Corticosteroid Weaning Research Articles

Oxidant stress in primary nephrotic syndrome: does it modulate the response to corticosteroids?

In order to assess the oxidative stress in newly diagnosed children with primary nephrotic syndrome (PNS), we serially measured serum total antioxidant capacity (TAC) and malondialdehyde (MDA) in 33 children with PNS and ten healthy matched controls. Patients were classified into two groups: those who had steroid-sensitive nephrotic syndrome (SSNS; n = 26) and those who had steroid-resistant nephrotic syndrome (SRNS; n = 7). Of the patients with SSNS, 15 were non-relapsers and 11 were relapsers. At the proteinuric phase, all patients had significantly higher MDA levels and lower TAC than the controls. These changes were more marked in patients with SRNS than in those with SSNS. During remission and still on corticosteroids, patients had higher TAC and similar MDA levels as in the proteinuric phase, but the TAC and MDA levels still significantly differed from those of the controls. More improvement in TAC and MDA levels occurred in patients following the weaning of corticosteroids, but TAC was still lower in the patients than in the controls. Moreover, TAC was higher in non-relapsers than in relapsers. Using a receiver operating characteristic curve, the initial response to corticosteroids could be predicted at serum TAC level > or =0.73 mM/L (sensitivity 89%, specificity 86%), while serum TAC levels < or = 1.14 mM/L after the weaning of corticosteroids could predict that the patient would not relapse (sensitivity 91%, specificity 80%). In conclusion, based on our results, PNS can be considered to be associated with oxidative stress even during remission. This stress may modulate the response to corticosteroids. Further prospective studies using larger numbers of patients are needed to validate these results.

W1187 Outcome Following Infliximab Therapy in Pediatric Patients with Ulcerative Colitis: Results from a Multicenter Study

Background: Children with severe ulcerative colitis resistant to corticosteroids either need to undergo surgery or be treated with more intensive immunosuppression (e.g. cyclosporine, tacrolimus, infliximab). The short and long term efficacy of such therapies is not well described in children. Methods: From 1994 to 2008, 52 children (26M; mean age 13y, range 4-21 y) with steroid-refractory colitis were treated with tacrolimus at our institution. Medical record reviewwas performed on these patients. Data extracted allowed the calculation of the Pediatric Ulcerative Colitis Activity Index (PUCAI). In addition, other measures of disease activity, adverse events, and long-term outcomes were assessed. Statistical analysis of outcomes was performed using SAS statistical software. Results: Out of 52 patients, 46 were treated with tacrolimus with the intent to transition to maintenance medical therapy, while 6 were treated to allow corticosteroid weaning prior to elective colectomy. The median dose of tacrolimus utilized was 0.2 mg/kg/day (range 0.1-0.5 mg/kg/day) in two divided doses; the median trough level during induction therapy was 11 ng/ml. The median length of stay after the institution of tacrolimus was 10 days (range 3-37 days). The mean PUCAI score was 66.8 (±14.3 SD) prior to the initiation of tacrolimus therapy, and 21.9 (±14.8 SD) at time of hospital discharge. Of the 46 patients that were treated with the aim of postponing surgery, 43/46 (94%) were discharged without surgery. Patients were maintained on tacrolimus for 3 to 6 months (median 114 days), and transitioned to maintenance therapy (6MP, AZA, or infliximab). The probability of colectomy in this patient cohort was 7% at 1 month, 14% at 3 months, 30% at 12 months, and 57% at 25 months. No colectomies were performed in patients followed for longer than 25 months (longest follow-up 13 years). The most common adverse events noted in the first three months included tremor (32%), hypertension (21%), infections (9%), creatinine >1.5 x baseline (9%), and hyperglycemia (8%). These adverse effects resolved with weaning of steroids or transition to maintenance therapy. Conclusion: Tacrolimus is effective induction therapy in corticosteroid refractory colitis, and is generally well tolerated. However, many patients will develop exacerbations of colitis upon transition to maintenance therapies. The long term colectomy rate in this challenging population remains approximately 60% over time.

W1188 Growth in Pediatric Patients with IBD Treated with Infliximab or 6-Mercaptopurine/Azathioprine

Background: Children with severe ulcerative colitis resistant to corticosteroids either need to undergo surgery or be treated with more intensive immunosuppression (e.g. cyclosporine, tacrolimus, infliximab). The short and long term efficacy of such therapies is not well described in children. Methods: From 1994 to 2008, 52 children (26M; mean age 13y, range 4-21 y) with steroid-refractory colitis were treated with tacrolimus at our institution. Medical record reviewwas performed on these patients. Data extracted allowed the calculation of the Pediatric Ulcerative Colitis Activity Index (PUCAI). In addition, other measures of disease activity, adverse events, and long-term outcomes were assessed. Statistical analysis of outcomes was performed using SAS statistical software. Results: Out of 52 patients, 46 were treated with tacrolimus with the intent to transition to maintenance medical therapy, while 6 were treated to allow corticosteroid weaning prior to elective colectomy. The median dose of tacrolimus utilized was 0.2 mg/kg/day (range 0.1-0.5 mg/kg/day) in two divided doses; the median trough level during induction therapy was 11 ng/ml. The median length of stay after the institution of tacrolimus was 10 days (range 3-37 days). The mean PUCAI score was 66.8 (±14.3 SD) prior to the initiation of tacrolimus therapy, and 21.9 (±14.8 SD) at time of hospital discharge. Of the 46 patients that were treated with the aim of postponing surgery, 43/46 (94%) were discharged without surgery. Patients were maintained on tacrolimus for 3 to 6 months (median 114 days), and transitioned to maintenance therapy (6MP, AZA, or infliximab). The probability of colectomy in this patient cohort was 7% at 1 month, 14% at 3 months, 30% at 12 months, and 57% at 25 months. No colectomies were performed in patients followed for longer than 25 months (longest follow-up 13 years). The most common adverse events noted in the first three months included tremor (32%), hypertension (21%), infections (9%), creatinine >1.5 x baseline (9%), and hyperglycemia (8%). These adverse effects resolved with weaning of steroids or transition to maintenance therapy. Conclusion: Tacrolimus is effective induction therapy in corticosteroid refractory colitis, and is generally well tolerated. However, many patients will develop exacerbations of colitis upon transition to maintenance therapies. The long term colectomy rate in this challenging population remains approximately 60% over time.

W1189 Indeterminate Colitis (IC) in Children: A Two-Year Follow-Up

Background: Children with severe ulcerative colitis resistant to corticosteroids either need to undergo surgery or be treated with more intensive immunosuppression (e.g. cyclosporine, tacrolimus, infliximab). The short and long term efficacy of such therapies is not well described in children. Methods: From 1994 to 2008, 52 children (26M; mean age 13y, range 4-21 y) with steroid-refractory colitis were treated with tacrolimus at our institution. Medical record reviewwas performed on these patients. Data extracted allowed the calculation of the Pediatric Ulcerative Colitis Activity Index (PUCAI). In addition, other measures of disease activity, adverse events, and long-term outcomes were assessed. Statistical analysis of outcomes was performed using SAS statistical software. Results: Out of 52 patients, 46 were treated with tacrolimus with the intent to transition to maintenance medical therapy, while 6 were treated to allow corticosteroid weaning prior to elective colectomy. The median dose of tacrolimus utilized was 0.2 mg/kg/day (range 0.1-0.5 mg/kg/day) in two divided doses; the median trough level during induction therapy was 11 ng/ml. The median length of stay after the institution of tacrolimus was 10 days (range 3-37 days). The mean PUCAI score was 66.8 (±14.3 SD) prior to the initiation of tacrolimus therapy, and 21.9 (±14.8 SD) at time of hospital discharge. Of the 46 patients that were treated with the aim of postponing surgery, 43/46 (94%) were discharged without surgery. Patients were maintained on tacrolimus for 3 to 6 months (median 114 days), and transitioned to maintenance therapy (6MP, AZA, or infliximab). The probability of colectomy in this patient cohort was 7% at 1 month, 14% at 3 months, 30% at 12 months, and 57% at 25 months. No colectomies were performed in patients followed for longer than 25 months (longest follow-up 13 years). The most common adverse events noted in the first three months included tremor (32%), hypertension (21%), infections (9%), creatinine >1.5 x baseline (9%), and hyperglycemia (8%). These adverse effects resolved with weaning of steroids or transition to maintenance therapy. Conclusion: Tacrolimus is effective induction therapy in corticosteroid refractory colitis, and is generally well tolerated. However, many patients will develop exacerbations of colitis upon transition to maintenance therapies. The long term colectomy rate in this challenging population remains approximately 60% over time.

W1186 Outcomes and Adverse Events in Children and Young Adults with Steroid-Refractory Colitis Treated with Tacrolimus

Background: Children with severe ulcerative colitis resistant to corticosteroids either need to undergo surgery or be treated with more intensive immunosuppression (e.g. cyclosporine, tacrolimus, infliximab). The short and long term efficacy of such therapies is not well described in children. Methods: From 1994 to 2008, 52 children (26M; mean age 13y, range 4-21 y) with steroid-refractory colitis were treated with tacrolimus at our institution. Medical record reviewwas performed on these patients. Data extracted allowed the calculation of the Pediatric Ulcerative Colitis Activity Index (PUCAI). In addition, other measures of disease activity, adverse events, and long-term outcomes were assessed. Statistical analysis of outcomes was performed using SAS statistical software. Results: Out of 52 patients, 46 were treated with tacrolimus with the intent to transition to maintenance medical therapy, while 6 were treated to allow corticosteroid weaning prior to elective colectomy. The median dose of tacrolimus utilized was 0.2 mg/kg/day (range 0.1-0.5 mg/kg/day) in two divided doses; the median trough level during induction therapy was 11 ng/ml. The median length of stay after the institution of tacrolimus was 10 days (range 3-37 days). The mean PUCAI score was 66.8 (±14.3 SD) prior to the initiation of tacrolimus therapy, and 21.9 (±14.8 SD) at time of hospital discharge. Of the 46 patients that were treated with the aim of postponing surgery, 43/46 (94%) were discharged without surgery. Patients were maintained on tacrolimus for 3 to 6 months (median 114 days), and transitioned to maintenance therapy (6MP, AZA, or infliximab). The probability of colectomy in this patient cohort was 7% at 1 month, 14% at 3 months, 30% at 12 months, and 57% at 25 months. No colectomies were performed in patients followed for longer than 25 months (longest follow-up 13 years). The most common adverse events noted in the first three months included tremor (32%), hypertension (21%), infections (9%), creatinine >1.5 x baseline (9%), and hyperglycemia (8%). These adverse effects resolved with weaning of steroids or transition to maintenance therapy. Conclusion: Tacrolimus is effective induction therapy in corticosteroid refractory colitis, and is generally well tolerated. However, many patients will develop exacerbations of colitis upon transition to maintenance therapies. The long term colectomy rate in this challenging population remains approximately 60% over time.

82: Long-Term Risks Post Steroid Weaning: Not so Rosy after All

Corticosteroids (CS) after heart transplant have significant adverse effects. In many programs, corticosteroid weaning (CSW) is successfully performed with good outcome. Yet there are risks to CSW in terms of late rejection, which may result in graft dysfunction. The purpose of this study is to characterize the risks involved in CSW and analyze the long term follow up of these patients.

Beyond five years: Long-term follow-up in pediatric liver transplantation

Pediatric liver transplant patients are now routinely surviving 10 years or more. Beyond the first year after transplant, surgical biliary or vascular complications are rare, and the incidence of acute rejection episodes falls precipitously. Attention is turning to minimizing the toxicity of immunosuppressive regimens and their potential negative impact on growth, bone health, cognitive development, renal function, and quality of life. Innovative combinations of immunosuppressive medications are being used as initial management after transplantation to minimize acute rejection and allow rapid weaning of corticosteroids and reduction in maintenance levels of calcineurin inhibitors. The substitution of potentially less toxic immunosuppressive agents, such as mycophenolate mofetil and rapamycin, is being studied in patients who develop renal dysfunction. A major current emphasis is on defining the natural history of long-term graft injury and elucidating histopathologic changes that mimic autoimmune chronic active hepatitis but are likely a form of chronic rejection due to production by the recipient of antibodies to foreign graft antigens. As patients survive longer, we are seeing various forms of immune dysregulation engendered by the presence of the graft and chronic immunosuppression of the host. By defining the resulting patterns of graft injury and understanding their immunopathogenesis, we can devise rational adjustments in immunosuppression that will preserve graft function and maximize graft life.

Immunosuppressive Therapy in Older Cardiac Transplant Patients

Cardiac transplantation has become an established intervention for end-stage heart disease. Clinical outcomes in older cardiac transplant patients have improved over the last decade and are almost similar to those in younger patients. Nevertheless, morbidity and mortality due to infections, cancer and chronic allograft vasculopathy remain problematic. On the other hand, older transplant patients seem to have lower incidences of acute rejection episodes than younger patients. Conventional immunosuppression with calcineurin-inhibiting drugs, azathioprine and corticosteroids is responsible for a number of adverse effects. Although these adverse effects can also be seen in younger patients, tolerance to these agents seems to decrease with increasing age. In particular, diabetes mellitus, osteoporosis and chronic renal insufficiency are associated with higher morbidity and mortality in older cardiac transplant patients. As the elderly become an ever-increasing segment of the cardiac transplant population, new and innovative immunosuppressive strategies will have to be developed and applied.Currently, the availability of new immunosuppressive drugs means more individualised immunosuppressive protocols can be used. New antibodies for induction therapy, a choice between ciclosporin and tacrolimus, and the advent of mycophenolate mofetil as well as proliferation signal inhibitors (everolimus, sirolimus) have changed immunosuppressive protocols dramatically. Therefore, a generalised protocol for all patients has been replaced by individualised immunosuppression depending on the patient group. Moreover, protocols can be modified during follow-up depending on the individual patient's requirements and problems. Hypertension and hyperlipidaemia could be influenced by the selection of tacrolimus over ciclosporin, and weaning of corticosteroids might have a positive impact on osteoporosis or diabetes. There is also no clear evidence that tacrolimus is associated with a higher risk for new onset of diabetes. Chronic renal insufficiency can be managed with calcineurin inhibitor-free immunosuppression consisting of mycophenolate mofetil and proliferation signal inhibitors. Both everolimus and sirolimus also seem to have a protective effect against the onset of graft vasculopathy and some sorts of cancer after cardiac transplantation. As a general rule, however, older cardiac transplant patients should be treated with lower doses and fewer immunosuppressive drugs to avoid over-immunosuppression.

Corticosteroid Therapy in the Age of Infliximab: Acute and 1-Year Outcomes in Newly Diagnosed Children With Crohn’s Disease

The aim of this study was to describe 3-month and 1-year outcomes of children with Crohn's disease (CD) treated with corticosteroids within 30 days of diagnosis, with particular emphasis on the influence of infliximab on these outcomes. We also aimed to determine whether there are clinical or laboratory characteristics associated with corticosteroid therapy outcomes. Data from 109 children were drawn from a multicenter observational registry that was started in 2002. Clinical characteristics and data on corticosteroid and other therapies were recorded prospectively. Corticosteroid therapy outcomes at 3 months were defined as complete acute response, partial response, or corticosteroid resistance. At 1 year, corticosteroid responsiveness, dependence, and surgical rates were determined. Infliximab's influence on short- and long-term outcomes also was investigated. At 3 months, 65 of 109 (60%) patients had a complete acute response to corticosteroids, 26 (24%) had a partial response, and 18 (17%) were corticosteroid resistant. At 1 year, 61% were corticosteroid responsive, 31% were corticosteroid dependent, and 8% required surgery. Irrespective of the duration of corticosteroid treatment, 16 of 24 of corticosteroid-dependent/resistant patients rapidly discontinued corticosteroids after starting infliximab. No clinical or laboratory characteristics at diagnosis predicted short-term outcome. Growth impairment at diagnosis increased risk for corticosteroid dependence or surgery at 1 year. At 3 months, 84% of children had a complete or partial response to corticosteroids. However, despite concomitant immunomodulators, at 1 year 31% were corticosteroid dependent and 8% required surgery. Infliximab improves outcomes of corticosteroid-dependent/resistant patients because the duration of corticosteroid use can be controlled by initiating treatment with infliximab.

Corticosteroid weaning in the tacrolimus and mycophenolate era in heart transplantation: Clinical and neurohormonal benefits

Background Compared with cyclosporine, tacrolimus-based immunosuppression yields improved metabolic outcomes in heart transplantation. Whether corticosteroid freedom provides incremental metabolic benefits in tacrolimus and mycophenolate mofetil immunoprophylaxis remains uncertain. Methods In a prospective trial, 41 heart transplant patients treated with tacrolimus and mycophenolate mofetil underwent steroid weaning immediately after transplantation until weaning was complete. Weaning was interrupted only for treated rejection with or without hemodynamic compromise. Benefits of steroid weaning assessed following the first year included B-type natriuretic peptide (BNP), late infections, lipids, blood pressure, hyperglycemia, and body mass index (BMI). Results Of this 41 patient cohort (age 53 ± 9 years, 50% black American, 35% women) followed for a total of 47 ± 5 months, 25 had corticosteroids discontinued (62%) by an average of 20 ± 11 months. No differences between the two groups were noted in baseline characteristics. Significant predictors of failure to wean steroids included higher rejection, BNP, and lower dose of mycophenolate mofetil. No significant benefits of steroid weaning were noted on lipids, blood pressure, hyperglycemia, and BMI. However, late infections (after 1 year) requiring hospitalizations were more frequent in the failure to wean group (0.60.4 vs 0 infections/patient/y, P < .001). Inferences Unlike known metabolic benefits of steroid withdrawal with cyclosporine, heart transplant recipients treated with tacrolimus and mycophenolate mofetil demonstrate no incremental metabolic benefits, but instead experience benefits of decreased serious late infections. Furthermore, failure to discontinue corticosteroids in this series is predicted by early allograft rejection, use of lower doses of mycophenolate mofetil, and higher BNP levels suggesting poor cardiac adaptation.

Concern of Corticosteroid Weaning after Heart Transplantation

Concern of Corticosteroid Weaning after Heart Transplantation

The Meaning of Mild Rejection During Corticosteroid Weaning in Heart Transplant Recipients.

398 Corticosteroid weaning after heart transplant has increased in popularity and has been performed early and late (> 6 months) after heart transplantation. The actual weaning schedule has varied from program to program (over 1 week to 5 months). Some heart transplant programs will reinstitute corticosteroids if routine endomyocardial biopsy during weaning reveals mild rejection. However, it has not been established whether mild rejection progresses to a more severe form of rejection at a higher rate during corticosteroid weaning. To answer this question, we reviewed 165 heart transplant patients between April 1989 and July 1997 who were undergoing corticosteroid weaning beginning at 6 months after transplant and decreasing by 1 mg per month from a 5 mg baseline dose. Only endomyocardial biopsy grades of ≥3A were treated with reinstitution of corticosteroids at high doses. During this corticosteroid-weaning period, there were a total of 835 endomyocardial biopsies performed. Of the total, 558 were grade 0, 238 were grade 1A, 9 were grade 1B, 25 were grade 2, 4 were grade 3A, and 1 was grade 3B. The 4 patients with grade 3A rejection had either grade 0 or grade 1A on their previous endomyocardial biopsies. The patient with grade 3B rejection had previous endomyocardial biopsy demonstrating grade 1B rejection. This meant 1/9 (11%) grade 1B rejections and only 2/238 (0.8%) grade 1A rejection progressed to ≥ grade 3A rejection. Four patients were withdrawn from the corticosteroid-weaning protocol due to LVEF decreasing to ≤ 45% (range 20-45%) and all 4 patients had either grade 0 or grade 1A on their endomyocardial biopsy at the time of removal from the corticosteroid-weaning protocol. Other patients were not successfully weaned due to adverse effects of weaning including myalgias, headaches, arthritis, and fatigue. Corticosteroid weaning was successful in 83.6% of patients. Conclusion: Corticosteroid weaning late after heart transplantation is successful in a majority of patients. Endomyocardial biopsies during the steroid-weaning protocol revealing grade 1A mild rejection rarely progress to a more severe from of rejection and therefore do not support removing the patient from the corticosteroid-weaning protocol. Endomyocardial biopsy grade 1B rejection during corticosteroid weaning should have close observation with follow-up endomyocardial biopsy.

The Meaning of Mild Rejection During Corticosteroid Weaning in Heart Transplant Recipients.

The Meaning of Mild Rejection During Corticosteroid Weaning in Heart Transplant Recipients.

Healing of severe recurrent ileitis with azathioprine therapy in patients with Crohn's disease

BACKGROUND & AIMS: Standard corticosteroid therapy for Crohn's ileitis induces symptom relief without improvement of endoscopically visible lesions. In this study, the effect of azathioprine therapy on the inflammatory lesions in the neoterminal ileum of patients with severe postoperative Crohn's recurrence was examined. METHODS: Macroscopic ileal lesions were studied endoscopically or radiologically after at least 6 months of azathioprine therapy after complete weaning of corticosteroids. All patients who underwent an ileocecal resection for Crohn's disease at our institution between January 1989 and December 1993 and who subsequently developed severe recurrent ileitis treated with azathioprine were included. RESULTS: Of the 19 patients treated with azathioprine for recurrent ileitis, 15 could be reevaluated by endoscopy or radiological examination. The therapy resulted in induction and maintenance of clinical remission in all 15 patients, at least 6 months after complete weaning of the corticosteroids. Complete macroscopic healing of the neoterminal ileum was observed in 6 of 15 patients, near-complete healing with only superficial erosions remaining in 5 of 15 patients, partial healing in 3 of 15 patients, and unchanged inflammatory lesions in 1 patient. CONCLUSIONS: It is concluded that azathioprine leads to mucosal healing in severe recurrent Crohn's ileitis and may be the treatment of choice in this indication. (Gastroenterology 1997 May;112(5):1475-81)