Gender May Influence the Immunosuppressive Actions of Prednisone in Young Patients With Inflammatory Bowel Disease

Abstract

Although the use of glucocorticoids (GC) is well established, the therapeutic response to these agents often shows important interindividual differences, in particular among young patients with inflammatory bowel diseases (IBD). Currently, GC resistance or dependence cannot be predicted by clinical or laboratory findings. The aim of this study was to investigate the association of gender and age with GC efficacy and with the expression of Glucocorticoid-Induced Leucine Zipper (GILZ). One hundred thirty patients (mean age at enrolment 12.6 years, 53 Crohn’s disease, 70 males) were enrolled in this retrospective study. IBD patients with active disease despite prednisone at a daily dose of up to 2 mg/kg over a period of 4 weeks were defined as steroid resistant. Patients who initially responded but relapsed upon dose reduction were considered steroid-dependent. Total RNA was extracted from biopsies of 14 patients (9 males) and the levels of GILZ mRNA were evaluated by real-time PCR. Association between clinical response to prednisone and the considered demographic variables was evaluated using logistic regression models. After 4 weeks of treatment, 112 patients were responders to prednisone and 18 were resistant; at this time-point, resistant patients were older than responders (p=0.032). After 12 weeks, 42, 71 and 12 patients were sensitive, dependent and resistant respectively; at this time-point, females were more prone than males to develop prednisone dependence vs a good response (p=0.028) while age had no effect. Age was associated with response both at 4 and 12 weeks in the subgroups of females: resistant patients were older than sensitive ones at 4 weeks (p=0.02). Likewise, at 12 weeks of therapy, dependent patients resulted older than sensitive ones (p=0.05). No association of age with prednisone response was found in males. In a subgroup of 14 patients (5 females), GILZ mRNA expression in intestinal biopsies was higher in males (p=0.0031). Patients with unfavorable response (7) presented lower GILZ expression at disease onset in comparison to the responder group (p=0.017). Older females with IBD have a higher incidence of prednisone unfavorable response and reduced intestinal expression of the GC pharmacodynamic marker GILZ.

Glucocorticoid Receptor β Isoform Predominates in the Human Dysplastic Brain Region and Is Modulated by Age, Sex, and Antiseizure Medication

“…Sex and age differences relating to GR have been implicated in inflammatory bowel disease (IBD) as well [16] which is consistent with our case, where a significant difference in the dysplastic vs. non-dysplastic GRα/GRβ ratio in female patients and in patients > 45 years old was identified. Reports also indicate that female patients with IBD were more likely to develop a dependence on glucocorticoid treatment compared to male patients, who were less likely to relapse after glucocorticoid dose reduction [16]. In general, sex differences have been identified in epilepsy, with FCD being more common in male pediatric epilepsy patients compared to females [17].…”

“…This could be further investigated. Additionally, age played a statistically significant role in glucocorticoid response in these IBD patients, with glucocorticoid-resistant patients being older than responders [16]. GRβ is known to be involved in glucocorticoid resistance in multiple diseases [18,19], so the current findings of GRβ overexpression and a dependency of sex and age in the GRα/GRβ ratio in dysplastic compared to non-dysplastic brain tissue are consistent with findings in other disorders related to inflammatory factors.…”

“…Although the expression and ratio of GRα and GRβ isoforms in epilepsy have not yet been reported until now, interestingly, this information has been found to be pertinent to other diseases such as asthma, rheumatoid arthritis, and glioma [7][8][9]. Sex and age differences relating to GR have been implicated in inflammatory bowel disease (IBD) as well [16] which is consistent with our case, where a significant difference in the dysplastic vs. non-dysplastic GRα/GRβ ratio in female patients and in patients > 45 years old was identified. Reports also indicate that female patients with IBD were more likely to develop a dependence on glucocorticoid treatment compared to male patients, who were less likely to relapse after glucocorticoid dose reduction [16].…”

Corticosteroid Treatment-Resistance in Myasthenia Gravis

“…Men with psoriasis, multiple sclerosis and SLE have a worse prognosis, in contrast to there not being a difference in rheumatoid arthritis ( 79 ). Young women also have a poorer response compared to men to GC therapy for inflammatory bowel disease ( 81 ). Mortality rates generally are higher among women with autoimmune diseases, but this data is difficult to interpret as to whether biological, social, comorbidies, or other factors drive these observations.…”

Impact of sex differences on the clinical presentation, pathogenesis, treatment and prognosis of Sjögren's syndrome

“…However, there are some reports of sex differences in the treatment of some of these drugs. For example, in the treatment of inflammatory bowel disease with prednisone, it has been found that women are more dependent on prednisone than men and that the anti‐inflammatory effects of glucocorticoids are reduced in adolescent women because of reduced glucocorticoid receptor activity [69]. In reports on the treatment of RA, methotrexate has been found to be teratogenic in pregnant women and glucocorticoids taken at doses greater than 7.5 mg per day may impair time‐to‐pregnancy (TTP) by direct effects on endometrial and ovarian function and by transient inhibition of the hypothalamic–pituitary‐ovarian axis [70].…”