Dataset Information

Adrenal steroidogenesis after B lymphocyte depletion therapy in new-onset Addison's disease.

ABSTRACT: A diagnosis of Addison's disease means lifelong dependence on daily glucocorticoid and mineralocorticoid therapy and is associated with increased morbidity and mortality as well as a risk of unexpected adrenal crisis.The objective of the study was to determine whether immunomodulatory therapy at an early stage of autoimmune Addison's disease could lead to preservation or improvement in adrenal steroidogenesis.This was an open-label, pilot study of B lymphocyte depletion therapy in new-onset idiopathic primary adrenal failure. Doses of iv rituximab (1 g) were given on d 1 and 15, after pretreatment with 125 mg iv methylprednisolone.Six patients (aged 17-47 yr; four females) were treated within 4 wk of the first diagnosis of idiopathic primary adrenal failure. Dynamic testing of adrenal function was performed every 3 months for at least 12 months.Serum cortisol levels declined rapidly and were less than 100 nmol/liter (3.6 ?g/dl) in all patients by 3 months after B lymphocyte depletion. Serum cortisol and aldosterone concentrations remained low in five of the six patients throughout the follow-up period. However, a single patient had sustained improvement in both serum cortisol [peak 434 nmol/liter (15.7 ?g/dl)] and aldosterone [peak 434 pmol/liter (15.7 ng/dl)] secretion. This patient was able to discontinue steroid medications 15 months after therapy and remains well, with improving serum cortisol levels 27 months after therapy.New-onset autoimmune Addison's disease should be considered as a potentially reversible condition in some patients. Future studies of immunomodulation in autoimmune Addison's disease may be warranted.

SUBMITTER: Pearce SH

PROVIDER: S-EPMC3462934 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Adrenal steroidogenesis after B lymphocyte depletion therapy in new-onset Addison's disease.

Pearce Simon H S SH Mitchell Anna L AL Bennett Stuart S King Phil P Chandran Sukesh S Nag Sath S Chen Shu S Smith Bernard Rees BR Isaacs John D JD Vaidya Bijay B

The Journal of clinical endocrinology and metabolism 20120705 10

<h4>Context</h4>A diagnosis of Addison's disease means lifelong dependence on daily glucocorticoid and mineralocorticoid therapy and is associated with increased morbidity and mortality as well as a risk of unexpected adrenal crisis.<h4>Objective</h4>The objective of the study was to determine whether immunomodulatory therapy at an early stage of autoimmune Addison's disease could lead to preservation or improvement in adrenal steroidogenesis.<h4>Design and intervention</h4>This was an open-labe ...[more]

PMID: 22767640

Similar Datasets

Project description:CONTEXT:In autoimmune Addison's disease (AAD), exogenous glucocorticoid (GC) therapy is an imperfect substitute for physiological GC secretion. Patients on long-term steroid replacement have increased morbidity, reduced life expectancy, and poorer quality of life. OBJECTIVE:The objective of this article is to restore adrenocortical steroidogenic function in recent-onset AAD. DESIGN:An open-label, multicenter trial of immunotherapy and trophic stimulation in new-onset AAD was conducted. Serial measurement of serum and urine corticosteroids at baseline and throughout a 72-week follow-up period was performed. SETTING:This study was conducted at the.endocrine departments and clinical research facilities at 5 UK tertiary centers. PATIENTS:Thirteen participants (9 female, 4 male; age 19-64 years) were included with AAD confirmed by high adrenocorticotropin, low circulating cortisol (basal < 100 nmol/L or post-tetracosactide < 300 nmol/L), and positive serum 21-hydroxylase antibodies. INTERVENTION:All participants received dual therapy with B-lymphocyte-depleting immunotherapy (rituximab 1 g given twice) and repeated depot tetracosactide (1 mg on alternate days for 12 weeks). MAIN OUTCOME MEASURE:Restoration of normal GC secretion (stimulated cortisol > 550 nmol/L) at week 48 was the main outcome measure. RESULTS:Ten of 13 (77%) participants had detectable stimulated serum cortisol (26-265 nmol/L) at trial entry. Following intervention, 7 of 13 (54%) had an increase in stimulated cortisol measurement, with a peak response of 325 nmol/L at week 18 in 1 participant. Increased steroid metabolites, assayed by urine gas chromatography-mass spectrometry at week 12 and week 48, was detected in 8 of 13 (62%) individuals, reflecting an increase in endogenous steroidogenesis. Four of 13 had residual adrenal function at 72 weeks. CONCLUSION:Combined treatment with rituximab and depot tetracosactide did not restore normal adrenal function. Nevertheless, adrenocortical plasticity is demonstrated in some patients, and this has the potential to be exploited to improve adrenal function.

Project description:Objective Patients with adrenal insufficiency (AI) need to adapt their glucocorticoid replacement under stressful conditions to prevent adrenal crisis (AC). Prednisone (PN) suppositories are used for emergency treatment. Pharmacokinetics of 100 mg PN suppositories after vaginal or rectal administration was evaluated. Design Single-center, open-label, sequence-randomized, cross-over, bioequivalence study. Methods Twelve females with primary AI were included. Comparison of pharmacokinetics after vaginal and rectal administration of 100 mg PN suppositories. Main outcome measures: bioequivalence (Cmax: maximum plasma concentration of prednisolone; AUC0 -360: area under the plasma concentration curve of prednisolone from administration to 360 min), adrenocorticotropin (ACTH) levels, safety and tolerability. Comparison of ACTH-suppressive effect with subcutaneous and intramuscular administration of 100 mg hydrocortisone. Results Vaginal administration of PN suppositories was not bioequivalent to rectal administration: Cmax and AUC0-360 were significantly lower after vaginal compared to rectal administration: 22 ng/mL (109%) vs 161 ng/mL (28%), P < 0.001; 4390 ng/mL * min (116%) vs 40,302 ng/mL * min (26%), P < 0.001; (mean (coefficient of variation), respectively). A suppression of ACTH by >50% of baseline values was observed 149 min (32%) after rectal PN administration; after vaginal PN administration, the maximum decrease within 360 min was only 44%. Adverse events were more frequent after vaginal administration and mainly attributable to the glucocorticoid deficit due to inadequate vaginal absorption. The ACTH-suppressive effect was more pronounced after parenteral hydrocortisone compared to rectal or vaginal PN. Conclusion Vaginal administration of PN suppositories in the available form is not useful for prevention of AC. Pharmacokinetics after rectal use of PN show inferiority compared to available data on parenteral glucocorticoids. In adrenal emergencies, hydrocortisone injection should be the first choice.

Dataset Information

Adrenal steroidogenesis after B lymphocyte depletion therapy in new-onset Addison's disease.

Publications

Adrenal steroidogenesis after B lymphocyte depletion therapy in new-onset Addison's disease.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets