Commensal bacteria promote azathioprine therapy failure in inflammatory bowel disease via decreasing 6-mercaptopurine bioavailability.

Azathioprine (AZA) therapy failure, though not the primary cause, contributes to disease relapse and progression in inflammatory bowel disease (IBD). However, the role of gut microbiota in AZA therapy failure remains poorly understood. We found a high prevalence of Blautia wexlerae in patients with IBD with AZA therapy failure, associated with shorter disease flare survival time. Colonization of B. wexlerae increased inflammatory macrophages and compromised AZA's therapeutic efficacy in mice with intestinal colitis. B. wexlerae colonization reduced 6-mercaptopurine (6-MP) bioavailability by enhancing selenium-dependent xanthine dehydrogenase (sd-XDH) activity. The enzyme sd-XDH converts 6-MP into its inactive metabolite, 6-thioxanthine (6-TX), thereby impairing its ability to inhibit inflammation in mice. Supplementation with Bacillus (B.) subtilis enriched in hypoxanthine phosphoribosyltransferase (HPRT) effectively mitigated B. wexlerae-induced AZA treatment failure in mice with intestinal colitis. These findings emphasize the need for tailored management strategies based on B. wexlerae levels in patients with IBD.

Impact of Chronotherapy on 6-Mercaptopurine Metabolites in Inflammatory Bowel Disease: A Pilot Crossover Trial.

INTRODUCTION: Chronotherapy is the timing of medication according to biological rhythms of the host to optimize drug efficacy and minimize toxicity. Efficacy and myelosuppression of azathioprine/6-mercaptopurine (AZA/6-MP) are correlated with the metabolite 6-thioguanine, while the metabolite 6-methylmercaptopurine correlates with hepatotoxicity. METHODS: This was a single-center, 10-week prospective crossover trial involving 26 participants with inactive inflammatory bowel disease (IBD) on a stable dose and time of AZA or 6-MP therapy. Participants were switched to the opposite delivery time (morning or evening) for 10 weeks, and metabolite measurements were at both time points. RESULTS: In the morning vs evening dosing, 6-thioguanine levels were 225.7 ± 155.1 vs 175.0 ± 106.9 ( P < 0.01), and 6-methylmercaptopurine levels were 825.1 ± 1,023.3 vs 2,395.3 ± 2,880.3 ( P < 0.01), with 69% (18 out of 26) of participants had better metabolite profiles in the morning. Participants with optimal dosing in the morning had an earlier chronotype by corrected midpoint of sleep. DISCUSSION: In the first study on a potential role of chronotherapy in IBD, we found (i) morning dosing of AZA or 6-MP resulted in more optimal metabolite profiles and (ii) host chronotype could help identify one-third of patients who would benefit from evening dosing. Circadian regulation of metabolic enzymes of AZA/6-MP activity in the liver is the likely cause of these differences. This pilot study confirms the need to incorporate chronotherapy in future multicenter clinical trials on IBD disease.

Temporal Changes in the Treatment Paradigm and Long-term Prognosis of Patients With Crohn's Disease: A Hospital-Based Cohort Study in China.

BACKGROUND: The temporal trends in medical treatment and long-term outcomes of patients with Crohn's disease (CD) have not been well elucidated in China over the past 2 decades. Accordingly, we aimed to evaluate the treatment paradigm and long-term clinical course of Chinese patients with CD in a hospital-based cohort. METHODS: All adult patients newly diagnosed with CD (n = 1338) between 1999 and 2019 in the Sir Run Run Shaw Hospital were included in this cohort. Medication utilization, disease outcomes, and risk factors were investigated. RESULTS: Overall, 48.7%, 35.6%, 67.8%, and 61.6% of patients used 5-aminosalicylates (5-ASA), corticosteroids, thiopurines, and infliximab (IFX), respectively. The cumulative risk of 5-ASA and corticosteroid initiation decreased during follow-up, whereas that of IFX initiation increased. Throughout a median follow-up duration of 26.4 (interquartile range, 12.0-49.2) months, a total of 486 and 300 patients underwent hospitalization and surgery, respectively. Of the 1097 patients with B1/B2 disease behavior at diagnosis, 10.3% experienced phenotype progression. The hospitalization rate decreased after 2015; however, surgery and phenotype progression rates did not significantly change. A Cox regression analysis indicated that IFX use since diagnosis was a contributing factor for lower rates of hospitalization and phenotype progression, whereas thiopurine use was associated with a lower surgery rate. CONCLUSIONS: Infliximab use was observed to increase as 5-ASA and corticosteroid use decreased. Additionally, hospitalization rates decreased following temporal changes in IFX management, yet the surgery and phenotype progression rates remained the same.

[Effect of genetic polymorphism of TPMT and NUDT15 on the tolerance of 6-mercaptopurine therapy in adult acute lymphoblastic leukemia].

Objective: To investigate the effect of genetic polymorphisms of TPMT*2 rs1800462, TPMT*3B rs1800460, TPMT*3C rs1142345, and NUDT15 rs116855232 on the tolerance of 6-mercaptopurine (6-MP) therapy in adult acute lymphoblastic leukemia (ALL) . Methods: A total of 216 adult patients who were diagnosed with ALL and treated with cyclophosphamide, cytarabine, and 6-MP [complementary and alternative medicine (CAM) regimen] from September 2015 to December 2019 were included. Polymorphisms were detected by TaqMan SNP Genotyping Assay. Combined with clinical data, the influence of genetic polymorphism on the tolerance of 6-MP in the treatment of ALL was analyzed. Results: Among the 216 patients, 185 (85.65%) patients had B-ALL and 31 (14.35%) patients had T-ALL. 216 (100%) patients had CC genotype for both TPMT*2 rs1800462 and TPMT*3B rs1800460. The number of TT and TC genotypes for TPMT*3C rs1142345 was 209 (96.76%) and 7 (3.24%) , respectively. The allele frequency was 1.62% for TPMT*3C rs1142345. The number of CC, CT, and TT genotypes for NUDT15 rs116855232 was 166 (76.85%) , 48 (22.22%) , and 2 (0.93%) , respectively. The allele frequency was 12.04% for NUDT15 rs116855232. The TPMT*3C rs1142345 mutant group (TC+CC genotype) had less transfusion volume of packed red blood cell than the wild group (CC genotype) (P=0.036) , and the mutant group (TC+CC genotype) had a higher risk to develop hepatotoxicity (increased aspartate aminotransferase) than the wild group (CC genotype) (OR=9.559, 95% CI 1.135-80.475, P=0.038) . The durations of white blood cells (WBC) <1×10(9)/L and absolute neutrophil count (ANC) <0.5×10(9)/L in the NUDT15 rs116855232 mutation group (CT+TT genotype) were longer than that in the wild group (CC genotype) (P=0.005, P=0.007) , and the transfusion volume of apheresis-derived platelets in the mutant group (CT+TT type) was greater than that in the wild group (CC genotype) (P=0.014) . Conclusion: Genetic polymorphism of TMPT and NUDT15 has an effect on the tolerance of 6-MP in the treatment of adult ALL. Detecting genotypes of patients with ALL before treatment helps to optimize the dosage of 6-MP, which may help shorten the bone marrow suppression duration and reduce blood transfusion volume.

Temporal trend of disease recognition, treatment paradigm, and clinical outcomes of Crohn disease in Thailand from 2000 through 2017: Is early use of thiopurines beneficial?

The prevalence of Crohn disease (CD) is increasing in Asia, but data from Southeast Asian population are scarce.The databases of 2 university-based national tertiary referral centers located in Bangkok, Thailand, were retrospectively reviewed for adult patients diagnosed with CD during January 2000 to December 2017. Disease characteristics, diagnosis, treatment, and outcomes were described and compared between the 2000 to 2009 cohort (cohort A) and the 2010 to 2017 cohort (cohort B).One hundred eighty-two patients (mean age: 46.4 years, 50% male) with 993 patient-years of follow-up were included. Thirteen percent had a history of intestinal resection, but were not diagnosed until disease recurrence. Another 6% were diagnosed at the time of first surgery. There was no improvement in diagnostic proficiency between cohorts. Mesalamine, corticosteroids, thiopurines, and biologics were prescribed in 75.8%, 81.3%, 84.6%, and 13.7% of patients, respectively (P > .05 between cohorts). Notably, thiopurines were started earlier in cohort B. Median time to the start of thiopurines was 6.2 and 1.65 months in cohort A and B, respectively (P < .01). However, the cumulative 5-year rates of disease behavior progression (P = .43), hospitalization (P = .14), and bowel surgery (P = .29) were not significantly different between cohorts. Subgroup analysis including only patients who required thiopurines showed the early use of thiopurines to be associated with lower risk of intestinal surgery after diagnosis (hazard ratio: 0.30, 95% confidence interval: 0.11-0.85).Early disease recognition and early introduction of immunomodulators may prevent long-term complications and reduce unnecessary surgery in CD.

Thiopurine Therapy for Inflammatory Bowel Disease During Pregnancy Is Not Associated with Anemia in the Infant.

INTRODUCTION: Thiopurine exposure throughout pregnancy in patients with inflammatory bowel diseases (IBD) is common and teratogenically safe. Late consequences of in utero exposure to thiopurines and its metabolite, 6-thioguanine nucleotides (6-TGN), such as neonatal and infant anemia are still disputed. AIM: To evaluate whether 6-TGN exposure during pregnancy influences anemia in infants at 1 year of life. METHODS: A comparative observational study was performed between 2009 and 2015 at a multidisciplinary IBD clinic dedicated to pregnant women. The hemoglobin level and signs of anemia between 9 and 15 months after birth of infants born to women exposed to thiopurines throughout the entire pregnancy was compared to infants of women with no thiopurine exposure during pregnancy. RESULTS: Altogether, 34 patients, 21 in the study group and 13 in the control group, were included. The median duration of maternal thiopurine exposure prior to pregnancy was 24 months (range 12-72 months), and median dosage was 100 mg (range 50-175 mg). Maternal IBD activity, infants' iron supplementation, and iron deficiency diagnoses were similar between both groups. The infants' mean hemoglobin level (gr/dL) in the thiopurine-exposed women versus the control group was 11.48 ± 0.8 versus 11.54 ± 0.6, respectively, p = 0.81. The composite risk of any sign of infant anemia was numerically higher in the thiopurine-exposed women, 10 (47%), compared to non-exposed women, 3 (23%), p = 0.17. The mean corpuscular volume, red cell distribution width, white blood cell, and platelet counts were similar among groups. CONCLUSIONS: Thiopurine therapy during pregnancy in women with IBD is safe for long-term neonatal outcomes; still large-scale confirmatory studies are required.

Towards improved control of inflammatory bowel disease.

Inflammatory bowel disease (IBD) is characterized by activation of both the innate and adaptive immune system in genetically susceptible individuals, resulting in chronic intestinal inflammation. The triggers that initiate and perpetuate this continuous inflammation are the subject of much speculation and research, although the central role of the intestinal microbiota is recognized, and is even a target for treatment in some circumstances. The mainstay of modern IBD treatment is suppression of the immune response towards as yet unspecified antigens, and conventional therapy includes corticosteroids, 5-aminosalicylic acid (5-ASA), thiopurines and methotrexate. Reducing activity of specific mediators has proven efficacious, including adhesion molecules, such as the gut-homing integrin α4 ß7 expressed on the surface of circulating immune cells, and cytokines, such as tumour necrosis factor α (TNF-α). This has been achieved using biologic agents including monoclonal antibodies. Recent discoveries in immunology and neuroscience have revealed that signals in the peripheral nervous system regulate inflammation, including levels of TNF-α. The understanding of the mechanisms of the neuro-immune communication involved in inflammation control in the gut is evolving, but is as yet incomplete. Clinical studies using implanted vagus nerve stimulators for treatment of IBD show encouraging results. Accordingly, the neural reflex control of inflammation is emerging as a potential therapeutic target in treatment of IBD. Here, we review current therapeutic options and neural reflex control of gut immunity in the context of intestinal inflammation.

Preclinical evaluation of NUDT15-guided thiopurine therapy and its effects on toxicity and antileukemic efficacy.

Thiopurines (eg, 6-mercaptopurine [MP]) are highly efficacious antileukemic agents, but they are also associated with dose-limiting toxicities. Recent studies by us and others have identified inherited NUDT15 deficiency as a novel genetic cause of thiopurine toxicity, and there is a strong rationale for NUDT15-guided dose individualization to preemptively mitigate adverse effects of these drugs. Using CRISPR-Cas9 genome editing, we established a Nudt15-/- mouse model to evaluate the effectiveness of this strategy in vivo. Across MP dosages, Nudt15-/- mice experienced severe leukopenia, rapid weight loss, earlier death resulting from toxicity, and more bone marrow hypocellularity compared with wild-type mice. Nudt15-/- mice also showed excessive accumulation of a thiopurine active metabolite (ie, DNA-incorporated thioguanine nucleotides [DNA-TG]) in an MP dose-dependent fashion, as a plausible cause of increased toxicity. MP dose reduction effectively normalized systemic exposure to DNA-TG in Nudt15-/- mice and largely eliminated Nudt15 deficiency-mediated toxicity. In 95 children with acute lymphoblastic leukemia, MP dose adjustment also directly led to alteration in DNA-TG levels, the effects of which were proportional to the degree of NUDT15 deficiency. Using leukemia-bearing mice with concordant Nudt15 genotype in leukemia and host, we also confirmed that therapeutic efficacy was preserved in Nudt15-/- mice receiving a reduced MP dose compared with Nudt15+/+ counterparts exposed to a standard dose. In conclusion, we demonstrated that NUDT15 genotype-guided MP dose individualization can preemptively mitigate toxicity without compromising therapeutic efficacy.

Cost-utility Analysis: Thiopurines Plus Endoscopy-guided Biological Step-up Therapy is the Optimal Management of Postoperative Crohn's Disease.

BACKGROUND: Postoperative recurrence of Crohn's disease is common. This study sought to assess whether the postoperative management should be based on biological therapy alone or combined with thiopurines and whether the therapy should be started immediately after surgery or guided by either endoscopic or clinical recurrence. METHODS: A Markov model was developed to estimate expected health outcomes in quality-adjusted life years (QALYs) and costs in Canadian dollars (CAD$) accrued by hypothetical patients with high recurrence risk after ileocolic resection. Eight strategies of postoperative management were evaluated. A lifetime time horizon, an annual discount rate of 5%, a societal perspective, and a cost-effectiveness threshold of 50,000 CAD$/QALY were assumed. Deterministic and probabilistic sensitivity analyses were conducted. The model was validated against randomized trials and historical cohorts. RESULTS: Three strategies dominated the others: endoscopy-guided full step-up therapy (14.80 QALYs, CAD$ 462,180), thiopurines immediately post-surgery plus endoscopy-guided biological step-up therapy (14.89 QALYs, CAD$ 464,099) and combination therapy immediately post-surgery (14.94 QALYs, CAD$ 483,685). The second strategy was the most cost-effective, assuming a cost-effectiveness threshold of 50,000 CAD$/QALY. Probabilistic sensitivity analysis showed that the second strategy has the highest probability of being the optimal alternative in all comparisons at cost-effectiveness thresholds from 30,000 to 100,000 CAD$/QALY. The strategies guided only by clinical recurrence and those using biologics alone were dominated. CONCLUSIONS: According to this decision analysis, thiopurines immediately after surgery and addition of biologics guided by endoscopic recurrence is the optimal strategy of postoperative management in patients with Crohn's disease with high risk of recurrence (see Video Abstract, Supplemental Digital Content 1, http://links.lww.com/IBD/B654).

Successful Treatment of Generalized Essential Telangiectasia With 6-Mercaptopurine.

Generalized essential telangiectasia (GET) is a notoriously difficult to treat disorder with no current satisfactory treatments. This case and discussion report the use of 6-mercaptopurine (6-MP) as a successful treatment for GET. Moreover, we show that GET may represent a state of increased angiogenesis, a paradigm shift from the current understanding that these telangiectasias represent dilatations of only pre-existing vessels. This new view of GET may drive others to look at novel agents for treatment.

J Drugs Dermatol. 2017;16(3):280-282.

A purine antimetabolite attenuates toll-like receptor-2, -4, and subarachnoid hemorrhage-induced brain apoptosis.

BACKGROUND: Upregulation of high-level toll-like receptors (TLRs) is observed in the serum of animals following experimental subarachnoid hemorrhage (SAH) and is highly related to SAH-induced early brain injury (EBI). The present study was of interest to examine the effect of 6-mercaptopurine (6-MP) on alternation of TLR-2, -3, and -4 in this model. METHODS: A rodent SAH model was used. Administration with 6-MP (0.5/1/2 mg/kg/d) was initiated 1 h after the induction of SAH via an osmotic minipump. Cerebral cortex was harvested to measure TLRs messenger RNA and protein (reverse transcription polymerase chain reaction [rt-PCR] and Western blot). Cerebral cortex was harvested for activated caspases (rt-PCR) measurement. RESULTS: Cellular evaluation revealed increased neuronal nuclei(+) neurons with vacuolated nuclear and glial fibrillary acidic protein(+) astrocytes in the SAH group, but absent in the 6-MP treatment and healthy controls. The TLR-3 levels were not significantly increased in animals subject to SAH, compared with the controls (no SAH). The levels of TLR-2 and -4 in the SAH only and SAH plus vehicle groups were significantly elevated (P < 0.01), and treatment with 6-MP reduced TLR-2, -3 (at 2 mg/kg), and -4 (dose-dependently) protein expression following SAH. Likewise, the TLR-4 messenger RNA levels were also significantly reduced in the 6-MP (at 1 mg/kg and 2 mg/kg) groups. Cleaved caspase-3 and caspase-9a were reduced at 2-mg/kg 6-MP treatment group. CONCLUSIONS: These results show that 6-MP attenuates the expression of TLR-2, -4, especially TLR-4, which play an antiapoptotic effect on SAH-induced EBI. This finding supported that through modulating TLRs, 6-MP can attenuate SAH-induced EBI. Those results offer credit to the neuroprotective effect of 6-MP.

Fecal microbial composition of ulcerative colitis and Crohn's disease patients in remission and subsequent exacerbation.

BACKGROUND: Limited studies have examined the intestinal microbiota composition in relation to changes in disease course of IBD over time. We aimed to study prospectively the fecal microbiota in IBD patients developing an exacerbation during follow-up. DESIGN: Fecal samples from 10 Crohn's disease (CD) and 9 ulcerative colitis (UC) patients during remission and subsequent exacerbation were included. Active disease was determined by colonoscopy and/or fecal calprotectine levels. Exclusion criteria were pregnancy, antibiotic use, enema use and/or medication changes between consecutive samples. The microbial composition was assessed by 16S rDNA pyrosequencing. RESULTS: After quality control, 6,194-11,030 sequences per sample were available for analysis. Patient-specific shifts in bacterial composition and diversity were observed during exacerbation compared to remission, but overarching shifts within UC or CD were not observed. Changes in the bacterial community composition between remission and exacerbation as assessed by Bray-Curtis dissimilarity, were significantly larger in CD versus UC patients (0.59 vs. 0.42, respectively; p = 0.025). Thiopurine use was found to be a significant cause of clustering as shown by Principal Coordinate Analysis and was associated with decreases in bacterial richness (Choa1 501.2 vs. 847.6 in non-users; p<0.001) and diversity (Shannon index: 5.13 vs. 6.78, respectively; p<0.01). CONCLUSION: Shifts in microbial composition in IBD patients with changing disease activity over time seem to be patient-specific, and are more pronounced in CD than in UC patients. Furthermore, thiopurine use was found to be associated with the microbial composition and diversity, and should be considered when studying the intestinal microbiota in relation to disease course.

Nutritional therapy versus 6-mercaptopurine as maintenance therapy in patients with Crohn's disease.

BACKGROUND: 6-Mercaptopurine is often used as maintenance therapy in patients with Crohn's disease. However, toxicities like myelosuppression limit its clinical benefit. AIMS: To evaluate the efficacy of elemental diet versus 6-mercaptopurine as maintenance therapy in Crohn's disease. METHODS: Ninety-five eligible patients with Crohn's disease activity index ≤150 were randomly assigned to: 6-mercaptopurine (0.5-1.5mg/kg/day, n=30); Elental as an elemental diet (≥900 kcal/day, n=32); none (control, n=33). In the three groups, patients were and remained on 5-aminosalicylic acid (2250-3000 mg/day). Patients were observed for 2 years and the rate of relapse (Crohn's disease activity index ≥200) was monitored. RESULTS: At 24 months, the fractions of patients who had maintained remission were 60%, 46.9% and 27.2% for 6-mercaptopurine, Elental and the control groups, respectively. Log-rank test showed better efficacy for 6-mercaptopurine (P=0.0041) and Elental (P=0.0348) versus control. No significant difference was found between 6-mercaptopurine and Elental. Further, in the 6-mercaptopurine group, 2 patients experienced liver injury and one developed alopecia. CONCLUSIONS: This 24 months comparison study showed that Elental as maintenance therapy in Crohn's disease patients was as effective as 6-mercaptopurine. Elental should be useful for long-term maintenance therapy in Crohn's disease. This is the first comparison study evaluating nutritional therapy versus 6-mercaptopurine.

Endoscopic ultrasound for perianal Crohn's disease: disease and fistula characteristics, and impact on therapy.

BACKGROUND AND AIM: Appropriate treatment of perianal fistulas in Crohn's disease (CD) involves accurate anatomic evaluation. EUS is an accepted imaging method for this purpose. The aim of the current study was to evaluate the clinical and endosonographic characteristics of perianal fistula in CD and to assess its impact on therapy. METHODS: All CD patients referred to the Sheba medical center from June 2004 to August 2008 for EUS examination of perianal fistulas were included. Perianal fistulas were diagnosed based on a clinical examination revealing at least one perianal cutaneous orifice. Demographic, clinical and therapeutic data was obtained. EUS was performed using an ultrasound scanner producing a 360° cross sectional image of the anal sphincters. RESULTS: Fifty six patients were included in the study. Four patients were excluded from the final analysis: 3 because no fistula could be detected by EUS, and one due to inability to tolerate the examination. The mean CD duration was 10±9.16 years (range 1-37). Mean perianal disease duration was 5.3±6.5 (range 1-29) years. 27 patients had perianal involvement at presentation. Among the fistulas diagnosed, 13 were simple (25%) and 39 were (75%) complex. No correlation was found between CD duration or location, patients' age and gender or fistula location with fistula type or complexity. EUS results influenced patient management in 86% of the patients. CONCLUSIONS: CD-associated perianal fistulas are mainly complex. EUS is a well tolerated and informative imaging modality, with significant impact on treatment.

[Effects of all-trans retinoic acid and compound huangdai tablet sequential maintenance treatment on the long-term efficacy of acute promyelocytic leukemia patients].

OBJECTIVE: To compare the difference in the long-term efficacy between all-trans retinoic acid (ATRA) combined Compound Huangdai Tablet and ATRA combined methotrexate (MTX) and 6-mercaptopurine (6MP) as the sequential maintenance treatment of acute promyelocytic leukemia (APL) patients. METHODS: Totally 83 APL patients in the molecular remission (PML/RARalpha negative) were randomly assigned to two groups, the treatment group (45 cases) and the control group (38 cases) after they were induced to the complete remission (CR) by ATRA combined chemotherapy, and treated by sequential chemotherapy as the consolidated treatment for 3 therapeutic courses. Those in the treatment group were sequentially treated with ATRA and Compound Huangdai Tablet as maintenance therapy, while those in the control group were treated with ATRA and MTX + 6MP as maintenance therapy. After a long-term follow-up (2003 -2011), the long-term therapeutic efficacy and adverse reactions were compared between the two therapeutic regimens. RESULTS: The 5-year relapse-free survival (RFS) rate was 84.4% +/- 5.4% in the treatment group and 63.2% +/- 7.8% in the control group, showing statistical difference between the two groups (P < 0.05). The 5-year overall survival rate (OSR) was 86.7% +/- 5. 1% in the treatment group and 78.7% +/- 6.7% in the control group, showing no statistical difference between the two groups (P > 0.05). There was no statistical difference in the adverse reaction between the two groups (P > 0.05). CONCLUSION: The application of ATRA and Compound Huangdai Tablet as maintenance therapy could elevate the long-term RFS rate of APL patients.

Drug therapy for ulcerative colitis.

Ulcerative colitis (UC) is an inflammatory destructive disease of the large intestine occurred usually in the rectum and lower part of the colon as well as the entire colon. Drug therapy is not the only choice for UC treatment and medical management should be as a comprehensive whole. Azulfidine, Asacol, Pentasa, Dipentum, and Rowasa all contain 5-aminosalicylic acid (5-ASA), which is the topical anti-inflammatory ingredient. Pentasa is more commonly used in treating Crohn's ileitis because Pentasa capsules release more 5-ASA into the small intestine than Asacol tablets. Pentasa can also be used for treating mild to moderate UC. Rowasa enemas are safe and effective in treating ulcerative proctitis and proctosigmoiditis. The sulfa-free 5-ASA agents (Asacol, Pentasa, Dipentum and Rowasa) have fewer side effects than sulfa-containing Azulfidine. In UC patients with moderate to severe disease and in patients who failed to respond to 5-ASA compounds, systemic (oral) corticosteroids should be used. Systemic corticosteroids (prednisone, prednisolone, cortisone, etc.) are potent and fast-acting drugs for treating UC, Crohn's ileitis and ileocolitis. Systemic corticosteroids are not effective in maintaining remission in patients with UC. Serious side effects can result from prolonged corticosteroid treatment. To minimize side effects, corticosteroids should be gradually reduced as soon as the disease remission is achieved. In patients with corticosteroid-dependent or unresponsive to corticosteroid treatment, surgery or immunomodulator is considered. Immunomodulators used for treating severe UC include azathioprine/6-MP, methotrexate, and cyclosporine. Integrated traditional Chinese and Western medicine is safe and effective in maintaining remission in patients with UC.

An open-label pilot study using thioguanine as a therapeutic alternative in Crohn's disease patients resistant to 6-mercaptopurine therapy.

BACKGROUND AND AIMS: A substantial number of patients with inflammatory bowel disease (IBD) fail to achieve a complete clinical response with 6-mercaptopurine (6-MP) and azathioprine (AZA). Inability to achieve therapeutic 6-thioguanine nucleotide (6-TGN) levels due to the preferential overproduction of 6-methylmercaptopurine ribonucleotides (6-MMPR) upon dose escalation characterizes a newly described subgroup of IBD patients resistant to 6-MP/AZA therapy. Treatment with 6-thioguanine (6-TG), a related thiopurine, which forms 6-TGNs more directly may be beneficial in such patients. This pilot study evaluated the safety, tolerance, and efficacy of 6-TG in the subgroup of Crohn's disease (CD) patients failing to attain adequate disease control with traditional 6-MP/AZA therapy. METHODS: Ten CD patients with preferential 6-MMPR production upon 6-MP/AZA dose escalation were enrolled in an open-label pilot study. Seven of 10 patients had experienced dose-related 6-MP toxicities. RESULTS: Seventy percent of the patients (7 of 10) responded or were in remission at week 16. Clinical response was evident by week 4 in most. 6-TGN levels were nine-fold higher with 6-TG treatment than with 6-MP, whereas 6-MMPR levels were undetectable. No patient developed a recurrence of hepatic or hematological toxicity. CONCLUSIONS: 6-TG was a safer and more efficacious thiopurine in this subgroup of IBD patients resistant to 6-MP therapy. Larger controlled trials are warranted to further evaluate both the short- and long-term safety and efficacy in this subgroup of patients as well as a broader spectrum of IBD patients.

Tratamento da retocolite ulcerativa inespecífica em crianças com enemas contendo butirato: relato de caso / Treatment of ulcerative colitis in child with enemas containing butyrate. Case report

Objetivo - Chamar a atenção para uma promissora alternativa terapêutica no tratamento de retocolite ulcerativa inespecífica em criança. Método - É descrito o caso de uma criança com diagnóstico de retocolite ulcerativa inespecífica, com forma evolutiva crônica contínua, refratária ao tratamento convencional e que foi tratada com enemas contendo butirato. Revisão de literatura pertinente ao caso foi realizada. Resultados - Paciente de 4 anos, feminina, parda, com diagnóstico de retocolite ulcerativa inespecífica desde 1 ano de idade e evolução refratária ao tratamento com corticóide (via oral e retal) e imunossupressor (6-mercaptopurina). Respondeu de modo satisfatório com melhora do quadro clínico, laboratorial, endoscópico e histológico, após o uso de enemas com butirato semelhante às descrições da literatura internacional. Conclusão - Embora sem estar esclarecido o mecanismo de ação do butirato na retocolite ulcerativa inespecífica, melhora significante foi observada neste caso, acenando como possibilidade terapêutica segura nos casos de retocolite ulcerativa inespecífica confinados a segmentos distais.