ACTH is a 39 amino acids polypeptide which stimulates adrenocortical steroid production. The N-terminal segment of ACTH(124) is biologically active and the C-terminal is considered to have greater antigenicity. In one previous (RoSA) and one current (RADS2) clinical trial synthetic ACTH (zinc tetracosactide; depot synacthen) was administered to autoimmune Addisons disease (AAD) patients to stimulate adrenocortical regeneration. 4/13 RoSA patients developed allergic cutaneous reactions following administration of depot Synacthen.
An ELISA was used to detect reactivity to ACTH(139), ACTH(124), ACTH(113), and ACTH(1839) peptides anchored to solid phase. Binding activity was measured in triplicate sera samples in 18 AAD trial participants and a control cohort of 100 A+E attenders. To determine seropositivity, the highest relative absorbance level of the control cohort was used as an arbitrary threshold.
No control sera showed reactivity to full-length ACTH(139) or to the ACTH(113) (αMSH) peptide. 3/18 (17%) trial participants showed reactivity to full-length ACTH(139), with an additional 2/18 (11%) showing reactivity to the ACTH(113) (αMSH) component in isolation. 2/18 (11%) AAD patients demonstrated reactivity to 124 post-treatment with depot tetracosactide, with steadily rising absorbance readings during the treatment course. Quantitatively, patient reactivity to tetracosactide depot (ACTH(124)-Zn) was higher at baseline than in controls (P=0.0002), but reactivity against soluble ACTH(124) was less in both groups (P=0.03). In those patients who had received concurrent rituximab therapy, no reactivity to depot tetracosactide was demonstrated.
A proportion of AAD patients receiving repeated doses of depot tetracosactide develop anti-ACTH antibodies, with varied reactivity to constituent portions of ACTH. Rising antibody concentrations during treatment may explain adverse effects in patients and resistance to long-term tetracosactide therapy. Furthermore, hypersensitivity to zinc phosphate in the tetracosactide depot preparation is likely to play a cumulative role in the mounting antibody response to ACTH(124).