OPTIMAL USE OF IMMUNOMODULATORS AND BIOLOGICS Edward V. Loftus, Jr., MD, FACG
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1 1C: Advances in Inflammatory Bowel Disease OPTIMAL USE OF IMMUNOMODULATORS AND BIOLOGICS Edward V. Loftus, Jr., MD, FACG narrow interpretation of this presentation topic would A be a discussion of dosing regimens and therapeutic drug monitoring of the thiopurines and the anti-tumor necrosis factor (TNF) biologics for the treatment of inflammatory bowel disease (IBD). Taken more broadly, however, this is a good opportunity to also discuss the indications for utilizing these drug classes and how to assess response to these agents. Which Medications Are We Talking About? Corticosteroids should only be used for induction of remission of IBD, not as maintenance therapy. The typical starting dose of prednisone is 40 mg po daily for 2 weeks or until response is seen, then tapered by 5 mg each week thereafter. Enteric delayed-release budesonide is primarily active in the ileum and right colon, and is approved for treatment of mildly to moderately active Crohn s disease. A typical dosing regimen is 9 mg po daily for 1-2 months, and then tapered by 3 mg per month thereafter. The recently available MMX formulation of budesonide is designed to release primarily in the colon, and is approved for induction therapy of mildly to moderately active ulcerative colitis. A typical dosing regimen for budesonide MMX would be 9 mg daily for 8 weeks. While budesonide formulations are in general not as potent as oral prednisone, they are associated with fewer corticosteroidrelated side effects. Immunomodulators The thiopurines, azathioprine (AZA) and mercaptopurine (6-MP) are metabolized through several steps to active thioguanine nucleotides (6-TGN), responsible for both efficacy and leukopenia, and methylated metabolites (6-MMP), which are thought to be responsible for hepatotoxicity. 6-TGN are incorporated into nucleic acid and inhibit synthesis of protein, RNA, and DNA. AZA/6-MP are indicated for steroiddependent Crohn s disease or UC. Meta-analyses of clinical trials point to a beneficial effect of these agents in Crohn s disease, although the effect is perhaps not as robust as once was commonly believed. The evidence for their efficacy in ulcerative colitis is even weaker. Importantly, the use of thiopurines, in combination with anti-tnf therapy, appears to potentiate the effect of the anti-tnf agent in both Crohn s disease and ulcerative colitis. Because the therapeutic window of these drugs is relatively narrow, and because there is considerable genetic heterogeneity in one of the primary metabolic enzymes, thiopurine methyltransferase (TPMT), the prescriber must pay close attention to the starting dose of these agents, and monitor patients carefully going forward. It is strongly recommended to check a TPMT genotype or phenotype prior to initiating thiopurine therapy. For the approximately 89% of the population with normal TPMT, the starting dose of AZA is mg/kg body weight daily, and the starting dose of 6-MP is mg/kg daily. In the approximately 11% of the population with intermediate TPMT, the starting dose is generally half of that in normal TPMT individuals (i.e., mg/kg AZA daily or mg/kg 6-MP daily). In the 0.3% of the population with very low or absent TPMT activity, the thiopurines in general should be avoided. These dosing guidelines will significantly reduce (but not completely eliminate) instances of early leukopenia; however, delayed leukopenia with thiopurine therapy has been well described. For this reason, all patients on thiopurines require periodic monitoring for leukopenia. One could consider checking a CBC monthly for the first year, and, if there have been no instances of leukopenia, every 3 months thereafter. Patients should be cautioned about dose-independent adverse events which typically occur within the first month of therapy, including fever, pancreatitis, and an influenza-like illness. I advise patients to assume that any new symptom occurring within the first month of starting AZA/6-MP is related to the drug, and that I should be notified if they cannot reach me, they should discontinue the medication. If it is not clear that the symptoms were related to the thiopurine, a rechallenge with a very low dose of drug (i.e., 25 mg daily) is in order. True idiosyncratic reactions typically recur within hours of a rechallenge. MTX is probably underutilized in Crohn s disease. For the 15% of patients who cannot tolerate thiopurine therapy, MTX is a great option. In Crohn s disease, it is best if MTX can be administered parenterally rather than orally as in rheumatoid arthritis the drug has poor oral bioavailability to begin with. The starting dose is typically 25 mg SC weekly, but in smaller patients a dose of 15 mg weekly may be sufficient. Folic acid 1 mg daily may reduce the incidence of side effects such as stomatitis. One can premedicate with ondansetron to reduce some of the nausea associated with the drug. Patients should be counseled to minimize or eliminate ingestion of alcoholic beverages while on MTX. I generally check a CBC and hepatic biochemistries once monthly in patients on MTX. The use of MTX in ulcerative colitis has not been well studied there is a multicenter trial sponsored by NIH and CCFA underway 1C: Advances in Inflammatory Bowel Disease 109
2 Table 1: Dosing Regimens for the Biologic Agents Drug* Indication Induction Dose Maintenance Dose Infliximab Crohn s, UC 5 mg/kg body weight IV weeks 0,2,6 5 mg/kg every 8 weeks IV, can escalate to 10 mg/kg for partial response/lor Adalimumab Crohn s, UC 160 mg SC week 0, 80 mg SC week 2 40 mg SC every 2 weeks, consider escalating to 40 mg weekly for partial response/lor Certolizumab pegol Crohn s 400 mg SC weeks 0, 2, mg SC every 4 weeks Golimumab UC 200 mg SC week 0, 100 mg SC week mg SC every 4 weeks Natalizumab Crohn s 300 mg IV at week mg IV every 4 weeks *The first 4 drugs are anti-tnf agents and natalizumab currently but in my experience it has been helpful for some patients with refractory disease. The calcineurin inhibitors, cyclosporine and tacrolimus, have generally been reserved for niche indications, such as acute severe steroid-refractory colitis or refractory/fistulizing Crohn s disease in patients who have lost response to or are intolerant of biologics, and a detailed discussion of these is outside the scope of this syllabus. Anti-TNF Biologics The anti-tnf agents, infliximab (IFX), adalimumab (ADA), certolizumab pegol (CZP), and golimumab (GLM), are clearly the most widely studied drug class in the treatment of IBD. Both IFX and ADA are approved for use in both Crohn s disease and ulcerative colitis, while CZP is approved for Crohn s disease and GLM is approved for ulcerative colitis. The labeling for IFX includes indications for: 1) reducing signs and symptoms and inducing and maintaining clinical remission in both adult and pediatric Crohn s disease patients who have had an inadequate response to therapy; 2) reducing the number of draining enterocutaneous and rectovaginal fistulas and maintaining fistula closure in adult patients with Crohn s disease; and 3) reducing signs and symptoms and inducing and maintaining clinical remission and mucosal healing, and eliminating corticosteroid use in adult patients with ulcerative colitis who have had an inadequate response to conventional therapy. ADA is indicated for: 1) reducing signs and symptoms and inducing and maintaining clinical remission in adult Crohn s disease patients who have had an inadequate response to conventional therapy; 2) reducing signs and symptoms and inducting clinical remission in adult Crohn s disease patients who have lost response to or are intolerant of infliximab; and 3) inducing and maintaining clinical remission in adult ulcerative colitis patients who have had an inadequate response to corticosteroids or thiopurines. The labeling for CZP includes reducing signs and symptoms and maintaining clinical response in adults with moderately to severely active Crohn s disease who have had an inadequate response to conventional therapy. Finally, GLM is indicated for inducing and maintaining clinical response in adults with moderately to severely active ulcerative colitis who have had an inadequate response to or were intolerant of previous therapy or were steroid-dependent, improving the endoscopic appearance of colonic mucosa during induction, inducing clinical remission, and achieving and sustaining clinical remission in induction responders. IFX is administered intravenously while the other 3 are given subcutaneously. IFX has weight-based dosing, while the other 3 have fixed dosing (see Table 1 for details). Dose escalation information is available for IFX and to a lesser extent ADA. Previous dogma was that one should fully optimize the dose of an anti-tnf before moving to another one (i.e., dose escalation, adding concomitant immunosuppressive if on monotherapy), but with the availability of drug/antibody monitoring (see below), this is changing. Meta-analyses of clinical trials of anti-tnf agents show that they are efficacious in inducing and maintaining remission in Crohn s disease. There are no head-to-head comparisons of any anti-tnf agents against each other. The decision to use one anti-tnf agent over another is often generated by physician familiarity and patient preference, but will be increasingly be dictated by third party payers. Natalizumab Natalizumab (NAT) is a humanized monoclonal antibody to the alpha-4 integrin which plays an important role in lymphocyte trafficking. This drug is approved by the FDA for inducing and maintaining clinical response and remission in adults with moderately to severely active Crohn s disease with evidence of inflammation (e.g., elevated CRP or fecal calprotectin, or inflammation visualized on endoscopy or enterography) who have had inadequate response to or 110 1C: Advances in Inflammatory Bowel Disease
3 can t tolerate conventional therapies and anti-tnf therapy. The use of NAT in Crohn s disease has been limited by the risk of progressive multifocal leukoencephalopathy (PML), a potentially fatal neurologic condition. Alpha-4 integrin is expressed not only in the gut but in the brain, and this allows, in rare patients, reactivation of the JC virus which results in PML. NAT can be prescribed through a special restricted distribution program called the TOUCH Prescribing Program. Furthermore, concomitant immunosuppressives are not permitted, and the use of corticosteroids is highly discouraged. The availability of a serology for JC virus has allowed some risk stratification for PML, and the use of NAT has expanded somewhat. For a patient who has failed an anti-tnf agent and who is JC virus antibody-negative, the decision to use NAT is entirely reasonable, since the risk of PML is infinitesimal. JC virus serology should be checked every 6 months. A Crohn s disease patient on NAT who is JC virus antibody-positive should be counseled that their annual risk of PML is in the range of 1%. Combination Therapy versus Monotherapy Unfortunately, a mixed message has been sent over the years about the benefits and risks of anti-tnf therapy in combination with immunosuppressives, resulting in considerable practice variation. In the relatively early days of IFX, it was recognized that giving immunosuppressive therapy was one of several tools (including loading dose, scheduled maintenance, and steroid premedications) to maximize IFX response. By 2006 and 2007, it became apparent that: 1) a small number of young males on combination therapy with a thiopurine were developing potentially fatal hepatosplenic T-cell lymphomas; and 2) several studies demonstrated an increased risk of serious/opportunistic infections on therapy, and the relative risk of infection increased with the number of medications given. Thus, for several years, many thought leaders recommended anti-tnf monotherapy for most patients starting biologics. However, with the advent of the SONIC trial results, and more recently the UC SUCCESS trial, it became apparent that the incremental benefit of combination therapy versus monotherapy was fairly significant. At this point in time, it would be safe to say that the majority of thought leaders in IBD are recommending combination therapy for most IBD patients who require anti-tnf therapy. It is fair to point out, however, that the evidence for this is based on a handful of trials, and more work needs to be done to solidify this recommendation. In my own practice, I recommend combination therapy for most patients in whom I am starting an anti-tnf agent. In a patient with a documented history of severe infection, or in an elderly patient, I may consider monotherapy. I personally do not believe that being a young male is a contraindication to combination therapy, since the absolute risk of hepatosplenic T-cell lymphoma in a young man on combination therapy is still extraordinarily low. An alternative immunosuppressive agent to consider in this situation is methotrexate, which seems to be less lymphomagenic, and has not been associated with the development of hepatosplenic T-cell lymphomas either alone or in combination with anti-tnf agents. Evolving Treatment Paradigms Treat Earlier in the Course of IBD Multiple lines of evidence suggest that we have probably been too conservative in our treatment of many patients with IBD, especially those with Crohn s disease. While everyone agrees that universal top-down therapy is overkill, since up to 40% of patients in population-based studies never require bowel resection, the challenge has been to identify the patient with a rockier prognosis. Natural history studies suggest that potential markers for high-risk Crohn s disease include younger age at diagnosis, ileal or ileocolonic extent relative to colonic, fistulizing disease at diagnosis, and multiply-positive IBD serologies. Thus, in the patient who fits many of these risk factors, you should seriously consider moving fairly early in the disease course to combination therapy. On the other hand, an older patient diagnosed with purely colonic Crohn s is more likely to have a milder clinical course, and one has time to pursue a step-up therapy strategy. For ulcerative colitis, risk factors for a severe disease course include male gender, extensive colitis, and early need for corticosteroids. Before Starting Treatment, Know What You Are Treating (Treatment Decisions Based on Objective Evidence) The symptoms of IBD are neither sensitive nor specific for bowel inflammation, and they overlap with numerous other conditions, including irritable bowel syndrome, microscopic colitis, bile salt diarrhea, small intestinal bacterial overgrowth, and celiac disease. Multiple studies now show a poor correlation between the Crohn s Disease Activity Index (primarily symptom-driven) and more objective markers of inflammation. A classic example of this comes from the SONIC trial, in the subgroup of Crohn s disease patients who had no endoscopic evidence of bowel inflammation at baseline, there were no differences in steroid-free remission rates among the 3 treatment arms, whereas in patients with elevated serum CRP levels and endoscopic inflammation, there was a 40% delta between the AZA monotherapy and combination therapy groups. Presumably, the symptoms among the patients with no endoscopic inflammation were due to other non-crohn s disease factors. It is therefore important, before making big treatment decisions such as initiating anti-tnf therapy, to assess your patient and determine that there is indeed bowel inflammation present. In other words, anti-tnf agents are not good irritable bowel syndrome drugs! 1C: Advances in Inflammatory Bowel Disease 111
4 Optimal Dosing Therapeutic Drug Monitoring Thiopurine metabolite levels can be quite helpful in finetuning the dose of AZA/6-MP and assessing why a patient may not be clinically responding to the drug. (In my own practice, I do not check thiopurine metabolites routinely, only in patients who aren t clinically responding.) One of 4 metabolite profiles can occur: 1) low 6-TGN and low 6-MMP means that either the dose of drug is too low or the patient is non-compliant; 2) therapeutic 6-TGN and low or normal 6-MMP is the ideal situation; 3) high 6-TGN and high 6-MMP means the dose is too high; and 4) low 6-TGN and high 6-MMP means the patient is a shunter (i.e., preferentially overproducing methylated metabolites at the expense of the therapeutic 6-TGN). Attempts to address the last group by increasing the dose of thiopurine usually results in no increased efficacy and increased hepatotoxicity. Experienced prescribers who are willing to monitor for leukopenia intensively could consider treating the shunters with allopurinol 100 mg daily and a severely reduced dose of thiopurine, usually 25% of the predicted weight- and TPMT-based dose. Thus, for a 70 kg patient with a normal TPMT, the appropriate starting dose of AZA, in the setting of concomitant allopurinol, would be 25 or 50 mg of AZA daily. For a 70 kg patient with an intermediate TPMT, the appropriate starting dose of 6-MP would quite low, in the order of 25 mg 6-MP every other day. These patients can become leukopenic rapidly and should initially have CBC s checked weekly. After 2 months of therapy, further thiopurine metabolite testing can guide dosing. The pharmacokinetics of anti-tnf agents are highly variable across individuals. The serum level of anti-tnf drug in an individual is thought be a function of body weight, gender, TNF burden, CRP levels, serum albumin, concomitant immunosuppressives, and the presence of anti-drug antibodies. Furthermore, patients with severe colonic inflammation may experience fecal loss of IFX (and presumably other anti-tnf agents) via a protein-losing colopathy. Reanalysis of clinical trials of anti-tnf agents in IBD and in other conditions shows a remarkably high correlation between serum drug levels and clinical response. In UC, detectable IFX trough levels is associated with higher rates clinical response and endoscopic remission, and lower rates of colectomy. On the other hand, the presence of anti-drug antibodies inversely correlates with both serum anti-tnf drug levels and clinical response. For all of these reasons, it makes sense that use of drug levels and antibody tests have great potential for optimizing patients drug regimens. A meta-analysis of 18 studies examining antibodies to infliximab (ATI) among over 3,000 patients showed a prevalence of 45.8% with episodic IFX and 12.4% with scheduled maintenance IFX. The presence of ATI doubled the risk of infusion reactions, and concomitant immunosuppressives reduced the risk of developing ATI by 50%. A retrospective analysis of the clinical utility of a first generation assay for serum IFX levels and antibodies to infliximab (ATI) showed that judicious use of the test could help aid in decision-making for patients who seemed to be losing response to IFX. For example, if IFX levels were subtherapeutic, and there were no ATI, increasing the dose of IFX resulted in a high rate of clinical response. On the other hand, if IFX levels were absent and ATI were present, switching the patient to another anti-tnf agent resulted in a higher rate of response. One study from France, however, suggested that increasing the dose of IFX despite the presence of ATI actually reduced or eliminated ATI, and many of these patients responded clinically. Further studies are needed on this point. Perhaps some of the discordant results are due to variations in the operating characteristics of commercially available assays. For patients with ongoing bowel inflammation despite therapeutic IFX levels, the best strategy is to switch to a different drug class/ mechanism of action. A second generation mobility shift assay has been developed that can measure ATI even when serum IFX is present. This assay was tested in almost 500 patients with Crohn s who were involved in IFX clinical trials or cohort studies. Patients with ATI present were more likely to have higher CRP levels, while patients with serum IFX >3mcg/mL were more likely to have lower CRP levels. More studies of the incremental clinical utility/benefit of the second generation assay compared to the first generation assays need to be performed. There have been fewer studies on the clinical utility of assays for serum ADA and antibodies to ADA (ATA). The prevalence of ATA has ranged from 0% to 17%. The presence of ATA tends to correlate with lower serum ADA levels, and lower trough levels are associated with a higher rate of ADA discontinuation due to lack of clinical response. Some, but not all, studies have suggested that ATA are negatively correlated to clinical response. Similar to the IFX studies, the discordant results may in part be explained by different assays. Recently, a commercial assay for ADA/ATA has become available in the U.S. This is a second generation mobility shift assay that allows for simultaneous measurement of ADA and ATA. This assay has been tested in 100 patients receiving ADA and shows a reasonably good inverse correlation between ADA levels and the presence of ATA. Defining Objective Treatment Endpoints, Not Based on Symptoms Alone As we had discussed previously, the correlation between symptoms of IBD and objective evidence of bowel inflammation is poor; therefore, relying on symptoms alone to gauge response 112 1C: Advances in Inflammatory Bowel Disease
5 to a change in therapy is fraught with difficulty. The treating provider should get into the habit of following up a major change in therapy with testing to determine if there has been a reduction in the level of bowel inflammation. For a patient with markedly elevated serum CRP or fecal calprotectin at baseline, perhaps a follow-up test 2 to 3 months after starting therapy would be in order. Endoscopic or enterographic re-evaluation of the patients 4 to 12 months after a change in therapy is probably warranted. SUGGESTED READING 1. Baumgart DC, Sandborn WJ. Crohn s disease. Lancet 2012;380: Ordas I, Eckmann L, Talamini M, et al. Ulcerative colitis. Lancet 2012;380: Khan KJ, Dubinsky MC, Ford AC, et al. Efficacy of immunosuppressive therapy for inflammatory bowel disease: A systematic review and meta-analysis. Am J Gastroenterol 2011;106: Ford AC, Sandborn WJ, Khan KJ, et al. Efficacy of biological therapies in inflammatory bowel disease: Systematic review and meta-analysis. Am J Gastroenterol 2011;106: Levesque BG, Loftus EV Jr. Initiating azathioprine for Crohn s disease. Clin Gastroenterol Hepatol 2012;10: Relling MV, Gardner EE, Sandborn WJ, et al. Clinical pharmacogenetics implementation consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing. Clin Pharmacol Ther 2013;93: Ordas I, Feagan BG, Sandborn WJ. Therapeutic drug monitoring of tumor necrosis factor antagonists in inflammatory bowel disease. Clin Gastroenterol Hepatol 2012;10: Khanna R, Sattin BD, Afif W, et al. Review article: A clinician s guide for therapeutic drug monitoring of infliximab in inflammatory bowel disease. Aliment Pharmacol Ther Doi: /apt C: Advances in Inflammatory Bowel Disease 113
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