnaire designed by the clinical team was distributed to parents via an online secure platform to capture their experiences. Of the 61 children with mean (SD) age 9.0 (4.9) years who commenced pump therapy through subsidised pump programs, 34 children commenced pump therapy after one year of diagnosis of T1D. The median (IQR) HbA1c (%) in 34 children at baseline was 8.3 (1.3), with no statistically significant change from baseline at six months [7.9 (1.4)], 12 months [8.0 (1.5)], 18 months [8.0 (1.3)] or 24 months [8.0 (1.3)]. The questionnaire response rate was 56%. 83% reported intention to continue pump therapy, however 58% of these families did not have avenue to acquire private health insurance. Families expressed inability to procure private health insurance due to low income and unreliable employment and remained largely unsure about the pathway to obtain the next pump. Children with T1D who commenced insulin pump therapy on subsidised pathways maintained glycaemic control for two years, and families favored pumps as a management option. However, financial limitations persist as a significant barrier to procure and continue pump therapy. Pathways for access need to be assessed and advocated.

Duvelisib Eliminates CLL B Cells, Impairs CLL-Supporting Cells, and Overcomes Ibrutinib Resistance in a Xenograft Model.

Inhibitors of Bruton's tyrosine kinase (BTKi) and PI3K (PI3Ki) have significantly improved therapy of chronic lymphocytic leukemia (CLL). However, the emergence of resistance to BTKi has introduced an unmet therapeutic need. Hence, we sought evidence for essential roles of PI3K-δi and PI3K-γi in treatment-naïve and BTKi-refractory CLL. Responses to PI3K-δi, PI3K-γi, and the dual-inhibitor duvelisib in each B, T, and myeloid cell compartments of CLL were studied in vitro, and in a xenograft mouse model using primary cells from treatment-naïve and ibrutinib-resistant patients, and finally, in a patient with ibrutinib-resistant CLL treated with duvelisib. We demonstrate the essential roles of PI3K-δ for CLL B-cell survival and migration, of PI3K-γ for T-cell migration and macrophage polarization, and of dual inhibition of PI3K-δ,γ for efficacious reduction of leukemia burden. We also show that samples from patients whose disease progressed on ibrutinib were responsive to duvelisib therapy in a xenograft model, irrespective of BTK mutations. In support of this, we report a patient with ibrutinib-resistant CLL, bearing a clone with BTK and PLCγ2 mutations, who responded immediately to single-agent duvelisib with redistribution lymphocytosis followed by a partial clinical remission associated with modulation of T and myeloid cells. Our data define the mechanism of action whereby dual inhibition of PI3K-δ,γ affects CLL B-cell numbers and T and myeloid cell pro-leukemia functions and support the use of duvelisib as a valuable approach for therapeutic interventions, including for patients refractory to BTKi.

Abstract 4933: Duvelisib eliminates CLL B Cells, impairs CLL-supporting cells, and overcomes ibrutinib resistance in a patient-derived xenograft model

Abstract Duvelisib (IPI-145), a first-in-class, oral, dual PI3K-δ,γ inhibitor, has been approved by the FDA for the treatment of patients with chronic lymphocytic leukemia (CLL), small lymphocytic and follicular lymphoma. Duvelisib potently inhibits PI3K-δ and PI3K-γ, thereby offering a novel therapeutic approach. Here we aimed to understand how duvelisib targets CLL cells and the tumor microenvironment (TME) and hence how it affects CLL, even with BTK-resistant disease. We first assessed the distinct contributions of PI3K-δ and PI3K-γ on CLL cell survival, proliferation, and migration in vitro by using PI3K-δ (PI3K-δi) or PI3K-γ (PI3K-γi) specific inhibitors in addition to duvelisib. We found a significant reduction in viable CLL cells after exposure to PI3K-δi and duvelisib. By measuring Ki67 and p-AKT levels, we found duvelisib and PI3K-δi more potently block CLL cell proliferation than PI3K-γi. PI3K-δi and duvelisib also significantly reduced the migration of CLL B cells into the spleen relative to control. In contrast, PI3K-γi inhibited T cell not B cell homing in vitro and in vivo. We then investigated the impact of single versus dual inhibitory agents on myeloid cells. Tumor-associated macrophages (TAMs) of the “M2 phenotype” contribute to a pro-tumor TME by preventing the induction of T cell mediated anti-tumor immunity. We expanded murine bone marrow derived monocytes and then polarized them to M2 macrophages, in the absence or presence of PI3Ki. At 100nM, PI3K-γi, but not PI3K-δi, significantly inhibited M2 polarization. Duvelisib significantly reduced Arg1 expression at doses equal to or above 10nM. While co-culturing leukemic B cells with M2-polarized murine macrophages increased CLL-cell survival, addition of duvelisib to such co-cultures significantly reduced CLL cell survival. Altogether, duvelisib sensitizes primary CLL cells to apoptosis and abrogates M2 cell-mediated CLL-cell survival. Finally, in a patient-derived xenograft mouse model (PDX), we demonstrated the essential roles of PI3K-δ and PI3K-γ in the CLL TME. Specifically, we found a more efficacious inhibition in CLL cell burden by dual inhibition of PI3K-δ,γ. Also, samples from patients whose disease progressed on ibrutinib were responsive to duvelisib therapy in PDX, irrespective of BTK mutations. In support of this, we identified an ibrutinib resistant CLL patient, with a clone exhibiting BTK and PLCγ2 mutations who responded immediately to single agent duvelisib with redistribution lymphocytosis followed by a partial clinical remission associated with subsequent modulation of T and myeloid cells. In conclusion, our data define the mechanism of action whereby dual inhibition of PI3K-δ,γ affects CLL B cell numbers and T and myeloid cell pro-leukemia functions, supporting the use of duvelisib as a potentially valuable therapeutic intervention, including for patients refractory to BTKi. Citation Format: Shih-Shih Chen, Jacqueline C. Barrientos, Gerardo Ferrer, Priyadarshini Ravichandran, Michael Ibrahim, Yasmine Kieso, Jeffery L. Kutok, Marisa Peluso, Sujata Sharma, David T. Weaver, Jonathan A. Pachter, Kanti R. Rai, Nicholas Chiorazzi. Duvelisib eliminates CLL B Cells, impairs CLL-supporting cells, and overcomes ibrutinib resistance in a patient-derived xenograft model. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4933.