Immunomodulators in Inflammatory Bowel Disease



Immunomodulators in Inflammatory Bowel Disease


Rizwan Ahmed

Richard S. Bloomfeld



INTRODUCTION

Patients with inflammatory bowel disease (IBD) who are refractory to therapy with 5-aminosalicylate (5-ASA) agents, antibiotics, and corticosteroids, or who are dependent upon corticosteroids, present a treatment challenge. Most corticosteroid users will experience adverse events, such as acne, moon facies, hirsutism, hypertension, ecchymosis, petechial bleeding, psychosis, glucose intolerance, myopathy, osteoporosis, cataracts, glaucoma, and increased risk of infection (1). Therefore, steroid-sparing therapy is crucial. Several immunomodulators have demonstrated efficacy in the treatment of such patients. These include azathioprine (AZA) and its metabolite, 6-mercaptopurine (6-MP), as well as methotrexate (MTX), cyclosporine, tacrolimus (FK506), and mycophenolate mofetil (MMF).


AZATHIOPRINE AND 6-MERCAPTOPURINE


Background

In 1969, Brooke et al. (2) first reported successful use of AZA in Crohn’s disease (CD) patients refractory to corticosteroid treatment. AZA and 6-MP are now commonly used to treat patients with CD and ulcerative colitis (UC) and to maintain remission off corticosteroids.


Mechanism of Action

AZA is a prodrug that is rapidly, nonenzymatically metabolized to 6-MP. Subsequently, 6-MP is either inactivated to 6-thiouric acid by xanthine oxidase, to 6-methylmercaptopurine by thiopurine S-methyltransferase (TPMT), or is metabolized to 6-thioguanine (6-TG) nucleotides through several steps. 6-TG nucleotides are the active metabolites, which inhibit purine ribonucleotide synthesis. AZA and 6-MP are known to inhibit cell-mediated immunity. A decline in activity of both natural killer cells and cytotoxic T cells is correlated with a clinical response.


Induction Therapy


Active Crohn’s Disease

Eight randomized controlled trials have examined the use of AZA or 6-MP in active CD (3, 4, 5, 6, 7, 8, 9 and 10). Two of the trials demonstrated a significant response compared with placebo.

Pearson et al. conducted a meta-analysis of randomized controlled trials from 1966 to 1994 to examine the utility of AZA and 6-MP in active CD (11). The odds ratio for a clinical response in active CD was 3.09 (95% CI, 2.45 to 3.91).


Active Ulcerative Colitis

Evidence-based data to support the efficacy of AZA in active UC are less conclusive than for CD. Only eight trials have been conducted to evaluate the utility of AZA for active UC (12, 13, 14, 15, 16, 17, 18 and 19). Although corticosteroid-sparing effects have been shown,
studies to determine whether AZA induces remission in active UC have been equivocal (12,14,15,17,18). Dosing in these trials has ranged from 1.5 to 2.5 mg/kg of AZA.

No controlled study of 6-MP in UC has been performed.


Corticosteroid-refractory and Corticosteroid-dependent IBD

Several studies have shown AZA to be effective in patients with CD who are refractory to even high doses of corticosteroid treatment or who are chronically dependent on corticosteroids (20, 21, 22, 23 and 24). Dosing in these trials ranged from 1.5 to 2.5 mg/kg/dayof AZA.

In UC patients faced with a similar challenge, many studies have demonstrated a similar corticosteroid-sparing response with AZA. Therapy was found to be effective for the first 6 months, but with diminishing effects on long-term follow-up (14,15,17).


Maintenance of Remission

Evidence-based data support the use of AZA and 6-MP in CD patients to maintain remission. Results of seven randomized controlled trials demonstrate efficacy of these medications for quiescent CD when compared with placebo (20,23, 24, 25, 26 and 27).

Furthermore, Pearson et al. (11) conducted a meta-analysis of randomized controlled trials from 1966 to 1994 to examine the utility of AZA and 6-MP in quiescent CD. The results support these immunomodulators for relapse prevention. The odds ratio for maintenance of remission while on AZA was 2.27 (95% CI, 1.76 to 2.93). The data are similarly favorable for using AZA for maintenance of remission in UC patients. In one study, long-term use of AZA reduced the 1-year relapse rate to 36% compared with 59% who were on placebo (12). In that same study, in a subgroup of patients who had been treated with AZA for 6 months prior to enrollment, 69% receiving AZA versus 39% receiving placebo maintained remission after 12 months (p < 0.01).

AZA alone may be sufficient to maintain remission in UC patients. In a study by Mantzaris et al. (18), patients receiving AZA plus olsalazine were compared to those receiving AZA alone. The time to relapse and UC Disease Activity Index scores were recorded over a 2-year span. No significant differences were apparent between these two groups. Moreover, the cost of treatment and number of adverse events were higher in the combination therapy group.


Prevention of Postoperative Recurrence

CD commonly recurs after surgical resection. Specifically, there is a 7% to 25% per year risk of symptomatic recurrence of CD, and a 50% likelihood of recurrent symptoms by 5 years after intestinal resection. Furthermore, endoscopic recurrence rates are typically higher, with a 73% to 93% risk approximately 1 year after resection (28,29).

6-MP and AZA have been studied in several clinical trials to evaluate their efficacy in decreasing postoperative recurrence. In a large multicenter, double-blind, double-dummy trial by Hanauer et al., efficacy of 6-MP (50 mg/day) and mesalamine (3 g/day) was compared to placebo in a cohort of CD patients who underwent resection (30). Over a span of 2 years, clinical and endoscopic recurrences in the three groups were recorded. Rates of endoscopic recurrence were found to be lower in 6-MP (43%) versus placebo (64%; p = 0.030). Clinical recurrence was also lower in the 6-MP group (50% vs. 77%; p = 0.045).

AZA (2 mg/kg/day) was also compared to mesalamine (3 g/day) for postoperative prophylaxis in a prospective, open-label, randomized study (31). After 24 months, the risk of clinical relapse was comparable in both groups. Similarly, no significant difference was observed with regard to surgical relapse. Limitations of the study include high dropout rates, lack of a placebo group, and lack of statistical
power to show a difference between the treatment groups. Therefore, use of AZA and 6-MP should be reserved for those at high risk for postoperative recurrences or in whom postoperative recurrence would have major deleterious effects.


Dosing

The optimal doses of 6-MP and AZA are not known and are the subject of ongoing investigation. Currently, the recommended doses for 6-MP and AZA are 1.0 to 1.5mg/kg/day and 2.0 to 3.0 mg/kg/day, respectively. Higher doses may be used for nonresponders.

There are several approaches to the initiation of 6-MP and AZA. One approach is the dose-escalating method, sometimes termed “start low, go slow.” Therapy is initiated at 50 mg/day and is increased by 25 mg every few weeks to the appropriate target dose (1.0 to 1.5 mg/kg/day and 2.0 to 3.0 mg/kg/day for 6-MP and AZA, respectively), while labs are carefully monitored.

Another approach is the initiation of weight-based dosing. Because approximately 11% of the general population has TPMT mutations, with resultant low or absent TPMT enzyme activity, excess production of 6-TG nucleotides from AZA and 6-MP can increase the risk of bone marrow toxicity. Current U.S. Food and Drug Administration (FDA) recommendations suggest that individuals should have their TPMT genotype or phenotype assessed before initiation of therapy in an effort to detect individuals with low enzyme activity. Those individuals heterozygous for a TPMT mutation (or intermediate enzyme activity) may start therapy at a reduced dose because of an increased risk of developing leukopenia (32). AZA and 6-MP should generally be avoided in patients homozygous for a TPMT mutation (or absent enzyme activity). Close laboratory monitoring during AZA or 6-MP use is still mandatory in patients known to have normal TPMT activity.

Both AZA and 6-MP have a delayed onset of action, showing clinical benefit after 2 to 3 months of treatment. If rapid clinical response is needed, another form of therapy, such as corticosteroids or possibly a biologic agent, can be used until the clinical onset of AZA or 6-MP begins. Response to intravenous loading appears to work no faster than oral dosing (33).


Monitoring Metabolites

Some investigators advocate the incorporation of 6-TG metabolite measurement in dose adjustment, but this is an area of controversy because no prospective, controlled studies have evaluated such a practice. Monitoring of metabolites may also be helpful in detecting noncompliance.


Toxicity and Laboratory Monitoring

Adverse reactions associated with AZA and 6-MP include nausea, vomiting, abdominal pain, arthralgia, infectious complications, and drug-induced hepatitis. A more troublesome toxicity is pancreatitis, occurring in 1.3% to 3.3% of patients (34,35). Pancreatitis typically develops after several weeks of therapy, but also typically resolves spontaneously after discontinuation.

Bone marrow suppression is another major concern with AZA and 6-MP, occurring in 2% to 5% of patients (35,36). Leukopenia is the most common presentation. For this reason, routine monitoring of blood work is recommended, with complete blood counts (CBCs) obtained weekly the first 4 weeks, biweekly for 4 weeks, then every 1 to 2 months (37). When a patient is well on a stable dose, the authors obtain CBCs with a differential every 3 months.

In addition, an increased risk of developing lymphoma has been linked to thiopurine therapy. Recently, a meta-analysis of six studies was conducted to determine the risk. Use of AZA and 6-MP was associated with a fourfold increase in the incidence of lymphoma in patients with IBD (38). Therefore, clinicians must weigh
the substantial benefits of therapy with the low risk of developing serious adverse events. Lewis et al. performed a decision analysis using a Markov model on AZA use in CD patients in corticosteroid-induced remission (39). AZA use resulted in an average increase in life expectancy of 0.04 years and 0.05 quality-adjusted years. This increase was greatest in young patients with the lowest baseline risk of lymphoma, and with the greatest life expectancy in the absence of a CD-related death.


Drug Interactions

Caution must be taken when prescribing allopurinol in those who take 6-MP or AZA. Allopurinol inhibits xanthine oxidase, thereby altering the metabolism of 6-MP and AZA, which can result in increased toxicity. 5-ASA medications (sulfasalazine, mesalamine, olsalazine, and balsalazide) may inhibit TPMT activity, which may augment the efficacy of 6-MP or AZA.


Practical Recommendations



  • Long-term therapy with corticosteroids should be avoided. AZA or 6-MP should be considered in patients with corticosteroid-dependent or corticosteroid-refractory CD and UC because of their effective steroidsparing abilities. AZA or 6-MP should be considered for maintenance of surgical remission in CD.


  • The recommended doses for 6-MP and AZA are 1.0 to 1.5 mg/kg/day and 2.0 to 3.0 mg/kg/day, respectively. A dose-escalating approach or a weight-based approach using TPMT assessment can be taken with the initiation of therapy.


  • CBCs should be obtained weekly the first 4 weeks, biweekly for 4 weeks, then every 3 months for the duration of therapy.


  • Metabolite measurement may be helpful in detecting noncompliance and aid in dose adjustment.


METHOTREXATE


Background

Over the past decade, studies have shown MTX to be an effective immunomodulator for the treatment of patients with CD.


Mechanism of Action

MTX is a folic acid antagonist known to inhibit dihydrofolate reductase, thymidine synthetase, and other enzymes involving DNA synthesis. MTX also impedes the production of proinflammatory cytokines, such as IL-1 and IL-2. Despite knowledge of the cellular activity of MTX, the mechanism by which it improves IBD is not entirely clear.

Jun 17, 2016 | Posted by in GASTROENTEROLOGY | Comments Off on Immunomodulators in Inflammatory Bowel Disease

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