Early Initiation of Biologics and Disease Outcomes in Adults and Children With Inflammatory Bowel Diseases: Results From the Epidemiology Group of the Nationwide Israeli Inflammatory Bowel Disease Research Nucleus Cohort.

BACKGROUND & AIMS: In this nationwide study, we explored whether early initiation of biologics is associated with improved outcomes in children and adults with Crohn's disease (CD) and ulcerative colitis (UC). METHODS: All patients diagnosed with CD or UC in Israel (2005-2020) were included in the Epidemiology Group of the Israeli Inflammatory Bowel Disease Research Nucleus cohort, encompassing 98% of the population. We compared disease duration at biologics initiation (ie, 0-3 months, >3-12 months, >1-2 years, and >2-3 years) using the cloning, censoring, and weighting by inverse probabilities method to emulate a target trial, adjusting for time-varying confounders and selection bias. RESULTS: Of the 34,375 included patients (of whom 5240 [15%] were children), 7452 of 19,264 (39%) with CD and 2235 of 15,111 (15%) with UC received biologics. In CD, by 10 years postdiagnosis, the probability of CD-related surgery decreased gradually but modestly with earlier initiation of biologics; a significant difference was noted between >2-3 years (31%) and 0-3 months (18%; P = .02; number needed to treat, 7.7), whereas there was no difference between the 0-3-month and >3-12-month periods. The 10-year probability of steroid dependency for the 0-3-month period (19%) differed both from the >2-3-year (31%; P < .001) and 1-2-year periods (37%; P < .001). In UC, no significant differences in colectomy or steroid dependency rates were observed between the treatment initiation periods. Similar trends were noted in the pediatric population. CONCLUSIONS: Very early initiation of biologics was not associated with some outcomes except for a modest risk reduction of surgery and steroid dependency for CD, which requires confirmation in future studies. In UC, early introduction of biologics was not associated with reduced risk of colectomy or steroid dependency.

Steroid-Dependency in Posner-Schlossman Syndrome: A Suggested Topical 2% Ganciclovir and Gradual Decrement of Topical Steroid Combination Therapy from Shanghai PSS Study.

PURPOSE: This study focused on the prevalence, unique features, and required treatment of steroid-dependent Posner-Schlossman syndrome (SD-PSS), and analyzed the outcome of 2% Ganciclovir and gradual decrement steroid combination therapy in SD-PSS patients. METHODS: Retrospective comparative and interventional study. SD-PSS was defined as PSS patients with continuous steroid use for over 3 months and relapsed within 2 weeks after steroid withdrawal or tapered dosage. Totally 74 SD-PSS eyes were compared with 78 randomly chosen non-steroid dependent PSS eyes. SD-PSS patients who underwent 2% GCV and gradual decrement steroid therapy with at least two follow-ups (n = 50) were analyzed for the treatment outcome. RESULTS: The prevalence of SD-PSS is 26.87% (97/361) in our PSS patients. SD-PSS patients demonstrated significantly younger onset age, longer disease course, higher intraocular pressure (IOP), and higher degree of iris depigmentation at the first visit. They required significantly more IOP-lowering medication and stronger steroid after the first visit. Our 2% GCV and gradual decrement steroid therapy helped 66% (33/50) SD-PSS patients with steroid withdrawal (median stable time: 13 weeks) and another 32% (16/50) SD-PSS managed to lower the dose or strength of topical steroid. Steroid-induced ocular hypertension happened in 5.26% (19/361) of the PSS patients. CONCLUSION: Young onset age, high IOP, and high iris depigmentation level during acute stage are indicators of steroid dependency in PSS patients. SD-PSS patients require more medical surveillance. Two percent ganciclovir and gradual decrement steroid combination therapy help with steroid withdrawal and minimize steroid use.

Burden of disease among patients with prevalent Crohn's disease: results from a large German sickness fund.

PURPOSE: The aim of this study was to investigate the burden of disease among a real-world cohort of patients with prevalent Crohn's disease (CD) in Germany. METHODS: We conducted a retrospective cohort analysis using administrative claims data from the German AOK PLUS health insurance fund. Continuously insured patients with a CD diagnosis between 01 October 2014 and 31 December 2018 were selected and followed for at least 12 months or longer until death or end of data availability on 31 December 2019. Medication use (biologics, immunosuppressants (IMS), steroids, 5-aminosalicylic acid) was assessed sequentially in the follow-up period. Among patients with no IMS or biologics (advanced therapy), we investigated indicators of active disease and corticosteroid use. RESULTS: Overall, 9284 prevalent CD patients were identified. Within the study period, 14.7% of CD patients were treated with biologics and 11.6% received IMS. Approximately 47% of all prevalent CD patients had mild disease, defined as no advanced therapy and signs of disease activity. Of 6836 (73.6%) patients who did not receive advanced therapy in the follow-up period, 36.3% showed signs of active disease; 40.1% used corticosteroids (including oral budesonide), with 9.9% exhibiting steroid dependency (≥ 1 prescription every 3 months for at least 12 months) in the available follow-up. CONCLUSIONS: This study suggests that there remains a large burden of disease among patients who do not receive IMS or biologics in the real world in Germany. A revision of treatment algorithms of patients in this setting according to the latest guidelines may improve patient outcomes.

Clinical characteristics of steroid-responsive but dependent chronic graft-versus-host disease: a multicenter retrospective analysis.

Chronic graft-versus-host disease (cGVHD) is a long-term complication of allogeneic hematopoietic stem cell transplantation. The clinical importance of long-term corticosteroid dependency in steroid-responsive cGVHD is undetermined. We retrospectively reviewed the data of 120 consecutive patients who received systemic steroid therapy for cGVHD between January 2007 and December 2018 at three institutions. Among patients with steroid-responsive cGVHD, those who successfully tapered off corticosteroids within 1 year were defined as the early withdrawal group (EW-cGVHD) and others were defined as the dependent group (Dp-cGVHD). Twenty-six patients were classified as EW-cGVHD and 55 as Dp-cGVHD. The proportion of men was significantly higher and performance status was significantly better in EW-cGVHD. The 5-year overall survival and cGVHD recurrence-free survival rates were significantly higher in EW-cGVHD than Dp-cGVHD (96% vs. 68%, p = 0.017 and 84% vs. 41%, p = 0.002, respectively). While the relapse-free survival rate did not differ significantly (84% vs. 65%, p = 0.15), the proportion of patients requiring readmission, mainly due to cGVHD recurrence or infection, was significantly increased in Dp-cGVHD (38% vs. 84%, p < 0.001). In summary, steroid dependency in cGVHD for more than 1 year was significantly associated with poor transplant outcomes.

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 (GRß) 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.

Childhood Idiopathic Nephrotic Syndrome: Does the Initial Steroid Treatment Modify the Outcome? A Multicentre, Prospective Cohort Study.

Background: A great majority of children with idiopathic nephrotic syndrome will relapse after successful treatment of the initial episode. The possibility that different steroid dosing regimens at onset, adjusted for risk factors, can reduce the rate of relapse represents an interesting option to investigate. Objectives: To evaluate the effect of the initial steroid regimen, adjusted for time to remission (TTR), on the frequency of relapses and steroid dependence, and to verify the influence of prognostic factors on disease course. Methods: A multicentre, prospective, cohort study. Children with nephrotic syndrome, with TTR ≤ 10 days (Group A), were given a 20-week prednisone regimen (2,828 mg/m2) and those with a TTR >10 days, a 22-week regimen (3,668 mg/m2) (Group B). Previously published retrospective data from the same centers were also evaluated. Main outcomes were: relapse rate, number of frequent relapsers + steroid dependent children and total prednisone dose after induction. Results: 143 children were enrolled. Rate of relapsed subjects (77 vs. 79%) and frequent relapsers + steroid dependent subjects (40 vs. 53%) did not differ between Groups A and B, or between the retrospective and prospective cohorts. The cumulative prednisone dose taken after the induction treatment was similar in both groups and in the retrospective and prospective cohorts. TTR was not associated with relapse risk. Age at onset and total serum protein were significantly lower in relapsing patients. At ROC analysis, the best cut-off was 5.3 years for age at onset and 4.2 g/dL for total serum protein. According to these cut-offs, older children with higher total serum protein had a higher relapse free survival rate (58%) than younger children with lower total serum protein (17%). Conclusions: TTR was not found to be a prognostic factor of relapse; because of this, different steroid regimens, adjusted for TTR, did not modify the relapse rate in any relevant measure. Conversely, younger age and low total serum protein were independent predictors of relapse risk, however this outcome was not modified by higher prednisone regimens. Clinical Trial Registration:https://www.ClinicalTrials.gov/, identifier: NCT01386957 (www.nefrokid.it).

SERPINB12 as a possible marker of steroid dependency in children with eosinophilic esophagitis: A pilot study.

BACKGROUND: Topical steroids are effective in eosinophilic esophagitis (EoE), but patients often show different tendencies to relapse. We assessed whether gene expression is associated with a sort of steroid dependency in EoE children. METHODS: Biopsy samples were prospectively collected on EoE children responding to topical steroids. Patients treated with viscous budesonide for 24 weeks were subsequently classified as early (6 months) or late (>6 months) relapsing. RNA was isolated from esophageal biopsies at the time of the relapse and analyzed by NGS for transcriptome profiling. RESULTS: Of 40 patients, 22 patients were considered for mRNA expression profile. Thirteen were included in the early-relapse group, and 9 were in the late-relapse. No significant difference was observed in the two groups for clinical, endoscopic or histological features. Using the mRNA expression profile we performed supervised clustering using the 10 top differentially expressed genes between early and late relapsing patients. The heatmap and PCA show a proper segregation among patients. SERPINB12 is the only gene attaining a significant differential expression between the two groups (FDR < 0.05). CONCLUSIONS: Different tendencies to relapse in EoE children responding to topical steroids might be related to altered mRNA expressions. SERPINB12 presented a significantly higher expression in the late relapse group and it deserves further investigations.

The prevalence and prognostic value of myelin oligodendrocyte glycoprotein antibody in adult optic neuritis.

BACKGROUND AND OBJECTIVE: Adult demyelinating optic neuritis (ON) with positive myelin-oligodendrocyte glycoprotein antibody (MOG-Ab) has distinct clinical features. This study aimed to investigate the point prevalence, relationship with steroid dependency and prognosis value of MOG-Ab in adult ON. METHODS: Clinical data analysis was undertaken in adults with ON admitted between December 2014 and January 2016. Patients were classified into three groups based on aquaporin-4 antibody (AQP4-Ab) and MOG-Ab status: AQP4-ON, MOG-ON and seronegative-ON. RESULTS: A total of 158 adults with ON (190 eyes) were assessed, including 31 MOG-ON (19.6%), 67 AQP4-ON (42.4%) and 60 seronegative-ON (38.0%) cases. The female-to-male ratio was significantly lower in MOG-ON (1.8:1) than that in AQP4-ON (8.6:1) groups (p = .005). The median age, percentage of bilateral ON and visual loss at the nadir at onset was similar among the three groups. Thirty-eight eyes (76%) in the MOG-ON group showed good visual recovery (>20/40) in the final visit, which is statistically better than that in the AQP4-ON and seronegative-ON groups (p < .001 and p = .006, resoectively). Fifteen adults with ON (9.5%) showed dependency on steroid, which was particularly prominent in the MOG-ON group (11/31, 35.5%) and rarely presented in the AQP4-ON (2, 3.0%) and seronegative-ON (2, 3.3%) groups. Results suggested less loss of pRNFL in MOG-ON than that in AQP4-ON group (p < .001), and a larger proportion of canalicular segment involved in MOG-ON adults (p = .007 and p < .001). CONCLUSION: MOG-ON had the smallest proportion of acute demyelinating ON in Chinese adults. One third of adults with MOG-ON predominantly showed a substantial dependency on steroids and relapse on steroid reduction or cessation, which rarely presented in AQP4-ON and seronegative-ON adults.

Treating the idiopathic nephrotic syndrome: are steroids the answer?

The use of steroids in idiopathic nephrotic syndrome is the major discovery of the twentieth century in the field of pediatric nephrology. At onset of the twenty-first century, steroids remain the first line of treatment at first flare. All the protocols to treat the first flare are similar by a common sequence including a first phase of daily prednisolone/prednisone at a dose of 60 mg/m2/day for at least 4 weeks followed by an alternate-day regimen for several weeks. It appears that a cumulated dose of 2240 mg/m2 given in 8 weeks at the first flare without tapering sequence is not inferior to increased dose and duration in terms of prevalence of frequent relapsers and the subsequent cumulated dose of steroids at 24 months of follow-up. A higher cumulated dose might only be interesting in patients aged below 4 years although a formal demonstration is still missing. Several retrospective studies are concordant to suggest that intravenous methylprednisolone pulses are useful to reach a full urinary remission in case of oral resistance to 4 weeks of oral prednisone/prednisolone. A majority of patients have multiple relapses after the treatment of the first flare and half meet the definition of steroid dependency. In those patients, long-lasting alternate-day prednisone/prednisolone therapy does not lead to long-lasting remission, opening the question of the best strategy of immunosuppression.

Predictive risk factors of steroid dependent nephrotic syndrome in children.

BACKGROUND: Development of steroid dependency is one of the difficult problems in the management of children with idiopathic nephrotic syndrome, leading to increased morbidity, complications and cost of treatment. Thus, predicting early in the disease course will be useful in counseling parents and may improve treatment strategy. OBJECTIVES: To determine the clinical characteristics that can predict the development of steroid dependency early in the initial episodes of steroid sensitive nephrotic syndrome (SSNS). PATIENTS AND METHODS: The study included 52 children with SSNS. Their ages ranged from 3 to 16 years. Patients were divided into two groups. Group A consisted of 24 patients with steroid dependency or frequent relapses nephrotic syndrome and group B consisted of 28 patients with complete remission or recurrent nephrotic syndrome. Data obtained retrospectively from patients' files. RESULTS: Children who require a cumulative steroid dose equal or more than 140 mg/kg to maintain remission during the first 6 months of the disease are at high risk to require steroid sparing agents (SSA) for disease control, and who did not achieve remission by day 20 of the initial prednisone course became steroid dependent with 96% specificity but with low sensitivity (50%). All steroid dependent children in this study showed relapses associated significantly with upper respiratory tract infections. CONCLUSIONS: Cumulative steroid dose in the first 6 months of treatment and the need of more than 20 days to achieve initial remission can predict steroid dependency in children with nephrotic syndrome.

Variability of diagnostic criteria and treatment of idiopathic nephrotic syndrome across European countries.

The aim of the surveys conducted by the Idiopathic Nephrotic Syndrome Working Group of the ESPN was to study the possible variability of treatment in Europe at different stages of the disease by means of questionnaires sent to members of the Working Group. Four surveys have been completed: treatment of the first flare, treatment of the first relapse and the issue of steroid dependency, use of rituximab, and the management of steroid-resistant patients. A uniform treatment of the first flare was applied in only three countries, and ten additional centers have adopted one of the three main protocols. Reported treatment of the first relapse was relatively uniform, whereas the use of additional immunosuppressants in steroid dependency was widely variable. Rituximab had already been used in hundreds of patients, although the formal evidence of efficiency in steroid dependency was relatively recent at the time of the survey. The definition of steroid resistance was variable in the European centers, but strikingly, the first-line treatment was uniform throughout the centers and included the combination of prednisone plus calcineurin antagonists. CONCLUSION: The variability in the approach of idiopathic nephrotic syndrome is unexpectedly large and affects treatment of the first flare, strategies in the case of steroid dependency, as well as the definitions of steroid resistance. What is Known: • Steroids and immunosuppressants are the universal treatment of idiopathic nephrotic syndrome. What is New: • The variability of treatments and strategy of treatment in European centers of pediatric nephrology.

Six year adalimumab efficacy in steroid-dependent Crohn's disease patients: A prospective single-center real life study.

BACKGROUND: Adalimumab is effective in the treatment of Crohn's disease. We have already reported data on the efficacy of adalimumab in 110 steroid-dependent patients. At the end of the study 90 patients (64.5%) maintained clinical remission. AIMS: To assess efficacy and safety of adalimumab after 6 years in patients of the original cohort who responded to treatment. METHODS: The present study is an extension of the published paper on 90/110 patients. We report results on clinical remission and safety of 6 year maintenance therapy with adalimumab. RESULTS: Of the original cohort 90 patients completed the study, 17 were lost to follow-up and 3 died. At the end of follow-up (74.16±10.3 months) 37/90 patients (41%) maintained clinical remission. Of these, 32 (86%) continued adalimumab and 5 (13%) discontinued treatment due to clinical remission and mucosal healing. Of the remaining 53/90 patients, 47 (52%) discontinued adalimumab due to clinical failure and 6 (7%) to adverse events. We obtained endoscopy data in 31/32 patients in clinical remission continuing adalimumab: 11 (36%) did not improve, 6 (19%) worsened, 14 (45%) improved. At univariable analysis no variables were related to treatment outcome. CONCLUSIONS: This "real life" prospective study shows that adalimumab is a long-term effective and safe maintenance treatment in steroid-dependent Crohn's disease patients.