This study aimed to evaluate the efficacy and safety of mycophenolate mofetil (MMF) or tacrolimus (TAC) compared with azathioprine (AZA) as maintenance therapy for active lupus nephritis (ALN). Patients with ALN who responded to 24 weeks of induction treatment were enrolled. Patients who received MMF or TAC as induction therapy continued MMF or TAC treatment during the maintenance period, whereas those who received intravenous cyclophosphamide were subjected to AZA treatment. The primary endpoint was the incidence of renal relapse. Secondary endpoints included extrarenal flares and composite endpoints (deaths, end-stage renal disease, or doubling of serum creatinine levels). A total of 123 ALN patients (47 in the MMF group, 37 in the TAC group, and 39 in the AZA group) were enrolled. The median follow-up time was 60 months. Ten MMF-treated patients, ten TAC-treated patients, and eight AZA-treated patients experienced renal relapses (P = 0.844). The cumulative renal relapse rates in the MMF group (P = 0.934) and TAC group (P = 0.673) were similar to the renal relapse rate in the AZA group. No significant difference in the incidence of severe adverse event was observed among the groups. Long-term maintenance therapies with MMF or TAC might have similarly low rates of renal relapse and similar safety profiles compared with AZA.
Humans ; Mycophenolic Acid/adverse effects* ; Azathioprine/adverse effects* ; Tacrolimus/therapeutic use* ; Lupus Nephritis/complications* ; Immunosuppressive Agents ; Treatment Outcome ; Recurrence

Adjuvants, Immunologic ; adverse effects ; therapeutic use ; Azathioprine ; adverse effects ; therapeutic use ; Cyclosporine ; adverse effects ; therapeutic use ; Glucocorticoids ; adverse effects ; therapeutic use ; Humans ; Mycophenolic Acid ; adverse effects ; analogs & derivatives ; therapeutic use ; Tacrolimus ; adverse effects ; therapeutic use

Acute pancreatitis is a serious disease with fatality rate up to 15%. We recently experienced a case of acute pancreatitis induced by multiple drugs in a patient with ulcerative colitis. A 20-year-old female visited with abdominal pain and hematochezia and diagnosed of ulcerative colitis. Sulfasalazine and prednisolone were used. However, acute pancreatitis occurred after 4 weeks of treatment with additional azathioprine treatment. Drug-induced pancreatitis was suspected, and she was recovered with conventional therapy for acute pancreatitis. Therefore, it was proposed that acute pancreatitis was induced by azathioprine. However, after the administration of sulfasalazine, pancreatitis relapsed. Furthermore, even the re-administration of 5-ASA and azathioprine induced relapse of acute pancreatitis. We concluded that acute pancreatitis was induced by multiple drugs in this patient with ulcerative colitis.
Acute Disease ; Anti-Inflammatory Agents, Non-Steroidal/adverse effects ; Antimetabolites/adverse effects ; Azathioprine/adverse effects ; Colitis, Ulcerative/diagnosis/*drug therapy ; Colonoscopy ; Female ; Humans ; Mesalamine/adverse effects ; Pancreatitis/*chemically induced/*diagnosis ; Sulfasalazine/adverse effects ; Tomography, X-Ray Computed ; Young Adult

Thiopurine S-methyltransferase (TPMT) methylates purine analogues, showing TPMT activity in inverse relation to concentrations of active metabolites such as 6-thioguanine nucleotide (6-TGN). With conventional dosing of thiopurines, patients with homozygous variant TPMT alleles consistently suffer from severe myelosuppression. Here, we report a patient with TPMT*3C/*3C who managed successfully with monitoring of thiopurine metabolites. The patient was an 18-year-old male diagnosed with Crohn's disease. The standard dose of azathioprine (AZA) (1.8 mg/kg/day) with mesalazine (55.6 mg/kg/day) was prescribed. Two weeks after starting AZA treatment, the patient developed leukopenia. The DNA sequence analysis of TPMT identified a homozygous missense variation (NM_000367.2: c.719A>G; p.Tyr240Cys), TPMT*3C/*3C. He was treated with adjusted doses of azathioprine (0.1-0.2 mg/kg/day) and his metabolites were closely monitored. Leukopenia did not reoccur during the follow-up period of 24 months. To our knowledge, this is the first case of a patient homozygous for TPMT*3C successfully treated with azathioprine in Korea. While a TPMT genotyping test may be helpful to determine a safe starting dose, it may not completely prevent myelosuppression. Monitoring metabolites as well as routine laboratory tests can contribute to assessing drug metabolism and optimizing drug dosing with minimized drug-induced toxicity.
Adolescent ; Azathioprine/adverse effects/*therapeutic use ; Homozygote ; Humans ; Inflammatory Bowel Diseases/*drug therapy/*enzymology/*genetics/metabolism ; Male ; Methyltransferases/*genetics

No abstract available.
6-Mercaptopurine/*adverse effects/metabolism/therapeutic use ; Antimetabolites, Antineoplastic/adverse effects/therapeutic use ; Azathioprine/*adverse effects/therapeutic use ; Cohort Studies ; Drug Therapy, Combination ; Humans ; Inflammatory Bowel Diseases/*drug therapy/etiology ; Leukopenia/chemically induced

BACKGROUNDThe thiopurine drugs are well established in the treatment of inflammatory bowel disease (IBD). However, uncertainty regarding the risk for neutropenia and hepatotoxicity deters its using. Thiopurine methyltransferase (TPMT) is the key enzyme in the metabolism of thiopurine. The aim of this study was to investigate the association of TPMT polymorphisms and activity with azathioprine (AZA)-related adverse events and clinical efficacy in Chinese Han patients with IBD.

METHODSFifty-two Han IBD patients treated with AZA were assessed for TPMT 2, 3A, 3B, and 3C, and for adverse events. Then, using reverse-phase high-performance liquid chromatography, TPMT activity was measured in 13 patients to analyze its correlation with AZA-related toxicity and clinical efficacy.

RESULTSOf the 52 patients, five experienced myelotoxicity and one experienced hepatotoxicity during treatment. No TPMT 2, 3A, 3B or 3C polymorphisms were detected in any of the 52 patients. In the 13 patients with TPMT activity measurement, TPMT activity ranged from 7.2 to 28.8 U/ml packed red blood cells (pRBCs). Among the 5 patients who suffered from myelotoxicity, 3 were affected in the early stage of AZA therapy. In these 3 patients, TPMT levels were significantly lower than those in patients without myelotoxicity, which reached statistical significance ((9.3 ± 2.1) U/ml pRBC vs. (18.0 ± 6.2) U/ml pRBC; P = 0.046). One patient who had higher TPMT activity (28.8 U/ml pRBC) suffered from hepatotoxicity during AZA therapy. Patients who achieved a clinical response had lower TPMT activity than those failed to respond ((13.7 ± 3.5) U/ml pRBC vs. (22.0 ± 5.5) U/ml pRBC; P = 0.009).

CONCLUSIONSTPMT variants do not completely account for the AZA-related myelotoxicity in Chinese Han IBD patients. However, measurement of TPMT activity may be helpful in reducing the risk of toxicity, and predicting the therapeutic efficacy.

Adolescent ; Adult ; Aged ; Antimetabolites ; therapeutic use ; Azathioprine ; adverse effects ; therapeutic use ; Female ; Humans ; Inflammatory Bowel Diseases ; drug therapy ; enzymology ; Male ; Methyltransferases ; genetics ; metabolism ; Middle Aged ; Polymorphism, Genetic

The risk of lymphoproliferative disorders (LPDs) has been reported to be increased in autoimmune diseases and chronic inflammatory diseases. Similar with other chronic inflammatory diseases such as rheumatoid arthritis, there is a concern about the risk of LPDs in patients with inflammatory bowel disease (IBD). Generally, in IBD patients, the risk of LPDs appears to be similar with or very slightly higher, compared to the general population. The association of therapeutic agents with the risk of LPDs is difficult to evaluate due to multiple other potentially involved factors and co-treatment with other agents. To date, data show that thiopurine is associated with a moderately increased risk of LPDs in patients with IBD. Evidence regarding the risk of LPDs in IBD patients using methotrexate is not sufficient, but the risk of LPDs seems low. The responsibility of anti-TNF-alpha agents on the risk of LPDs is difficult to determine, because most of IBD patients receiving anti-TNF-alpha agents are co-treated with thiopurines. Attention should be given to the high risk of hepatosplenic T-cell lymphoma in young male patients treated with anti-TNF-alpha agents together with thiopurines. The risk and benefit of immunosuppressive therapy for IBD should be carefully evaluated and individualized considering the risk of LPDs.
Anti-Inflammatory Agents/therapeutic use ; Antibodies, Monoclonal/therapeutic use ; Azathioprine/adverse effects/therapeutic use ; Humans ; Immunosuppressive Agents/adverse effects/therapeutic use ; Inflammatory Bowel Diseases/complications/*drug therapy ; Lymphoproliferative Disorders/chemically induced/*etiology ; Methotrexate/therapeutic use ; Risk Factors

BACKGROUND/AIMS: This study was to evaluate the frequency and the course of the adverse effects of AZA/6-MP in Korean patients with inflammatory bowel disease (IBD). METHODS: Medical records of the patients with IBD treated with AZA/6-MP at Severance hospital from June 1996 to September 2006 were retrospectively analyzed. RESULTS: A total of 133 patients were studied. Male to female ratio was 1.3:1. The mean age was 31.7+/-10.9 year. Adverse effects included leukopenia occurred in 75 cases (56.4%), nausea/vomiting in 32 cases (24.1%), arthralgia in 6 cases (4.5%), hepatitis in 6 cases (4.5%), skin rash in 4 cases (3.0%), herpes zoster in 3 cases (2.3%), and headache in 1 case (0.8%). Most of leucopenia (58.7%) developed within 3 months after maximal tolerated dose of AZA/6-MP and nausea/vomiting frequently occurred within 3 months after start of AZA/6-MP treatment. Thirty-eight patients (28.6%) required the discontinuation of medication due to adverse effects. CONCLUSIONS: Leukopenia was the most common adverse effect of AZA/6-MP treatment. Leukopenia and nausea/vomiting developed frequently in the early period of treatment of AZA/6-MP in patients with IBD. AZA/6-MP should be used cautiously to scrutinize bone marrow suppression.
6-Mercaptopurine/*adverse effects/therapeutic use ; Adolescent ; Adult ; Azathioprine/*adverse effects/therapeutic use ; Behcet Syndrome/drug therapy/etiology ; Cohort Studies ; Drug Therapy, Combination ; Female ; Humans ; Immunosuppressive Agents/*adverse effects/therapeutic use ; Inflammatory Bowel Diseases/*drug therapy/etiology ; Leukopenia/chemically induced ; Male ; Middle Aged ; Retrospective Studies ; Time Factors

PURPOSE: This study aimed to assess the role of thiopurine S-methyltransferase (TPMT) and 6-thioguanine nucleotide (6-TGN) as predictors of clinical response and side effects to azathioprine (AZA), and estimate the optimal AZA dose in Korean pediatric inflammatory bowel disease (IBD) patients. MATERIALS AND METHODS: One hundred and nine pediatric IBD patients in whom AZA treatment was required were enrolled. Thiopurine metabolites were monitored since September 2010. Among them, 83 patients who had prescribed AZA for at least 3 months prior to September 2010 were enrolled and followed until October 2011 to evaluate optimal AZA dose, adverse effects and disease activity before and after thiopurine metabolite monitoring. RESULTS: The result of the TPMT genotype was that 102 patients were *1/*1 (wild type), four were *1/*3C, one was *1/*6, one was *1/*16 (heterozygote) and one was *3C/*3C (homozygote). Adverse effects happened in 31 patients pre-metabolite monitoring and in only nine patients post-metabolite monitoring. AZA dose was 1.4+/-0.31 mg/kg/day before monitoring and 1.1+/-0.46 mg/kg/day after monitoring (p<0.001). However, there were no statistical differences in disease activity during metabolite monitoring period (p=0.34). Adverse effects noticeably decreased although reduction of the AZA dose since monitoring. CONCLUSION: TPMT genotype and thiopurine metabolite monitoring could be helpful to examine TPMT genotypes before administering AZA and to measure 6-TGN concentrations during prescribing AZA in IBD patients.
Adolescent ; Adult ; Azathioprine/*adverse effects/therapeutic use ; Child ; Child, Preschool ; Female ; Genotype ; Guanine Nucleotides/metabolism ; Humans ; Inflammatory Bowel Diseases/*drug therapy/metabolism ; Male ; Methyltransferases/genetics/metabolism ; Republic of Korea ; Risk Factors ; Thionucleotides/metabolism ; Treatment Outcome

BACKGROUND: Thiopurine S-methyltransferase (TPMT) is an important enzyme in the metabolism of thiopurines including azathioprine (AZA), 6-mercaptopurine, and 6-thioguanine. TPMT genotyping is widely used for screening of AZA-related toxicity during routine clinical practice in Korea. However, the data of TPMT genotypes and its AZA-related toxicity have not been studied in the field of dermatology. OBJECTIVE: The aim of this study was to evaluate the genetic basis of TPMT polymorphism in Korean dermatologic patients and subsequently to investigate the relationship between mutant TPMT and adverse responses to AZA treatment. METHODS: This study was retrospective, single-center study. One hundred forty-nine Korean dermatologic patients who underwent TPMT screening test were included. Each patient's medical records, the result of TPMT screening test, dose and treatment period of AZA, and side effects, were reviewed. Laboratory tests were assessed at each visit in order to monitor adverse drug reactions. Leukopenia grading was used in accordance with the common terminology criteria for adverse events (CTCAE) ver. 4.03. RESULTS: Behçet's disease was the leading disorder among the patients. The frequency of TPMT mutation was 4.0% (6/149) among the participants in this study. Four of the six patients with genetic alterations were treated with a low-dose AZA regimen, but no AZA-related adverse events were observed. CONCLUSION: Our results suggest that 1) TPMT polymorphisms in Korean dermatologic patients are similar to those previously reported in Asian patients with the most common mutant allele being TPMT*3C and 2) AZA can be used in the patients with these polymorphisms under a careful dosing regimen.
6-Mercaptopurine ; Alleles ; Asian Continental Ancestry Group ; Azathioprine ; Behcet Syndrome ; Dermatology ; Drug-Related Side Effects and Adverse Reactions ; Genotype ; Humans ; Korea ; Leukopenia ; Mass Screening ; Medical Records ; Metabolism ; Retrospective Studies ; Thioguanine