J. Maté

Fecal Calprotectin and Lactoferrin for the Prediction of Inflammatory Bowel Disease Relapse

Background: The purpose of the study was to determine the role of fecal calprotectin and lactoferrin in the prediction of inflammatory bowel disease relapses, both in patients with ulcerative colitis (UC) and Crohns disease (CD), in a large, long‐term, follow‐up study. Methods: The prospective multicenter study included CD and UC patients who had been in clinical remission for 6 months. At baseline, patients provided a single stool sample for calprotectin and lactoferrin determination. Follow‐up was 12 months in patients showing no relapse and until activity flare in relapsing patients. Results: In all, 163 patients (89 CD, 74 UC) were included. Twenty‐six patients (16%) relapsed during follow‐up. Calprotectin concentrations in patients who suffered a relapse were higher than in nonrelapsing patients (239 ± 150 versus 136 ± 158 μg/g; P < 0.001). Relapse risk was higher in patients having high (>150 μg/g) calprotectin concentrations (30% versus 7.8%; P < 0.001) or positive lactoferrin (25% versus 10%; P < 0.05). Fecal calprotectin (>150 μg/g) sensitivity and specificity to predict relapse were 69% and 69%, respectively. Corresponding values for lactoferrin were 62% and 65%, respectively. The area under the receiver operating characteristic curve to predict relapse using calprotectin determination was 0.73 (0.69 for UC and 0.77 for CD). Better results were obtained when only colonic CD disease or only relapses during the first 3 months were considered (100% sensitivity). High fecal calprotectin levels or lactoferrin positivity was associated with clinical relapse in Kaplan–Meier survival analysis, and both fecal tests were associated with relapse in the multivariate analysis. Conclusions: Fecal calprotectin and lactoferrin determination may be useful in predicting impending clinical relapse—especially during the following 3 months—in both CD and UC patients. (Inflamm Bowel Dis 2009)

Meta‐analysis: the efficacy of azathioprine and mercaptopurine in ulcerative colitis

Background  Debate exists regarding to whether thiopurine therapy is as effective in ulcerative colitis (UC) as it is in Crohns disease.

Safety of Thiopurines and Anti-TNF-α Drugs During Pregnancy in Patients With Inflammatory Bowel Disease

OBJECTIVES:The safety of thiopurines and anti-tumor necrosis factor-α (TNF-α) drugs during pregnancy remains controversial, as the experience with these drugs in this situation is limited. Our aim is to assess the safety of thiopurines and anti-TNF-α drugs for the treatment of inflammatory bowel disease (IBD) during pregnancy.METHODS:Retrospective, multicenter study in IBD patients. Pregnancies were classified according to the therapeutic regimens during pregnancy or during the 3 months before the conception: non-exposed group, pregnancies exposed to thiopurines alone (group A), and pregnancies exposed to anti-TNF-α drugs (group B). An unfavorable Global Pregnancy Outcome (GPO) was considered if pregnancy developed with obstetric complications in the mother and in the newborn.RESULTS:A total of 187 pregnancies in the group A, 66 pregnancies in the group B, and 318 pregnancies in the non-exposed group were included. The rate of unfavorable GPO was different among the three groups (31.8% in non-exposed group, 21.9% in group A, and 34.8% in group B), being lower in pregnancies under thiopurines than among non-exposed (P=0.01). The rate of pregnancy complications was similar among the three groups (27.7% in non-exposed, 20.9% in group A, and 30.3% in group B). The rate of neonatal complications was different among the three groups (23.3% in non-exposed group, 13.9% in group A, and 21.2% in group B), being lower in pregnancies under thiopurines than among non-exposed (P=0.01). In the multivariate analysis, the treatment with thiopurines (odds ratio=0.6; 95% confidence interval=0.4–0.9, P=0.02) was the only predictor of favorable GPO, whereas maternal age >35 years at conception was the only predictor of unfavorable GPO. The treatment with anti-TNF-α drugs was not associated with an unfavorable GPO.CONCLUSION:The treatment with thiopurines and anti-TNF-α drugs does not seem to increase the risk of complications during pregnancy and does seem to be safe for the newborn.

Systematic review: infliximab therapy in ulcerative colitis

To perform a systematic review and meta‐analysis on the efficacy and tolerance of infliximab in ulcerative colitis.

5‐Aminosalicylates and renal function in inflammatory bowel disease: A systematic review

Abstract Nephrotoxicity has been described in some patients with inflammatory bowel disease (IBD) treated with 5‐aminosalicylic acid (5‐ASA). Studies with 5‐ASA treatment in which serum creatinine or creatinine clearance was measured regularly show that nephrotoxicity is exceptional (mean rate of only 0.26% per patient‐year). There have been several case reports, including 46 patients, of renal disease associated with 5‐ASA treatment in patients with IBD. 5‐ASA treatment‐related nephrotoxicity is reported most often within the first 12 months, but also delayed presentation after several years has been shown. The absence of a clear relationship between 5‐ASA dose and the risk of nephrotoxicity suggests that this complication is idiosyncratic rather than dose‐related. Most of the patients with renal disease associated with 5‐ASA treatment suffered interstitial nephritis, with symptoms and signs being nonspecific, which may delay detection for many months. The nephrotoxicity potential of mesalazine and sulfasalazine seems to be similar. The risk with different oral preparations of 5‐ASA is probably too small to influence the choice of agent. Mesalazine should be withdrawn when renal impairment manifests in a patient with IBD; if this does not result in a fall in serum creatinine, then renal biopsy should be considered. A trial of high‐dose steroid may be recommended in patients whose renal function does not respond to drug withdrawal. The optimal monitoring schedule of serum creatinine in patients receiving 5‐ASA treatment remains to be established, as there is no evidence to date that either the test, or the frequency of testing, improves patient outcomes. (Inflamm Bowel Dis 2007)

Thiopurine-Induced Liver Injury in Patients With Inflammatory Bowel Disease: A Systematic Review

The mean prevalence of azathioprine (AZA) or 6-mercaptopurine (MP)-induced liver injury in patients with inflammatory bowel disease was approximately 3%, and the mean annual drug-induced liver disorder rate was only 1.4%. However, this low figure calculated from retrospective studies contrasts with a much higher incidence (>10%) reported by a prospective study. Thiopurine-induced hepatotoxicity can be grouped into three syndromes: hypersensitivity, idiosyncratic cholestatic reaction, and endothelial cell injury (with resultant raised portal pressures, veno-occlusive disease, or peliosis hepatis). A small percentage of patients present with a slight elevation of liver tests (LTs) that do not have clinical implications and LTs return to normal values during the follow-up, indicating that it is not always necessary to adjust the dose of the immunomodulator. However, when abnormalities in LTs are more marked, the dose of AZA/MP may be reduced 50%, with posterior clinical and analytical controls. With this strategy, LTs frequently normalize spontaneously, and the initial AZA/MP dose may be cautiously prescribed again. Thiopurines may induce an unusual severe cholestatic jaundice that may not regress but even progress despite thiopurine withdrawal. Therefore, these drugs should be completely withdrawn, and not only tapered, in those patients presenting clinically significant jaundice. Despite a lack of evidence that monitoring of LTs is necessary in patients receiving AZA/MP, routinely performed laboratory controls including LTs seem recommendable. However, the optimal monitoring schedule remains to be established. As long-term hepatotoxicity seems to be an unpredictable and potentially severe adverse drug reaction of 6-thioguanine, this drug should not be administered outside a clinical trial setting.

Safety of thiopurine therapy in inflammatory bowel disease: long-term follow-up study of 3931 patients.

Background:To evaluate the safety of thiopurines in patients with inflammatory bowel disease. To identify predictive factors associated with the development of thiopurine-induced adverse events. Methods:Long-term incidence of adverse events was estimated in patients from a prospectively maintained Spanish nationwide database using Kaplan–Meier analysis. Cox regression analysis was performed to identify potential predictive factors of adverse events. Results:Three thousand nine hundred and thirty-one patients were included. Ninety-five percent of patients were on azathioprine. The median follow-up with thiopurines was 44 months (range, 0–420). Adverse events occurred at a median of 1 month after starting treatment. The cumulative incidence of adverse events was 26%, with an annual risk of 7% per patient-year of treatment. Most frequent adverse events were nausea (8%), hepatotoxicity (4%), myelotoxicity (4%), and pancreatitis (4%). Four patients had lymphoma. Female and Crohns disease increased the risk of having nausea. The risk of hepatotoxicity was lower in females and higher in Crohns disease. The risk of myelotoxicity was significantly higher in patients treated with mercaptopurine and in females. The risk of pancreatitis was higher in Crohns disease. Overall, 17% of patients discontinued thiopurine treatment due to adverse events. Thirty-seven percent of these patients started thiopurines again and 40% of them had adverse events again. Conclusions:As many as 1 of 4 patients on thiopurine therapy had adverse events during follow-up. A relatively high proportion of patients (17%) had to discontinue the treatment with thiopurines due to adverse events. However, more than half of patients that restarted thiopurine treatment after its discontinuation due to adverse events tolerated it. Several predictive factors for some adverse events have been identified.

Liver injury in inflammatory bowel disease: long-term follow-up study of 786 patients.

Background: The aim of the study was to evaluate the incidence of abnormality of liver tests (LTs) or hepatotoxicity in a large group of inflammatory bowel disease (IBD) patients and, specifically, to assess the incidence of azathioprine (AZA) / mercaptopurine (MP)‐induced liver injury in a long‐term follow‐up study. Methods: All consecutive IBD patients followed for at least 5 years were included in this retrospective study. LTs including alanine transaminase, aspartate transaminase, alkaline phosphatase, &ggr;‐glutamyl transferase, and bilirubin were periodically monitored. “Abnormality‐of‐LTs” was defined as LTs between N (upper limit of the normal range) and 2 N, and “liver injury/hepatotoxicity” as LTs >2 N. Results: A total of 786 patients were included, and 138 received AZA/MP; 120 patients (15%) and 39 (5%) presented abnormality of LTs or hepatotoxicity, respectively, during follow‐up. The most frequent explanations were AZA/MP treatment and fatty liver disease. Among AZA/MP‐treated patients (690 patient‐years follow‐up) the incidence of abnormal LTs and hepatotoxicity was, respectively, 7.1% and 2.6% per patient‐year. Most patients spontaneously normalized LTs despite maintaining AZA/MP. These drugs were withdrawn due to hepatotoxicity (LTs >5 N and lack of decrease despite 50% dose reduction) in 3.6% of the patients and all of them normalized LTs. Conclusions: In IBD patients, AZA or MP treatment induces abnormality of LTs in a relatively high proportion of the cases, but the development of true hepatotoxicity/liver injury is exceptional. Moreover, most of the cases of thiopurine‐induced hepatotoxicity in IBD patients are mild, and the abnormalities in LTs spontaneously return to normal values despite AZA/MP being maintained, therapy withdrawal being necessary in only ≈4% of the patients.

Thiopurine Methyltransferase Activity in Spain: A Study of 14,545 Patients

We sought to assess the activity of thiopurine methyltransferase (TPMT) in 14,545 Spanish patients with different diseases amenable to treatment with azathioprine/6-mercaptopurine (6-MP), and to evaluate the proportion of patients with low TPMT activity and therefore a higher risk of myelotoxicity with these drugs. TPMT activity in red blood cells (RBCs) was measured by a radiochemical method. The association between several clinical variables and TPMT activity was assessed by multiple linear regression. We included 14,545 patients: autoimmune hepatitis (n=359 patients), inflammatory bowel disease (n=7,046), multiple sclerosis (n = 814), myasthenia gravis (n=344), pemphigus (n=133), and other diseases (n=5,849). Mean TPMT activity was 20.1 ± 6 U/mL, but differed depending on the disease (P < .001). TPMT distribution was low (<5) in 0.5%; intermediate (5.0–13.7) in 11.9%; or high (≥13.8) in 87.6%. Only when TPMT activity was considered separately in each disease did it reveal a normal distribution. In the multivariate analysis, gender, hematocrit, and treatment with 5-aminosalicylates/steroids/azathioprine/6-MP statistically influenced TPMT activity, although, probably, in a clinically irrelevant manner. This study shows, in a large sample of 14,545 patients, that 0.5% had low TPMT activity, indicating a higher risk of myelotoxicity with azathioprine/6-MP, a figure similar or slightly higher than that reported in other areas. Nevertheless, the trimodal distribution of TPMT activity varied depending on disease, and the proportion of patients with low activity values ranged from 0–0.8%. The drugs prescribed for the treatment of autoimmune diseases, including azathioprine/6-MP, modified TPMT activity, but the magnitude of this effect was very small and the differences found are probably irrelevant from the clinical point of view.

REVIEW: Role of 5-Aminosalicylic Acid (5-ASA) in Treatment of Inflammatory Bowel Disease: A Systemic Review

Sulfasalazine has been used in the treatment of inflammatory bowel disease (IBD), both for ulcerative colitis (UC) and for Crohn’s disease (CD), for more than 50 years. Although sulfasalazine has undoubted benefits for many patients with IBD, it has two major limitations. Firstly, it has limited efficacy, both in the acute-phase treatment and in the maintenance treatment for prevention of relapses/recurrences. Secondly, side effects and allergic reactions are common, occurring in up to one third of patients taking standard maintenance doses and in up to half of those taking therapeutic doses (1). In 1977, Azad Khan et al (2) studied the therapeutic activity of the component parts of sulfasalazine and found that 5-aminosalicylic acid (5-ASA; mesalamine or mesalazine) was the therapeutically active component of the drug. As mesalamine is believed to act locally from within the gut lumen in patients with IBD, three methods have been widely used for delivering mesalamine to the colon: linking the mesalamine molecule with an azo bond to either another mesalamine molecule (olsalazine) or an inert carrier (balsalazide), so that it is activated by colonic bacterial azoreductase, enteric coating, or prolongedrelease of the drug through semipermeable membrane (Table 1)(3, 4). Our aim was to perform a systematic review of the efficacy of 5-ASA compounds (oral and topical) in the treatment of IBD (UC and CD), both in the acute phase for inducing remission and for prevention of relapses/recurrences. In addition, we have aimed to evaluate the influence of several factors (such as, dosage schedule, disease location or type of formulation) on the efficacy of 5-ASA therapy in IBD.