Steroid-dependent Patients Research Articles

Systematic review: Methotrexate-A poorly understood and underused medication in inflammatory bowel disease.

Methotrexate, an immunosuppressant used for the treatment of inflammatory bowel disease (IBD) for over 30 years, remains underused compared to thiopurines. To review the efficacy, safety, optimal dosing and delivery regimens of methotrexate in adults with IBD. We conducted a systematic review of studies involving patients with IBD treated with methotrexate from inception to August 2023. All studies were included from the MEDLINE database via PubMed. For Crohn's disease, we included eight randomised controlled trials (RCTs) and 17 observational studies. Parenteral methotrexate effectively increased remission rates in steroid-dependent patients at 25 mg/week for 16 weeks and at 15 mg/week for maintenance. Methotrexate can be used in combination with anti-tumour necrosis factor (TNF) agents to reduce immunogenicity. Data comparing thiopurines and methotrexate remain scarce. For ulcerative colitis (UC), we included five RCTs and 10 observational studies were included; there was no evidence to support the use of methotrexate in (UC). We extracted safety data from 17 studies; mild-to-moderate adverse effects were common. The incidence of liver fibrosis or cirrhosis was low. Methotrexate is effective at inducing and maintaining remission in steroid-refractory Crohn's disease and can reduce anti-TNF-induced immunogenicity when used in combination therapy. Data regarding tolerance and safety are reassuring. These findings challenge preconceived ideas on methotrexate and suggest that it is a valid first-line conventional option for the treatment of mild-to-moderate Crohn's disease.

Allergic bronchopullmonary aspergillosis (ABPA) - an Update

Allergic bronchopulmonary aspergillosis (ABPA) is a regular occurrence in everyday pneumology. ABPA should be considered in patients with severe asthma, in mould allergic patients with very high serum IgE levels and in patients with cystic fibrosis. The aim should be to make the diagnosis as early as possible in the course of the disease to avoid late complications such as bronchiectasis and fibrotic lung remodelling. Symptoms are highly variable and rather non-specific, overlapping with those of the underlying primary disease. However, clearly defined diagnostic criteria exist, so that the diagnosis can be made relatively easily if one thinks of it. In therapy, systemic steroids and antifungals (mainly azoles) play the leading role. However, biologics have been gaining in importance in recent years, especially in cases of insufficient therapy response or occurrence of side effects to standard therapies, as well as an alternative in permanently steroid-dependent patients.

Long-Term Efficacy of Mepolizumab at 3 Years in Patients with Severe Asthma: Comparison with Clinical Trials and Super Responders.

The efficacy mepolizumab in severe asthmatic patients is proven in the literature. Primarily to study the effect of mepolizumab on exacerbations, steroid dependence, and the continuation of efficacy in the long term. Secondarily to evaluate the effect of the drug on nasal polyps. Analyzing data from SANI (Severe Asthma Network Italy) clinics, we observed severe asthmatic patients treated with mepolizumab 100 mg/4 weeks, for a period of 3 years. 157 patients were observed. Exacerbations were reduced from the first year (-84.6%) and progressively to 90 and 95% in the second and third ones. Steroid-dependent patients decreased from 54% to 21% and subsequently to 11% in the second year and 6% in the third year. Patients with concomitant nasal polyps, assessed by SNOT-22, showed a 49% reduction in value from baseline to the third year. The study demonstrated the long-term efficacy of mepolizumab in a real-life setting.

BEVACIZUMAB FOR SYMPTOMATIC RADIATION NECROSIS IN BRAIN METASTASES: OUTCOMES FROM A SINGLE-CENTER RETROSPECTIVE ANALYSIS

Abstract Radiation necrosis is a late complication after radiotherapy and can be treated with bevacizumab, however predictors of response are not well established. We performed a single-institution retrospective chart review of patients with previously irradiated brain metastases who developed radiation necrosis and were treated with bevacizumab. 19 patients (86% female, median age of 62 years) were included. 50% had metastatic lung cancer, 37% had breast cancer and 11 % had melanoma. 18 had perfusion imaging, 9 had chemical exchange saturation transfer (CEST) imaging to increase diagnostic confidence. 6 cases were tissue-confirmed, 3 before treatment, and 3 upon recurrence after bevacizumab. All patients received a dose of 7.5 mg/kg per infusion every 3 weeks and 63% received 4 infusions. All were symptomatic before treatment. Clinical response was seen in 89% while radiographic response was achieved in 95% of patients. Dexamethasone was successfully discontinued in 71% of steroid-dependent patients. The median duration of response (interval between first infusion and recurrence) was 7.2 months (range: 2.3 to 43.2). Of the nine diagnosed using perfusion and CEST imaging, 89% had clinical response, 100% had a reduction in T2/FLAIR volume and 89% in T1 post-gadolinium enhancement, 83% discontinued dexamethasone. Grade 1/2 adverse events occurred in 8 patients (hypertension, fatigue, rash, joint pain, intracranial hemorrhage). One patient developed a grade 3 bowel perforation requiring surgery. Bevacizumab resulted in significant and prolonged clinical and radiographic improvement in a series of carefully selected patients. CEST imaging helped select responders to bevacizumab in our cohort.

Estimation of patients affected by inflammatory bowel disease potentially eligible for biological treatment in a real-world setting

Background/aimsThis analysis estimated the number of inflammatory bowel disease (IBD) patients presenting criteria of eligibility for biological therapies in an Italian real-world setting. MethodsAn observational analysis was performed on administrative databases of a sample of Local Health Units, covering 11.3% of the national population. Adult IBD patients (CD or UC) from 2010 to the end of data availability were included. Eligibility criteria for biologics were the following: Criterion A, steroid-refractory active disease; Criterion B, steroid-dependent patients; Criterion C, intolerance or contraindication to conventional therapies; Criterion D, severe relapsing disease; Criterion E (CD only), highly active CD disease and poor prognosis. ResultsOf 26,781 IBD patient identified, 18,264 (68.2%) were treated: 3,125 (11.7%) with biologics and 15,139 (56.5%) non-biotreated. Among non-biotreated, 7,651 (28.6%) met at least one eligibility criterion for biologics, with criterion B (steroid-dependence) and criterion D (relapse) as the most represented (58–27% and 56–76%, respectively). Data reportioned to the Italian population estimated 67,635 patients as potentially eligible for biologics. ConclusionsThis real-world analysis showed a trend towards undertreatment with biologics in IBD patients with 28.6% being potentially eligible, suggesting that an unmet medical need still exists among the Italian general clinical practice for IBD management.

Immunosuppressive Agent Options for Primary Nephrotic Syndrome: A Review of Network Meta-Analyses and Cost-Effectiveness Analysis.

Therapeutic options with immunosuppressive agents for glomerular diseases have widened with refinements to the Kidney Disease Improving Global Outcomes (KDIGO) guidelines from 2012 to 2021. However, international guidelines do not necessarily match the reality in each country. Expensive therapies such as rituximab and calcineurin inhibitors are sometimes inaccessible to patients with refractory nephrotic syndrome due to cost or regulations. Under the Japanese medical insurance system, rituximab is accessible but still limited to steroid-dependent patients who developed idiopathic nephrotic syndrome in childhood. Based on international KDIGO guidelines and other national guidelines, possible applications of immunosuppressive agents for nephrotic syndrome are comprehensively examined in this review. While rituximab has become the mainstay of immunosuppressive therapy for nephrotic syndrome, clinical trials have indicated that options such as cyclophosphamide, calcineurin inhibitors, and mycophenolate mofetil would be preferable. Given the rising number of patients with nephrotic syndrome worldwide, KDIGO guidelines mention the need for further consideration of cost-effectiveness. If the new option of rituximab is to be the first choice in combination with steroids for nephrotic syndrome, its cost-effectiveness should also be verified. Among the few studies examining the cost-effectiveness of treatments for nephrotic syndrome, administration of rituximab to young adults has been shown to be cost-beneficial, at least in Japan. However, further large-scale studies involving multiple facilities are needed to verify such findings. Network meta-analyses have concluded that the efficacy of rituximab remains controversial and confirmation through high-quality studies of large cohorts is needed. To this end, the mechanisms of action underlying immunosuppressive agents, both old and new, need to be understood and experience must be accumulated to evaluate possible effects and side effects.

P771 Biologics versus azathioprine in steroid-dependent ulcerative colitis: results from the A.U.R.O.R.A. database

Abstract Background The A.U.R.O.R.A. database is an Italian multicenter retrospective cohort of patients with ulcerative colitis (UC) treated with the first biological drugs (infliximab biosimilar- IFX-B, adalimumab-ADA, golimumab-GOL, vedolizumab-VDZ) approved in Italy after patent expire of IFX-originator. In a previous published study,1 we showed similar efficacy among all drugs according to the rigorous outcome of 1-year “continuous clinical remission” (CCR). In this study, we focused only on steroid-dependent UC, by comparing all drugs to each other and to patients treated with steroids followed by azatioprine (AZA) monotherapy. Methods All consecutive patients with steroid-dependent UC, treated with IFX-B, ADA, GOL or VDZ after their approval in 2014-2019, were followed-up for 1 year or until drug discontinuation for relapse or adverse events. All drugs were compared to each other and to steroid-dependent patients treated with steroids + AZA in 2006-2014. A propensity score analysis was performed to balance differences at baseline. The primary endpoint was the 1-year CCR, defined as steroid-free clinical remission with Mayo partial score ≤2 (with no bleeding), without any clinical relapse or treatment optimization after the first remission was achieved, and without drug withdrawal due to adverse events. Treatment optimization was defined as the addition of systemic/topical steroids, oral/topical mesalazine or any dose escalation of biologics Results 370 patients (IFX-B=62, ADA=68, GOL=56, VDZ=100, AZA 84) with steroid-dependent UC were included. No significant differences were found among each biological drug according to the 1-year CCR primary end-point (34%, 29%, 30%, 39%, respectively). In patients naive to immunesuppressors and biologics (n= 17, 25, 24 10, 79, respectively), AZA showed significantly higher rate of CCR (68%) than each biological drug (35%, 44%, 33%, 60%; p=0.000 for each comparison) or all biologics as a whole (41%; p=0.012). Adverse events occurred significantly less frequently with ADA (8%) than IFX (29%), GOL (20%) and AZA (26%) in the overall population, but were similar across all drugs in the naive population. Discontinuation for adverse events occurred more frequently (p<0.05) with both IFX-B (16%) and AZA (14%) than ADA (3%), GOL (4%), and VDZ (1%) in the overall population, but not in the naive population (18%, 15%, 4%, 4%, 0%, respectively). Conclusion In steroid-dependent UC, anti-TNF-alpha agents and VDZ were equally effective at 1 year according to the concept of CCR. AZA still appears an effective first-line strategy in the biological era. 1Cassinotti A. et al. Eur J Gastroenterol Hepatol. 2022;34:1238-46. Guided Poster Session

Clinico-biochemical Profile of Biopsy-proven Minimal Change Disease in Adults from a Tertiary Care Center in South India.

Minimal change disease (MCD) is the most common cause of nephrotic syndrome (NS) in children, and in adults, it contributes to 10%-25% of NS. MCD in adults follows a slightly different course associated with increased incidence of steroid resistance, hematuria, and HTN. This is a prospective-record analysis study aimed to analyze the profile of MCD in adults, response to treatment, and relapse rates. A retrospective observational study was carried out and data were collected retrospectively from all biopsy-proven MCD patients between 2012 and 2018. A total of 86 adults were diagnosed to have biopsy-proven MCD. Of these, 32 were excluded due to insufficient data/lost for follow-up. The IBM SPSS Statistics version 22.0 was used for the statistical analysis. Descriptive analysis includes expression of all the explanatory and outcome variables in terms of frequency and proportions for categorical variables whereas in terms of mean ± standard deviation for continuous variables. Chi-square test was used to compare the age, gender, remission, renal failure and response of different drugs, treatment durations, comorbidity conditions, relapse episodes, and different types of infections based on the degree of proteinuria among study patients. A total of 54 biopsy-proven adult MCD patients were analyzed. The mean age of the patients studied was 36.67 years, with the oldest patient being 76 years. In the study group, 37 (68.5%) patients were male and 14 (31.5%) were female. In the study population, 20 (37%) were hypertensive, 3 (5.6%) were diabetic, and 10 (18.5%) had renal failure at presentation. On treatment, 52 out of 54 patients received steroids, of which 41 (75.9%) were steroid responsive, 6 (11.1%) steroid dependent, and 7 (13%) steroid resistant. The mean time for remission in steroidsensitive patients was 8.8 weeks. Among the steroid-dependent and steroid-resistant patients, 11 patients received calcineurin inhibitors (CNIs), of which 3 were CNI resistant. In the study Group 1 patient received cyclophosphamide and two received rituximab. In the study population, two patients failed to achieve remission and one patient was initiated on hemodialysis and later lost for follow-up. Minimal change NS is a type of NS which is highly responsive to steroids with good prognosis in children. Adult MCD patients require a higher and prolonged course of steroid when compared to children. CNIs and rituximab form a promising second-line drug in patients who are steroid resistant/dependent. However, CNI dependency or relapse after stopping steroids is a concern.

QOL-01. RISK FACTORS FOR AND CONSEQUENCES OF PROLONGED DEXAMETHASONE USE IN PATIENTS WITH GLIOBLASTOMA (GBM)

Abstract BACKGROUND Dexamethasone is the primary treatment for tumor-associated edema. Prolonged use can have significant side effects and may negatively impact survival in GBM. Factors associated with steroid dependence and steroid associated side effects (SASEs) are not well established. METHODS We performed a retrospective study of patients with newly diagnosed, IDH-wildtype GBM at our center. Demographics, clinical and tumor characteristics, dexamethasone usage, and SASEs (infections, myopathy, hypertension, fractures, mood symptoms, weight gain, and hyperglycemia) were extracted through chart review. We compared survival outcomes (OS) between patients with and without steroid dependence. Risk factors for steroid dependence were identified through logistic regression analysis. RESULTS 39/92 (35.9%) patients developed steroid dependence. Of these, 26/39 (66.7%) were on steroids at the start of initial treatment. Patients who developed steroid dependence were older, more likely to have STR/biopsy, bilateral disease, KPS < 90, baseline neurological deficits, and to be obese (BMI ≥ 30). 94.9% of patients with steroid dependence experienced ≥ 1 SASE (vs. 34%) and 46.2% experienced ≥ 3 SASEs (vs. 3.8%). Mood symptoms (69.2% vs. 26.4%), hyperglycemia (53.8% vs. 7.5%) and infections (51.3% vs. 7.5%) were the most common SASEs. Median OS was inferior in steroid-dependent patients (18 vs 25 mo). Baseline obesity was identified as a risk factor for developing steroid dependence (OR 5.9). DISCUSSION SASEs are common in patients on prolonged steroids. Obesity may increase the risk of developing steroid dependence. Identifying patients at highest risk for steroid dependence may help guide future interventions to mitigate the negative effects of prolonged dexamethasone use.

Introducing technology to improve patient safety in adrenal insufficiency: a proof-of-concept delivery of a new smartphone app in steroid-dependent patients

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Regulation of the Intestinal Extra-Adrenal Steroidogenic Pathway Component LRH-1 by Glucocorticoids in Ulcerative Colitis.

Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) and can be treated with glucocorticoids (GC), although some patients are unresponsive to this therapy. The transcription factor LRH-1/NR5A2 is critical to intestinal cortisol production (intestinal steroidogenesis), being reduced in UC patients. However, the relationship between LRH-1 expression and distribution with altered corticosteroid responses is unknown. To address this, we categorized UC patients by their steroid response. Here, we found that steroid-dependent and refractory patients presented reduced glucocorticoid receptor (GR)-mediated intestinal steroidogenesis compared to healthy individuals and responder patients, possibly related to increased colonic mucosa GR isoform beta (GRβ) content and cytoplasmic LRH-1 levels in epithelial and lamina propria cells. Interestingly, an intestinal epithelium-specific GR-induced knockout (GRiKO) dextran sodium sulfate (DSS)-colitis mice model presented decreased epithelial LRH-1 expression, whilst it increased in the lamina propria compared to DSS-treated control mice. Mechanistically, GR directly induced NR5A2 gene expression in CCD841CoN cells and human colonic organoids. Furthermore, GR bound to two glucocorticoid-response elements within the NR5A2 promoter in dexamethasone-stimulated CCD841CoN cells. We conclude that GR contributes to intestinal steroidogenesis by inducing LRH-1 in epithelial cells, suggesting LRH-1 as a potential marker for glucocorticoid-impaired response in UC. However, further studies with a larger patient cohort will be necessary to confirm role of LRH-1 as a therapeutic biomarker.

The Role of Rituximab in Primary Focal Segmental Glomerular Sclerosis of the Adult

IntroductionPrimary focal segmental glomerular sclerosis (FSGS) is a rare, likely immune-mediated disease. Rituximab (RTX) may play a role in management, although data in adults are scanty.MethodsWe collected cases of RTX-treated primary FSGS within the Italian Society of Nephrology Immunopathology Working Group and explored response rate (24-hour proteinuria <3.5 g and <50% compared with baseline, stable estimated glomerular filtration rate).ResultsA total of 31 patients were followed for at least 12 months; further follow-up (median 17 months, interquartile range [IQR] 15–33.5) was available for 11. At first RTX administration, median creatinine and 24-hour proteinuria were 1.17 mg/dl (IQR 0.83–1.62) and 5.2 g (IQR 3.3–8.81), respectively. Response rate at 3, 6, and 12 months was 39%, 52%, and 42%, respectively. In the first 12 months, creatinine level remained stable whereas proteinuria and serum albumin level improved, with an increase in the proportion of patients tapering other immunosuppressants. There were 6 patients who were retreated with RTX within 12 months, either for proteinuria increase or refractory disease; only the 2 responders to the first RTX course experienced a further response. At univariate analysis, 6-month response was more frequent in steroid-dependent patients (odds ratio [OR] 7.7 [95% CI 1.16–52.17]) and those with proteinuria <5 g/24 h (OR 8.25 [1.45–46.86]). During long-term follow-up, 4 of 5 responders at 12 months maintained a sustained response, either without further immunosuppression (2 of 4) or with pre-emptive RTX (2 of 4); 1 relapsed and responded to RTX retreatment.ConclusionRTX may be an option in primary FSGS, especially in steroid-dependent patients, with 24-hour proteinuria <5 g and previously responders to RTX. Optimal long-term management for responders is unclear, with some patients experiencing sustained remission and others requiring RTX retreatment, either preemptive or after rising proteinuria.

Could Antinuclear Antibody Positivity Be a Factor Affecting Treatment Response in Immune Thrombocytopenia Patients on Eltrombopag?

Objective:Eltrombopag remains a prominent option in the treatment of steroid-dependent or steroid-refractory immune thrombocytopenia (ITP) patients. Unfortunately, not all patients respond to eltrombopag. Antinuclear antibody (ANA) positivity can be seen at rates of up to 30% in ITP patients. Despite being widely used, more markers to predict the response to eltrombopag are still needed. In the present study, we aimed to show the association between ANA positivity and eltrombopag response in ITP patients.Materials and Methods:Patients who were diagnosed with ITP in the Trakya University Faculty of Medicine’s Department of Hematology and who underwent eltrombopag treatment due to their resistance to steroids and other treatments were included in our study. ANA measurement was performed by indirect fluorescent antibody method and titers of 1:160 and above were considered positive. ANA measurements were made before starting eltrombopag.Results:Forty-five patients were included in our study, 33 being women and 12 men. The mean age of the patients was 45.73 years. There were 14 patients with ANA positivity and 31 patients were found to be ANA-negative. Response rates were higher in ANA-negative patients compared to ANA-positive patients in the 1st and 6th months of eltrombopag treatment (p<0.05).Conclusion:ANA positivity in ITP may indicate unresponsiveness to eltrombopag treatment, a finding that should be further supported by prospective studies involving more patients.

Rituximab treatment in pediatric patients with steroid-dependent nephrotic syndrome: A tertiary hospital

BackgroundCorticosteroids have had a central role in the treatment of nephrotic syndrome. The management of these patients who become dependent to steroids is complex, involving different immunosuppressive drugs patterns. The monoclonal antibody anti CD20, Rituximab, is likely to have beneficial effects in cases of steroid-dependent nephrotic syndrome patients with no easy resolution, even when we cannot make a statement about the specific role in the impact. We bring our personal experience in pediatric patients treated with this medication during the last years, to provide a thorough overview and useful information about the role of Rituximab in this pathology. MethodsRetrospective study in patients with steroid-dependent idiopathic nephrotic syndrome controlled in the division of Pediatric Nephrology of a Spanish tertiary hospital in those patients who had received at least one treatment cycle of Rituximab, at any moment along the evolution of the disease. ResultsThe study involved 8 patients. All of them previously received immunosuppressive therapy. The Rituximab were administered as an intravenous infusion, in a dose of 375 mg/m2, and all doses were administered in a period during which the disease was in remission. The depletion of lymphocytes B (CD19, 0%) were confirmed after the first dose of Rituximab except for one, with a lymphocyte count of 1%. The period of depletion lasts 10,3 months (median; range 6,5–16 months), and only one of the patients registered a relapse of the disease in this period. A reduction of relapses suffered by patients has been shown after the treatment began (3,6 relapses/year in the previous year to the start of the treatment versus 0,1 relapses/year during the first year post-rituximab). The relapse-free survival in the first year reached 83,3% in patients who suffered more than one relapse (75% of patients), and without a relapse after the treatment began in 2 cases. One or more drugs could be removed in 87,5% of patients after the first cycle of rituximab. After the rituximab treatment, we reached a 96,5% decrease in the corticosteroids doses administered (28,5 mg/m2/day during the 3 months pre-treatment versus 1 mg/m2/day in the last 3 months of patient monitoring). Not a significant observed adverse effect attributed to the drug after the post-rituximab monitoring period (median 46,5 months, range 5–97 months). ConclusionThe favorable results reported after rituximab treatment in our patients seems to confirm the effectiveness of this drug in the steroid-dependent nephrotic syndrome, making that therapeutic option into consideration and legitimating the use of the drug in complex cases involving pediatric patients. Even so, it seems recommendable to design pertinent studies to clarify, among others, the optimum regimen of the treatment (dose, interval and cycles), clinical repercussion and potential adverse effects in long terms.

P593 Biologicals and small molecule combotherapies: promising experience in refractory IBD patients

Abstract Background It has been hypothesized that combination of two biologics or with a small molecule could ”break the ceiling” of the efficacy (~60%) of currently available biological therapies for IBD patients. The best combinations and their safety are, however, unknown. Methods A chart review of Inselspital, Bern University hospital und Crohn and colitis center Beaulieu Lausanne, of IBD patients on combination therapy have been performed. Data on disease phenotype, previous treatment and efficacy and safety of the new combinations have been collected and studied to help moving forward the use of this armentarium. Results Among 18 identified IBD patients (39% women, 10 ulcerative colitis, 8 Crohn’s disease) with extended and refractiry luminal disease (indication) who received 21 combination therapies between June 2017 and November 2021. They suffered from steroid-dependency and half of them were refractory to at least two anti-TNF alpha agents. These treatments have been started after a median duration of disease of 6 years (range 1–25) for a mean period of combo treatment of 11 months (range 1–52), 8 were still ongoing. Various combotherapies and clinical response (arrows; red=bad, green=good response) are presented in Figure 1. A partial or complete response was observed in 15/21 therapies (71%) with a mean decrease of CRP of 11 mg/l (range+23 to -59) and calprotectin of 399 mcg/g (range 0 – 1745) among the reponders. Concerning safety, 2 infections (otitis media, skin mycosis), 1 non hodgkin Lymphoma and 4 minor adverse events (tumefaction left parotide, eczema, 2x lymphopenia) have been reported, mostly when small molecules have been involved. Conclusion Ustekinumab combined with anti-TNF agents in Crohn’s disease is more effective than vedolizumab and tofactinib in ulcerative colitis. Combining with small molecules increases the risk of lymphopenia, of cancer (1 case of non hodgkin lymphoma) and minor infections in severe refractory and steroid-dependent inflammatory bowel disease patients.

A QIP to improve quality of care in adrenal insufficiency and steroid dependent patients

A QIP to improve quality of care in adrenal insufficiency and steroid dependent patients

Short Stature in Patients with Diamond-Blackfan Anemia: A Cross-Sectional Study

To systematically describe the short stature of patients with Diamond-Blackfan anemia and to explore factors affecting the height development of patients with Diamond-Blackfan anemia. This cross-sectional study was conducted at the Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, and the height, weight, and clinical data of 129 patients with Diamond-Blackfan anemia were collected from June 2020 to September2020. The median height-age-z score (HAZ) of children affected by Diamond-Blackfan anemia was -1.54 (-6.36-1.96). Short stature was found in 37.98% of the patients. Specific Diamond-Blackfan anemia growth curves were developed for weight, height, and body mass index, separately for male and female patients. Multivariable logistic regression models showed that female sex (aOR 4.92; 95% CI 1.29-18.71; P=.0195), underweight (aOR 10.41, 95% CI 1.41-76.98, P=.0217), cardiovascular malformations (aOR 216.65; 95% CI 3.29-14279.79; P=.0118), and RPL11(aOR 29.14; 95% CI 1.18-719.10; P=.0392) or RPS26 (aOR 53.49; 95% CI 1.40-2044.30; P=.0323) mutations were independent risk factors for short stature. In the subgroup of patients who were steroid-dependent, patients with a duration of steroid therapy over 2years (OR 2.95; 95% CI 1.00-8.66; P=.0494) or maintenance dose of prednisone >0.1mg/kg per day (OR 3.30; 95% CI 1.02-10.72; P=.0470) had a higher incidence of short stature. Patients with Diamond-Blackfan anemia had a high prevalence of short stature. The risk of short stature increased with age and was associated with sex, underweight, congenital malformations, and RPL11 or RPS26 mutations. The duration of steroid therapy and maintenance dose of steroid was significantly associated with the incidence of short stature in steroid-dependent patients with Diamond-Blackfan anemia.

Eltrombopag in the Treatment of Immune Thrombocytopenia: Two-Center Experience from Istanbul.

Immune Thrombocytopenia (ITP) is a disease caused by autoantibodies forming against platelets and T cell dysregulation and is characterized by platelet count falling below 100 × 109/L. Corticosteroids remain as the first-line of treatment, but in the light of recent developments, thrombopoietin receptor agonists are gradually replacing splenectomy in steroid-dependent or refractory patients. In this study, it was aimed to retrospectively evaluate the efficacy, safety and side-effect profile of eltrombopag treatment for chronic ITP. A total of 23 chronic ITP patients treated with eltrombopag from two health institutions in Istanbul were evaluated retrospectively. Overall response rate (partial or complete) was 87%, complete response rate was 78.3%, and the median time from treatment until reaching platelet counts above 50 × 109/L was 14days (min-max: 4-126). Treatment was discontinued in four patients due to persistent response, two of these were still fully responsive. During treatment, one patient developed basal cell carcinoma, and another developed chronic myelomonocytic leukemia. Although its long-term side effects are not yet known, eltrombopag is a very effective treatment option in ITP and may provide favorable outcomes in patients.

Initial Results of KD025-208: A Phase 2a Open Label Trial of KD025 for Steroid-Dependent Chronic Graft Versus Host Disease

Introduction: cGVHD occurs in approximately 50% of patients undergoing allogeneic hematopoietic stem cell transplantation and it remains a leading cause of post-transplant morbidity and mortality. cGVHD typically exhibits features of both autoimmune and fibrotic diseases and can affect single or multiple organ systems. Corticosteroids are the primary treatment modality and while not uniformly effective, often cause additional adverse effects in patients with prolonged use. Despite major advances in the understanding of cGVHD biology, no targeted therapy has been approved for cGVHD. KD025 is an orally available Rho-associated coiled-coil kinase 2 (ROCK2) selective inhibitor currently in Phase 2 clinical development for autoimmune and fibrotic indications. KD025 has been shown to downregulate pro-inflammatory T helper 17 cells and T follicular helper cells while upregulating anti-inflammatory regulatory T cells, which may potentially correct the immunological imbalance seen in cGVHD.Methods: Seventeen adult patients were enrolled in KD025-208, a Phase 2a, open-label study. Enrollment is planned for three cohorts (200 mg QD, 200 mg BID, and 400 mg QD) of 16 steroid-dependent cGVHD patients per cohort. The primary activity endpoint is the percentage of patients who meet the NIH Consensus Conference-defined overall response criteria (Partial Response (PR) + Complete Response (CR)) at 24 weeks. Secondary efficacy endpoints include changes in corticosteroid and calcineurin inhibitor dose and changes in cGVHD severity using the Physician-Reported Global cGVHD Activity Assessment. Exploratory endpoints include changes in symptom burden/bother using the Lee cGVHD Symptom Scale.Results: Seventeen patients with a median age of 50 years, median time from transplant to cGVHD diagnosis of 9.1 months, median time from initial cGVHD diagnosis to KD025 treatment initiation of 25.9 months, and median number of prior treatment regimens of three were enrolled in the 200 mg QD cohort. KD025 demonstrated an overall response rate (PR or CR at any evaluation time point) of 71% (12/17). Three patients discontinued KD025 treatment prior to 24 weeks (one cancer relapse, one cGVHD progression, and one adverse event of headache). Each of the three discontinued patients had demonstrated responses (PR) prior to study discontinuation. Fourteen of 17 (82%) patients remained on treatment at 24 weeks. At week 24, KD025 demonstrated clinical responses (CR or PR) in 57% (8/14) of the remaining evaluable patients. In addition to the eight responders, four patients had stable disease (SD) at 24 weeks; therefore, CR, PR or SD occurred in 86% (12/14) of patients. Importantly, of patients remaining on treatment at 24 weeks, 57% (8/14) had a reduction in steroid dose and 67% (4/6) had a reduction in tacrolimus dose. Moreover, 57% (8/14) of patients had a reduction in symptoms as measured by the Lee cGVHD Symptom Scale score. Patients with PR or SD were permitted to remain on KD025 for an additional 24 weeks. Eleven of 14 patients elected to remain on KD025 treatment after 24 weeks. Two patients were discontinued due to lack of response at 24 weeks and one patient with stable cGVHD was discontinued due to an unrelated adverse event of nephrotic syndrome.In addition, KD025 demonstrated an overall clinical benefit rate (PR or CR at any evaluation time point or SD at 24 weeks) of 88% (15/17) in all cGVHD patients.No treatment-related serious adverse events (SAEs) have been reported and no definitive treatment-related elevations in liver function tests (LFTs) (ALT, AST, ALP, and Bili) have been observed. Elevations in LFTs were commonly observed prior to KD025 dosing and may be attributable to cGVHD liver involvement. KD025 has been well tolerated and the overall adverse event profile appears consistent with cGVHD. Other low-grade treatment emergent adverse events seen in three or more patients were anemia (24%), diarrhea (24%), and nausea (24%).Conclusions: Treatment of cGVHD with KD025 demonstrated encouraging clinical responses and a favorable safety profile in patients with steroid-dependent cGVHD when administered at 200 mg QD. Eight of 14 patients (57%) demonstrated a 2014 NIH Consensus Conference-defined PR. No drug-related SAEs were reported. Enrollment in the dose-escalating cohorts is ongoing. DisclosuresLee:Kadmon: Other: One-time advisory board member; Bristol-Myers-Squibb: Other: One-time advisory board member; Amgen: Other: One-time advisory board member; Mallinckrodt: Honoraria. Salhotra:Kadmon: Consultancy. Jagasia:Mallinckrodt: Consultancy; Janssen: Consultancy, Research Funding; Therakos: Consultancy, Research Funding. Schueller:Kadmon: Employment, Equity Ownership.

P671 Effect of genetic polymorphisms in the folate pathway on the efficacy and safety of methotrexate in Crohn’s disease

Abstract Background Methotrexate (MTX) is currently used in steroid-dependent patients with moderate-to-severe Crohn’s disease (CD) when thiopurines have failed or are contraindicated. Although its efficacy has been proved for both induction and maintenance of remission, its use is limited due to the rate of associated adverse events. Polymorphisms in the folate pathway might predict the efficacy and toxicity of MTX. Our aims were to evaluate the predictive value of these polymorphisms of MTX efficacy and safety in CD. Methods Patients from ENEIDA registry of GETECCU who were treated with MTX on monotherapy and of whom genomic DNA was available, were identified. Clinical efficacy and MTX-related toxicity were collected, and 10 variants from ATIC, DHFR, MTHFR, RFC1, ABCB1 and ABCC3 genes were genotyped with TaqMan assays. Results One hundred and twenty nine patients were included, 55% were female and 31% active smokers. MTX was used as first and second-line therapy in 10% and 60% of patients, respectively, at a mean dose of 22 mg and for a median time of 14 months. Thirty-seven per cent of patients achieved clinical remission, whereas 34% were non-responders (MTX failure). Forty patients (30%) developed MTX-related toxicity, with nausea and vomiting, myelotoxicity and hepatotoxicity as the most frequent adverse events (37%, 15% and 15%, respectively). MTX was discontineud in 19% of the patients due to toxicity. In the multivariable analysis, patients with the AA genotype for the rs408626 DHFR variant was predictive of a higher efficacy as compared to the G allele carriers (RR 0.372, p=0.026), and smoking was associated with a higher risk of MTX therapy failure (RR 2.676, p=0.015). Moreover, the CC genotype for the rs1476413 MTHFR variant and the TT genotype for the rs4793665 ABCC3 variant were independently associated with a higher risk of MTX toxicity (RR 2.357, p=0.038 and RR 2.368, p=0.044, respectively). Conclusion Genetic polymorphisms related to the folate pathway (mainly the variant rs408626 of DHFR, rs1476413 of MTHFR and rs4793665 of ABCC3) seem to impact on MTX efficacy and toxicity in CD. Smoking could also influence MTX efficacy.