Background and aim-The immunosuppressive properties of 6-mercaptopurine and its parent compound azathioprine are mediated by their intracellular metabolism into active 6-thioguanine (6-TG) metabolites. Measurement of erythrocyte 6-TG metabolite levels has been proposed as a useful clinical tool for assessing treatment eYcacy in patients with inflammatory bowel disease (IBD). Aim-The purpose of the study was to establish a therapeutic index of treatment eYcacy based on measurement of erythrocyte 6-TG metabolite levels, and apply it clinically to guide therapy. Methods-Heparinised blood was obtained from 82 adult patients with IBD on long term (more than three months) antimetabolite therapy (63 Crohn's disease; 19 ulcerative colitis). Erythrocyte 6-TG metabolite levels were measured using reverse phase high performance chromatography, and correlated with treatment eYcacy. In 22 patients with refractory Crohn's disease despite long term azathioprine therapy, their dosage was increased by 25 mg/day at eight week intervals as needed. Serial erythrocyte 6-TG metabolite levels were measured at each clinic visit and correlated with treatment eYcacy. Results-Clinical remission, as defined by a low disease index score in patients weaned oV or on a low alternate day dose (<20 mg on alternate days) of corticosteroid, was achieved in 68% of patients on long term antimetabolite therapy. Treatment eYcacy correlated with erythrocyte 6-TG levels greater than 250 pmol/8×10 Conclusion-Measurement of erythrocyte 6-TG metabolite levels is helpful in determining the adequacy of azathioprine dosage and can be used to optimise the dose of antimetabolite therapy to achieve an improved clinical response without inducing leucopenia. Patients who are clinically refractory to azathioprine therapy despite achieving high erythrocyte 6-TG levels (>250) should be considered for adjunct or alternative forms of immunosuppressive therapy or surgery. (Gut 2001;48:642-646)

During the past 2 decades, medical therapy for Crohn's disease (CD) and ulcerative colitis (UC) has grown to incorporate a variety of immunesuppressing agents. At the same time, basic insights into the aberrant mucosal immune response underlying inflammatory bowel disease (IBD) have expanded dramatically. The interplay of host susceptibility to infection and the safety and efficacy of immunization for vaccine-preventable diseases has been explored in other immune-mediated disease states but only rarely in IBD. The purpose of this review is to formulate best-practice recommendations for immunization in children and adults with IBD by considering the effects of the IBD disease state and its treatments on both the safety and efficacy of immunization. To do so, we first considered the routine recommendations for immunization of children, adults and distinct populations at increased risk for vaccine-preventable disease. Because it was rarely possible to examine direct data on safety and efficacy of immunization in IBD populations, we relied to a large extent upon extrapolation from similar populations and from knowledge of basic mechanisms. The literature suggests that efficacy of immunization may be diminished in some patients whose immune status is compromised by immune suppression. However, except for live agent vaccines, most immunizations may be safely administered to patients with IBD even when immune compromised. Conversely, protection against vaccine-preventable illness may be of even greater benefit to those at risk for morbid or lethal complications of infections because of an immune compromised state. We conclude that for most patients with IBD, recommendations for immunization do not deviate from recommended schedules for the general population.

Background & Aims One of the most common symptoms among patients with inflammatory bowel diseases (IBD) is diarrhea, which is thought to be contributed by changes in electrolyte transport associated with intestinal inflammation. This study is designed to test the hypothesis that intestinal Na+-related transporters/channels and their regulatory proteins may be down-regulated as a potential contributor to IBD-associated diarrhea. Methods SDS-PAGE and Western blotting and/or confocal immunomicroscopy were used to examine the expression of Na+/H+-exchangers 1-3 (NHE1-3), epithelial Na+ channel (ENaC), Na+/K+-ATPase, the intracellular Cl- channel 5 (ClC-5), and NHE3 regulatory factors (NHERF1 & 2), in ileal and colonic pinch biopsies from IBD patients and noninflammatory controls, as well as from colonic mucosa of DSS- and TNBS-induced acute murine IBD models. Results NHE1&3 (but not NHE2), β-ENaC, Na+/K+-ATPase-α, ClC-5 and NHERF1 were all down-regulated in sigmoid mucosal biopsies from most cases of active UC and/or CD, compared to controls. NHE3 was also decreased in ileal mucosal biopsies of active CD, as well as in ~50% of sigmoid biopsies from inactive UC or CD. Importantly, similar down-regulation of NHE1&3, β-ENaC, and NHERF1&2 was also observed in the mouse colon (but not ileum) of DSS- and TNBS-induced colitis. Conclusions IBD-associated diarrhea may be due to a coordinated down regulation of multiple Na+ transporter and related regulatory proteins, including NHE1&3, Na+/K+-ATPase, and ENaC, as well as NHERF1 & 2, and ClC-5, all of which are involved directly or indirectly in intestinal Na+ absorption.

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