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SHORT COMMUNICATION
Allopurinol Co-prescription Improves the Outcome of Azathioprine Treatment in Chronic Eczema
Floor M. GARRITSEN 1 , Jorien VAN DER SCHAFT 1 , Marlies DE GRAAF 1 , Dirk Jan HIJNEN 1 , Carla A. F. BRUIJNZEEL-KOOMEN 1 ,
Marcel P. H. VAN DEN BROEK 2 and Marjolein S. DE BRUIN-WELLER 1
1
Department of Dermatology and Allergology, and 2 Department of Clinical Pharmacy, University Medical Center Utrecht, Post Box 85500,
NL-3508 GA Utrecht, The Netherlands. E-mail: [email protected]
Accepted Nov 13, 2017; Epub ahead of print Nov 14, 2017
The efficacy of azathioprine (AZA) treatment for atopic
dermatitis (AD) has been demonstrated in a number of
randomized controlled trials and open-label studies (1),
but recent studies in daily clinical practice have shown
less favourable results (2, 3). AZA is a thiopurine prodrug
that does not itself have immunosuppressive activity. After
convertion in the liver, the most important metabolites
are 6-thioguanine nucleotide (6-TGN) and methylated
6-methylmercaptopurine (6-MMP). The immunosuppres-
sive effect of AZA is caused by the 6-TGN metabolites.
Highly elevated 6-TGN concentrations are associated
with the development of myelotoxicity; highly elevated
6-MMP concentrations are associated with the develop-
ment of hepatotoxicity.
New insights from assessment of patients with inflam-
matory bowel disease (IBD) who were on AZA treatment
led to strategies to reduce the risk of toxicity and optimize
effectiveness and safety. Increased 6-MMP/6-TGN ratios
indicate that the patients preferentially metabolize thiopuri-
ne to 6-MMP at the expense of the therapeutically active
6-TGN. This phenomenon of skewed drug metabolism,
also known as ”thiopurine hypermethylation”, occurs in up
to 20% of the population (4). Treatment with a combination
of AZA and allopurinol can bypass thiopurine-related side-
effects (5, 6) because allopurinol can shift AZA metabolism
towards 6-TGN production (Fig. S1 1 ).
The aim of this study is to investigate the effects of al-
lopurinol co-prescription in patients with AD and chronic
hand/foot eczema who are being treated with AZA, with
regard to metabolite levels (6-TGN, 6-MMP), side-effects
and clinical effectiveness.
METHODS
This prospective observational study, performed between 1 Ja-
nuary 2015 and 1 October 2016, included adult patients with AD
and/or chronic hand/foot eczema, which failed to respond to AZA
monotherapy, who were starting combination therapy of AZA
and allopurinol. Reasons for AZA failure were lack of clinical
effectiveness of therapeutic doses of AZA, side-effects, and/or
a skewed metabolism. A fixed dose of allopurinol, 100 mg/day,
was used. In order to prevent myelotoxic levels of 6-TGN after
allopurinol co-prescription, the AZA dose was decreased by at
least 50% in all patients.
6-TGN and 6-MMP metabolites were analysed in whole blood
by the Clinical Pharmaceutical and Toxicological Laboratory of the
Department of Pharmacy, University Medical Center Utrecht, the
https://www.medicaljournals.se/acta/content/abstract/10.2340/00015555-2839
1
Netherlands, using liquid chromatography-tandem mass spectro-
metry (LC-MS/MS). The Dervieux-method was used (7). Values
were expressed in picomoles/8×10 8 (red blood cells).
6-TGN and 6-MMP levels were measured before and at least 3
weeks after addition of allopurinol, assuming steady-state levels.
6-MMP/6-TGN ratios were calculated.
Clinical responsiveness before and after allopurinol co-prescrip-
tion was determined, using the Investigator Global Assessment
(IGA, 6-point scale) (8). A responder was defined as an IGA score
of 0–2 or a decrease of 2 points in IGA. Non-responders were
patients with an IGA score of 3–5 (except those patients with a
decrease of 2 points in IGA score, those were responders) or with
concomitant oral corticosteroids treatment. Clinical responsiveness
and therapeutic drug monitoring were assessed at the same visit.
Hepatotoxicity was defined as an alanine aminotransferase
(ALT) or aspartate aminotransferase (AST) twice the upper limit
of normal (ALT: > 45 U/l in men and > 35 U/l in women; AST: > 35
U/l in men, > 30 U/l in women). Bone marrow suppression was
defined as white blood cell count < 4 × 10 9 /l and/or thrombocyto-
paenia (platelet count < 150×10 9 /l). Subjective side-effects were
evaluated before and after allopurinol co-prescription.
All statistical analyses were performed using SPSS statistics
21. Frequencies, percentages and medians with interquartile
ranges (IQR) were calculated. The Mann-Whitney U test was
used to test whether differences in 6-TGN level, 6-MMP level or
6-MMP/6-TGN ratio before and after the addition of allopurinol
were significantly different.
RESULTS
Fifteen patients were enrolled, including 9 patients with
AD (60.0%) and 6 patients (40