CONVENTIONAL GLUCOCORTICOID REPLACEMENT THERAPY VS. DUAL-RELEASE HYDROCORTISONE: EFFECTS ON INFLAMMATION AND IMMUNE PROFILE IN PATIENTS WITH PRIMARY ADRENAL INSUFFICIENCY AND IMPLICATIONS OF THERAPY RESPONSE PREDICTORS

Abstract

Primary adrenal insufficiency (PAI), whose autoimmune adrenalitis is the main cause, is characterised by an inadequate cortisol secretion, due to a destruction of adrenal gland and a consequent lack of glucocorticoid and mineralocorticoid production. Autoimmune conditions are caused by a loss of tolerance for self-antigens, with regulatory T lymphocytes failing in limiting auto-reactivity, and the increase of pro-inflammatory processes. Generally, corticosteroids exert anti-inflammatory and immunosuppressive actions by regulating the expression of inflammatory and immunomodulatory proteins and by modulating the lymphocyte pattern, including the regulatory T-cells (Tregs) induction. Conventional glucocorticoids - including cortisone acetate and hydrocortisone administered two or three times a day - are the mainstay of the treatment of patients with PAI, but in the most recent years the innovative dual-release hydrocortisone (DR-HC) - administered once daily - has been used as replacement therapy. DR-HC has shown favourable effects on cardiovascular risk factors, glucose metabolism and bone parameters compared to conventional steroids. Moreover, it has shown to improve the immune system cell profile expression, restoring a more physiological circadian glucocorticoid rhythm. According to this evidence, this study investigates whether conventional replacement steroid (CRS) or DR-HC elicit different response in terms of anti-inflammatory or immunomodulatory effects, by measurement of anthropometric, metabolic, serum inflammatory parameters and gene expression levels of IL-6, IL-17A, COX-2, HSP-70, IDO, PD-L1, hnRNPA2/B, iNOS and TXN-1. Additionally, a cytofluorimetric analysis was performed to evaluate a modulation in the activation status of T-cells, including CD4+CD25+Foxp3+Treg population. The study included 15 patients with PAI on conventional glucocorticoid therapy and 15 patients on DR-HC. The outcomes of the study were evaluated by isolation of peripheral blood mononuclear cells at baseline and after 12 months of treatment. 10 healthy patients (controls) were evaluated at the time of enrolment. In patients treated with CRS, a significant increase in c-reactive protein, erythrocyte sedimentation rate and fibrinogen were observed after 12 months of treatment compared to baseline. At 12 months, significantly lower waist circumference, glucose, c-reactive protein, erythrocyte sedimentation rate and neutrophile-to-lymphocyte ratio was observed in patients treated with DR-HC compared to those treated with conventional treatment. A significant decrease in the transcription of COX-2 and HSP-70 (along with IL-6) was observed together with a significant increase in mRNA expression of IDO and PD-L1 in patients treated with DR-HC after 12 months of observation. Compared to CRS, DR-HC treatment improves the inflammatory and immune patterns in patients with PAI modulating several proteins involved in inflammatory response in a Treg-independent manner. Moreover, we can suppose that the transcription levels of IL-6, COX-2, HSP-70, IDO and PD-L1 could be considered to predict and evaluate the response to steroidal therapies in PAI and their different efficacies, based on our findings on anthropometric, metabolic, and biochemical outcomes. However, further larger and controlled studies are needed to confirm our preliminary results and the relevance of this assumption.