Unravelling the mechanism of action of low-dose glucocorticoids: a study of oral versus parenteral glucocorticoids.

The mechanism of action of low doses of oral prednis(o)l)one (i.e. ≤7.5 mg) is not clear. Since this dose roughly corresponds to the daily physiological production of glucocorticoids (GCs) by the adrenal gland, a systemic immunosuppressive effect of ≤7.5mg predni(so)lone by virtue of supraphysiological systemic GC concentrations seems very unlikely. We here hypothesise that this immunosuppressive effect is explained by hepatic first-pass effects of oral GC, exposing only the liver to supraphysiological concentrations via the portal circulation. A study addressing this hypothesis is clinically important, as it can provide insight into the mechanism of action of this commonly used GC drug regime, but may also open a new paradigm for anti-inflammatory treatments (‘hepatic first-pass targeting’) of other sorts. Although it is difficult to directly test this hypothesis in humans, there is an indirect way of doing so: if indeed low dose GCs exert their effect by virtue of a hepatic first pass effect, oral administration should be more effective than systemic administration. We therefore propose to perform a proof-of-concept study in GC treatment-naïve patients with polymyalgia rheumatica (PMR), rheumatoid arthritis (RA) or psoriatic arthritis (PsA). These patients will be randomized to initiate a 4-day course of low dose GC therapy either via the oral or the parenteral route, and then cross over to 4 days via the other route. Before starting this proof-of-concept study, we will first perform a dose-finding study to examine which dose of prednisolone (5, 7.5 or 10 mg) renders a clearly identifiable decrease in Erythrocyte Sedimentation Rate (ESR) within 4 days.

The hypothesis is that low dose GC therapy exerts its anti-inflammatory effect by virtue of a first-pass effect through the liver. It is difficult to directly address the hypothesis, but there is an indirect way of doing so: if indeed low dose GCs exert their effect mainly by virtue of a hepatic first pass effect, oral administration should be more effective than systemic administration.

Measurements will take place at baseline, day 5 and day 9 in the main study.
Measurements will take place at baseline and day 5 in dose-finding study (pilot study).

Patients will be randomized to initiate a 4-day course of low dose GC therapy either via the oral or the parenteral route, and then cross over to 4 days via the other route. Before starting this proof-of-concept study, we will first perform a dose-finding study to examine which dose of prednisolone (5, 7.5 or 10 mg) renders a clearly identifiable decrease in Erythrocyte Sedimentation Rate (ESR) within 4 days.