Optimizing Thiopurine Therapy with a Xanthine Oxidase Inhibitor in Patients with Systemic Autoimmune Diseases: A Single-Centre Experience.

BACKGROUND: Thiopurines are a mainstay of therapy for autoimmune diseases. However, up to 20% to 30% of patients experience overproduction of the methylated metabolites, known as 6-MMP, to the detriment of the active metabolite, 6-thioguanine nucleotide (6-TGN). These patients, commonly referred to as "shunters", are predisposed to thiopurine resistance and hepatotoxicity. In patients with inflammatory bowel diseases, the combination of thiopurine with a xanthine oxidase inhibitor (XOI) is used to reverse this skewed metabolism and to prevent treatment failure or hepatotoxicity. Data on the use of this strategy for patients with other diseases are limited. OBJECTIVES: To investigate and describe the use of thiopurine-XOI combination therapy in shunters with systemic autoimmune diseases. METHODS: Shunters treated in the study hospital between January 1, 2005, and December 31, 2015, were identified using the hospital's laboratory database, and clinical data were collected retrospectively. For each patient with optimization of thiopurine therapy, clinical and laboratory data were assessed over a 6-month period. RESULTS: Thirty-four patients were identified as shunters; for 14 of these patients, thiopurine therapy was optimized with an XOI. In these 14 patients, the median dose of azathioprine was reduced from 1.95 to 0.78 mg/kg with combination therapy. In addition, median 6-TGN level increased from 135 to 385 pmol/8 × 108 erythrocytes (p = 0.001); furthermore, 6-TGN levels rose to above 235 pmol/8 ×108 erythrocytes for 11 of the 14 patients. Conversely, the median 6-MMP level decreased from 6267 to 271 pmol/8 × 108 erythrocytes (p = 0.001). Except for a 12% increase in mean corpuscular volume, no clinically significant changes in blood count were recorded. Notable infections were reported in 3 patients, and 1 patient had to discontinue treatment because of cytopenia. After 6 months, median prednisone daily dose was reduced by 74%, from 16.7 mg to 4.4 mg (p = 0.005), and 4 patients had been weaned off corticosteroids. Of the 14 patients, 11 (79%) were in full remission, and 2 (14%) were in partial remission. CONCLUSION: Optimizing thiopurine therapy with an XOI may be a safe and effective strategy for patients with systemic autoimmune diseases.

CONTEXTE: Les thiopurines sont des piliers de l'intervention thérapeutique contre les maladies auto-immunes. Cependant, 20 % à 30 % des patients surproduisent des métabolites méthylés (connus sous le nom 6-MMP), au détriment du métabolite actif, le nucléotide 6-thioguanine (6-TGN). Ces patients, communément appelés « courts-circuiteurs ¼ sont prédisposés à résister à la thiopurine et à l'hépatotoxicité. Pour les patients ayant des maladies inflammatoires intestinales, on utilise la combinaison de thiopurine avec une xanthine oxydase inhibitrice (XOI) afin d'inverser ce métabolisme anormal et prévenir l'échec du traitement ou l'hépatotoxicité. Les données concernant l'adoption de cette stratégie pour les patients atteints d'autres maladies sont limitées. OBJECTIFS: Étudier et décrire l'utilisation de la thérapie combinée de thiopurine et de XOI pour les « courts-circuiteurs ¼ ayant des maladies auto-immunes systémiques. MÉTHODES: Les « courts-circuiteurs ¼ traités dans l'hôpital où s'est déroulée l'étude entre le 1er janvier 2005 et le 31 décembre 2015 ont été identifiés à l'aide de la base de données du laboratoire de l'hôpital et les données cliniques ont été recueillies de manière rétrospective. L'évaluation des données cliniques et de laboratoire de chaque patient bénéficiant d'une optimisation de la thérapie par la thiopurine a porté sur six mois de traitement. RÉSULTATS: Trente-quatre patients ont été identifiés comme « courts-circuiteurs ¼ et 14 d'entre eux ont bénéficié d'une optimisation de la thérapie par la thiopurine à l'aide d'une XOI. Ces derniers ont subi une thérapie de combinaison qui a fait passer la dose moyenne d'azathioprine de 1,95 à 0,78 mg/kg. De plus, le niveau moyen de 6-TGN est passé de 135 à 385 pmol/8 × 108 érythrocytes (p = 0,001). En outre, 11 des 14 patients ont vu le niveau de 6-TGN passer à plus de 235 pmol/8 ×108 érythrocytes. Inversement, le niveau moyen de 6-MMP est passé de 6267 à 271 pmol/8 × 108 érythrocytes (p = 0,001). À l'exception d'une augmentation de 12 % du volume corpusculaire moyen, aucun changement clinique important dans la numération globulaire n'a été noté. Trois patients ont développé des infections notables et l'un d'eux a dû arrêter le traitement à cause d'une cytopénie. Après six mois, la dose moyenne quotidienne de prednisone a été réduite de 74 %, pour passer de 16,7 mg à 4,4 mg (p = 0,005), et quatre patients ont été sevrés des corticostéroïdes. Sur les 14 patients, 11 (79 %) ont été déclarés en rémission totale et 2 (14 %) en rémission partielle. CONCLUSION: L'optimisation de la thérapie par la thiopurine associée à une XOI pourrait être sécuritaire et constituer une stratégie efficace pour les patients ayant une maladie auto-immune systémique.

Clozapine intoxication with severe adverse effects induced by an inflammatory and infectious process: a case report.

BACKGROUND: Clozapine intoxication can be life-threatening. Outside of the common drug-drug interactions, tobacco smoking, and caffeine consumption, infectious and inflammatory processes are important contributors to clozapine intoxication. Although this relationship has been reported previously, the literature is scant of proper research articles describing the presentation and management of this unpredictable interaction. Therefore, clinicians need to rely heavily on case reports describing clozapine intoxication caused by inflammation and/or infection. CASE PRESENTATION: A 64-year-old Caucasian woman known for schizophrenia was brought to the emergency department (ED) with severe signs and symptoms of clozapine intoxication (general deterioration, drowsiness, neutropenia, and ileus). She was on clozapine 700 mg daily amongst other medications. The clozapine dose was stable for over 3 years, and there were no recent changes in her medications. The initial culprit was determined to be an infectious/inflammatory process of gastrointestinal origin with contribution from dehydration and constipation. Clozapine and norclozapine serum concentrations confirmed the intoxication: 1315 ng/mL and 653 ng/mL, respectively. She drastically improved with clozapine dose reduction and antibiotic therapy. She remained stable for years with clozapine 600 mg daily with stable clozapine serum levels. CONCLUSION: This case report illustrates the possibility of severe toxicity associated with an acute infectious and/or inflammatory process in patients on clozapine therapy. Clinicians must maintain a high level of suspicion in patients taking clozapine who develop and an infectious and/or inflammatory process. Constipation secondary to clozapine intoxication can exacerbate the initial intoxication process.

Clinical Importance of Monitoring Unbound Valproic Acid Concentration in Patients with Hypoalbuminemia.

STUDY OBJECTIVE: Because the pharmacokinetic evaluation of valproic acid (VPA) based on total drug concentration may be misleading in patients with hypoalbuminemia as a result of saturable protein binding and saturable metabolism, we sought to investigate the usefulness of therapeutic drug monitoring of unbound VPA concentration in a real-world clinical context, with a focus on clinically significant neurologic adverse outcomes. DESIGN: Retrospective analysis. SETTING: Large academic tertiary care hospital in Montreal, Canada. PATIENTS: Forty-one adults, hospitalized or followed as outpatients, for whom unbound VPA concentration testing was performed between January 1, 2008, and April 30, 2015. Patients were retrospectively identified by using the hospital's central laboratory database. MEASUREMENTS AND MAIN RESULTS: In the multiple linear regression analysis, the two variables that significantly predicted unbound VPA concentration were total VPA concentration (p<0.001) and albumin concentration (p<0.001). The correlation between total VPA concentration and the number of neurologic adverse symptoms was 0.187 (p=0.241), whereas the correlation between unbound VPA concentration and the number of neurologic adverse symptoms was 0.384 (p=0.013). The performance of total and unbound VPA concentrations in predicting the presence of at least one neurologic adverse symptom, as determined by the receiver operating characteristic curve, was 0.642 (95% confidence interval [CI] 0.449-0.836, p=0.167) and 0.776 (95% CI 0.629-0.923, p=0.007), respectively. CONCLUSION: This study showed that in the presence of hypoalbuminemia, high unbound VPA concentrations can be observed despite normal or low total VPA concentrations. It also demonstrated that high unbound VPA concentrations are associated with clinically significant neurologic adverse symptoms. Clinicians should be aware that unbound VPA concentration monitoring may be required in the presence of hypoalbuminemia.

Metabolite monitoring to guide thiopurine therapy in systemic autoimmune diseases.

6-Thioguanine nucleotide (6-TGN) is the active metabolite of thiopurine drugs azathioprine and 6-mercaptopurine. 6-Methylmercaptopurine (6-MMP) is an inactive and potentially hepatotoxic metabolite. A subgroup of patients (shunters) preferentially produce 6-MMP instead of 6-TGN, therefore displaying thiopurine resistance and risk for hepatotoxicity. Outside inflammatory bowel disease literature, few data exist regarding individualized thiopurine therapy based on metabolite monitoring. This study sought to describe metabolite monitoring in patients receiving weight-based thiopurine for systemic autoimmune diseases. Patients were enrolled using a laboratory database, and data were retrospectively collected. The correlation between the highest thiopurine dose (mg/kg) and the 6-TGN concentration (pmol/8 × 108 erythrocytes) was estimated with Pearson's correlation coefficient. Seventy-one patients with various systemic autoimmune conditions were enrolled. The correlation between the thiopurine dose and the 6-TGN level was weak for the overall patient sample (r = 0.201, p = 0.092) and for the subgroup of non-shunters (r = 0.278, p = 0.053). Subjects with 6-MMP levels >5700 pmol/8 × 108 erythrocytes had more hepatic cytolysis compared to subjects with 6-MMP <5700, OR = 4.36 (CI 95% 1.18-16.13, p = 0.027). Twenty-two patients (31%) were identified as shunters. Six shunters developed hepatotoxicity, five of which had 6-MMP concentration >5700. Eleven non-shunters had hepatotoxicity, one of which had 6-MMP >5700. Thiopurine metabolite monitoring shows wide variability in 6-TGN levels among patients treated with weight-based thiopurine for systemic autoimmune diseases. Thirty-one percent of the patients in our series fulfilled the shunter definition. Thiopurine metabolite monitoring and dose adjustment to improve maintenance of remission and avoid hepatotoxicity should be studied prospectively.

Chronic Diarrhea Associated with High Teriflunomide Blood Concentration.

OBJECTIVE: To report the case of a patient treated with leflunomide that presented with chronic diarrhea associated with high teriflunomide blood concentration. An 84-year-old woman taking leflunomide 20 mg once daily for the past 2 years to treat rheumatoid arthritis (RA) was investigated for severe chronic diarrhea that had been worsening for the past 5 months. The patient's general condition progressively deteriorated and included electrolyte imbalances and a transient loss of consciousness. Therefore, hospitalization was required. Teriflunomide blood concentration was 156 mg/L. After 11 days of cholestyramine washout therapy, teriflunomide blood concentration was reduced to 6 mg/L. As the teriflunomide levels decreased, diarrhea improved. All other possible causes of diarrhea were ruled out. The patient's diarrhea finally resolved 26 days after treatment with cholestyramine. DISCUSSION: Diarrhea is a known adverse effect of leflunomide. In this report, the severe diarrhea was associated with high blood teriflunomide concentrations. Available data suggests an association between teriflunomide concentrations greater than 50 mg/L and lower disease activity, but toxic teriflunomide levels still have to be clarified. CONCLUSION: Further studies are needed to establish the optimal therapeutic levels of teriflunomide. However, therapeutic drug monitoring of teriflunomide blood concentrations may be helpful to improve effectiveness and to prevent toxicity in patients taking leflunomide for RA, particularly in those with suboptimal therapeutic response to leflunomide or in patients with toxicity suspected to be induced by leflunomide.

A metoprolol-terbinafine combination induced bradycardia.

To report a sinus bradycardia induced by metoprolol and terbinafine drug-drug interaction and its management. A 63 year-old Caucasian man on metoprolol 200 mg/day for stable coronary artery disease was prescribed a 90-day course of oral terbinafine 250 mg/day for onychomycosis. On the 49th day of terbinafine therapy, he was brought to the emergency room for a decrease of his global health status, confusion and falls. The electrocardiogram revealed a 37 beats/min sinus bradycardia. A score of 7 on the Naranjo adverse drug reaction probability scale indicates a probable relationship between the patient's sinus bradycardia and the drug interaction between metoprolol and terbinafine. The heart rate ameliorated first with a decrease in the dose of metoprolol. It was subsequently changed to bisoprolol and the heart rate remained normal. By inhibiting the cytochrome P450 2D6, terbinafine had decreased metoprolol's clearance, leading in metoprolol accumulation which has resulted in clinically significant sinus bradycardia.

Interrater agreement for two systems used to determine the probability of heparin-induced thrombocytopenia.

PURPOSE: The interrater reliability of the 4T's method and the HIT expert probability (HEP) score for clinical evaluation of suspected heparin-induced thrombocytopenia (HIT) was investigated. METHODS: Patients hospitalized over a three-year period who were tested for HIT via anti-platelet factor 4 (anti-PF4) antigen assay were identified using laboratory data; 127 patient cases met the study inclusion criteria. Nine clinical pharmacists with expertise in HIT management evaluated the 127 cases using two pretest scoring systems: the 4T's score and the HEP score. Each case was independently evaluated using both 4T's and HEP scores. The primary endpoint was interrater agreement of overall 4T's and HEP scores and individual item scores. RESULTS: Raw agreement of values assigned by the two raters for each of the four items comprising the 4T's score ranged from 0.54 to 0.86, with agreement of 0.63 for final patient categorizations. Raw agreement of rater weightings of the eight HEP scoring items ranged from 0.34 to 1.0; for dichotomization of patients at the suggested screening cutoff value (>2.0), agreement was 0.65. Kappa coefficients were 0.15-0.45 for 4T's item scores and 0.17-0.70 for HEP score item scores. With both scoring systems, low rater agreement mainly related to determination of the timing of thrombocytopenia and possible other causes of the disorder. CONCLUSION: In a retrospective study, inter-rater agreement in scoring of HIT probability via the 4T's and HEP scoring systems was relatively low. The HEP score did not increase interrater reliability or correlation with anti-PF4 antibodies compared with the 4T's score.

Febuxostat as a novel option to optimize thiopurines' metabolism in patients with inadequate metabolite levels.

OBJECTIVE: To report the use of febuxostat in order to potentiate thiopurines' metabolism in a patient on azathioprine (AZA) therapy with low metabolite 6-thioguanine nucleotides (6-TGN) levels and elevated metabolite 6-methylmercaptopurine (6-MMP) levels. CASE SUMMARY: A 44-year-old woman with a history of anti-signal recognition particle necrotizing myopathy was treated with AZA-allopurinol combination therapy. When she developed an atypical drug-induced hypersensitivity syndrome, allopurinol was replaced by the new xanthine oxidase (XO) inhibitor febuxostat, at a daily dose of 40 mg. Febuxostat-AZA combination was successful with 6-TGN reaching therapeutic levels while 6-MMP levels remained low. After 5 months, she developed similar manifestations that she had presented on AZA-allopurinol combination. Febuxostat and AZA were then stopped. DISCUSSION: AZA and 6-MP are both inactive pro-drugs that undergo a complex metabolic transformation leading to active 6-TGN and potentially hepatotoxic 6-MMP. Some patients with unfavorable thiopurine metabolism might benefit from addition of XO inhibitor allopurinol in order to potentiate 6-TGN and reduce 6-MMP levels. It is likely that febuxostat, via its XO inhibition, would exhibit the same effect on thiopurines' metabolism. CONCLUSION: It has been shown that low dose of febuxostat was able to prevent hypermethylation and to potentiate 6-TGN levels in an AZA-treated patient. Thus, febuxostat could be useful in optimizing thiopurines' metabolism, but more data are needed before this practice can be recommended. The mechanisms by which febuxostat optimizes thiopurines' metabolism remain to be confirmed. Also, the optimal dose of febuxostat for this use remains to be determined.