Predicting therapy response to mycophenolic acid using UGT1A9 genotyping: towards personalized medicine in atopic dermatitis

Abstract

Atopic dermatitis (AD) is a very common chronic inflammatory skin disease requiring long-term treatment. Mycophenolic acid (MPA) is used off-label in treatment of patients with severe AD failing Cyclosporin A (CsA) treatment, however clinical efficacy is observed in only half of the AD patients. In blood, MPA levels are known to have a large interindividual variability. Low MPA exposure and increased enzyme activity correlates with the presence of UGT1A9 polymorphisms. In this retrospective study, 65 adult AD patients treated with MPA were classified as responder or non-responder to MPA treatment. UGT1A9 polymorphisms were determined using PCR. A significantly higher number of UGT1A9 polymorphisms was found in the group that did not respond to MPA treatment. Of the patients that carried a UGT1A9 polymorphism, 85.7% were non-responsive to MPA treatment. This implies that non-responsiveness in AD patients is more likely to occur in carriers of a UGT1A9 polymorphism. In a binary logistic regression analysis the odds ratio (OR) was 8.65 (95% confidence interval: 0.93-80.17). Our results show that UGT1A9 polymorphisms can be used to identify patients with non-responsiveness to MPA. Patients with UGT1A9 polymorphisms might benefit from higher MPA dosage. ARTICLE HISTORY

<p>Treatment resistant atopic dermatitis: challenges and solutions</p>

“…MMF and mycophenolate sodium inhibit purine synthesis in B and T lymphocytes by directly inhibiting inosine monophosphate dehydrogenase 54. The overall efficacy of MMF is dependent on a UGT1A9 polymorphism that ultimately affects the metabolism of MMF 55. In a 2017 study assessing UGT1A9 enzyme activity and MMF bioavailability, 85% of subjects who carried the UGT1A9 polymorphism were MMF nonresponders, presumably due to a suboptimal exposure to MMF 55.…”

Systemic Treatment of Adult Atopic Dermatitis: A Review

“…Conversely, MMF was successfully used as long-term treatment (1–2 g daily over 12–29 months) in three patients with a chronic form of atopic eczema [ 85 ]. A recent retrospective study demonstrated that there was a direct correlation between UGT1A9 polymorphisms and MPA therapy unresponsiveness in patients with AD [ 86 ]. The main side effects reported during MPA therapy were nausea, fatigue, flu-like syndrome and liver enzyme alteration [ 80 , 87 , 88 ].…”

Handlungsempfehlung zur Therapieumstellung von Immunsuppressiva auf Dupilumab bei Patienten mit atopischer Dermatitis

“…Für die topische Applikation stehen dabei Glukokortikoide (TGK) [6] in unterschiedlichen Wirkstärken, mit einem variablen therapeutischen Index [7,8] und in unterschiedlichen Galeniken sowie verschiedene Calcineurininhibitoren (TCI) [9] zur reaktiven und proaktiven Therapie zur Verfügung. In der Systemtherapie können in Ausnahmefällen Glukokortikoide (SGK), indikationsgerecht Ciclosporin (CSA) [10] oder Dupilumab [11], und als Off-label-Therapien Methotrexat (MTX) [12,13], Azathioprin (AZA) [14][15][16][17] oder Mycophenolsäurederivate (MPA) [18] eingesetzt werden. Für ein chronisches Handekzem im Rahmen des atopischen Syndroms kann auch eine Therapie mit Alitretinoin (ALI) erwogen werden [19].…”