Corticosteroid cross-reactivity: clinical and molecular modelling tools

Area of Science:

• Dermatology
• Immunology
• Computational Chemistry

Background:

• Corticosteroids are classified into four groups (A, B, C, D1, D2) based on contact allergenicity.
• Distinguishing C(16)-methylated and nonmethylated corticosteroids is crucial due to differing allergenic potentials.
• Nonmethylated forms bind selectively with arginine, leading to more pronounced allergic reactions.

Purpose of the Study:

• To compare molecular modeling with patch test results for corticosteroid cross-reactivity.
• To investigate the influence of electrostatic and steric fields on corticosteroid-induced allergic reactions.
• To refine the classification of corticosteroid contact allergens.

Main Methods:

• Analysis of patch test results from 315 sensitized subjects across 66 corticosteroid molecules.
• Correlation of clinical data with in silico molecular modeling, including electrostatic and steric field analysis.
• Clustering of molecules based on computational predictions of hydrolysis products.

Main Results:

• A three-cluster classification emerged post in silico hydrolysis of C(21) and C(17) esters.
• Patients allergic to cluster 2 (Group B, halogenated, C(16)/C(17) cis ketal/diol) and cluster 3 (Groups C/D1, halogenated, C(16)-methylated) also reacted to cluster 1 (Groups A/D2, non-halogenated, non-methylated, budesonide).
• Reactions were not universally bidirectional; cluster 1 allergens did not elicit reactions to clusters 2 or 3.

Conclusions:

• Two distinct patient allergy profiles were identified.
• Profile 1 patients reacted only to cluster 1, suggesting importance of electrostatic fields (molecular charge).
• Profile 2 patients reacted to multiple clusters, indicating steric fields (molecular structure) are key, possibly recognizing the core corticosteroid skeleton. A revised classification is proposed.