A Glance at the Use of Glucocorticoids in Rare Inflammatory and Autoimmune Diseases: Still an Indispensable Pharmacological Tool?

Abstract

Since their discovery, glucocorticoids (GCs) have been used to treat almost all autoimmune and chronic inflammatory diseases, as well as allergies and some forms of malignancies, because of their immunosuppressive and anti-inflammatory effects. Although GCs provide only symptomatic relief and do not eliminate the cause of the pathology, in the majority of treatments, GCs frequently cannot be replaced by other classes of drugs. Consequently, long-term treatments cause adverse effects that may, in turn, lead to new pathologies that sometimes require the withdrawal of GC therapy. Therefore, thus far, researchers have focused their efforts on molecules that have the same efficacy as that of GCs but cause fewer adverse effects. To this end, some GC-induced proteins, such as glucocorticoid-induced leucine zipper (GILZ), have been used as drugs in mouse models of inflammatory pathologies. In this review, we focus on some important but rare autoimmune and chronic inflammatory diseases for which the biomedical research investment in new therapies is less likely. Additionally, we critically evaluate the possibility of treating such diseases with other drugs, either GC-related or unrelated.

Keywords: autoimmunity; glucocorticoid-induced leucine zipper; glucocorticoids; inflammation; rare disease.

Figure 1

Complex regulation of glucocorticoid (GC) activity during pharmacological administration: GCs exert immunomodulatory activities, both by transactivating anti-inflammatory proteins such as glucocorticoid-induced leucine zipper (GILZ) and transrepressing pro-inflammatory genes, such as those encoding for pro-inflammatory cytokines, and therefore exerting powerful anti-inflammatory and immunosuppressive effects. They can also favor inflammation, e.g., by induction of inflammasome. Importantly, long-term GC treatment causes undesired adverse drug reactions (ADR), which can often result in severe pathologies such as diabetes, osteoporosis, and metabolic disorders. The hypothalamic–pituitary–adrenal (HPA) axis is inevitably suppressed after long-term treatment, thus indicating the use of dose-escalating regimens to avoid life-threatening consequences. The occurrence of resistance to GC efficacy can further complicate the management of autoimmune and inflammatory diseases, especially for diseases whose treatments other than GCs are not available.

Figure 2

Rare diseases on autoimmune or inflammatory basis. The figure summarizes the pathologies described in the text and the known pathogenesis and highlights the glucocorticoids (GC) benefits as monotherapy (+) or combination therapies (+-); (++) benefit represents remission close to 100%.

Figure 3

Efficacy of glucocorticoid-induced leucine zipper (GILZ)-based proteins in experimental models. Summary of GILZ proteins/peptides that have been used in rodent models of autoimmune or inflammatory diseases and proven efficacious. The underlying molecular and cellular mechanisms are also indicated.