Treatment of luminal and fistulizing Crohn's disease with infliximab

Gastroenterol Clin N Am 33 (2004) 387–406

Treatment of luminal and fistulizing Crohn’s disease with infliximab Lawrence W. Comerford, MD, Stephen J. Bickston, MD* University of Virginia Digestive Health Center of Excellence, Box 800708, UVA Health System, Charlottesville, VA 22908, USA

Crohn’s disease (CD) is a chronic inflammatory disorder of the gastrointestinal tract of unknown etiology that results in significant morbidity and health care costs. More than 400,000 people in the United States have CD. The prevalence continues to increase because of its rising incidence and improved survival [1]. The chronic nature of the illness causes frequent hospitalizations; most patients eventually require surgery secondary to complications, such as strictures, abscesses, fistula, or refractory disease. The disease seems to occur when the intestinal immune cascade is triggered by an antigen in genetically susceptible individuals. Overactivation of the enteric immune and inflammatory pathways causes mucosal damage resulting in the clinical signs and symptoms. Various medications, including 5-aminosalicylates, antibiotics, corticosteroids, and immunomodulators, such as purine antimetabolites and methotrexate, have traditionally been used to control inflammation. Their use is intended to prevent surgery and improve the patient’s quality of life. None cure the disease and unfortunately, many patients require steroids to control their symptoms. A wide range of dose-related adverse effects makes this an unappealing strategy. Immunomodulators are effective maintenance drugs, but have a slow onset of action with clinical remission rates of approximately 40%. The limitations of conventional agents leave the clinician in need of a medication that is steroid-sparing, quick acting, and maintains remission [2]. Genetic engineering advances have produced endogenous proteins in sufficient quantities to be used therapeutically. This process, called recombinant technology, involves incorporating mammalian DNA that codes for a specific protein into bacteria or cells. Pure proteins can then be

Drs. Comerford and Bickston have received honoraria from Centocor for lectures. * Corresponding author. E-mail address: [email protected] (S.J. Bickston). 0889-8553/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.gtc.2004.02.014

388

L.W. Comerford, S.J. Bickston / Gastroenterol Clin N Am 33 (2004) 387–406

produced in large quantities; the monoclonal antibody is a useful class of protein that evolved from recombinant technology [3]. These antibodies bind to a particular antigen with high affinity and specificity [4]. Monoclonal antibodies are currently used to treat immune-mediated inflammatory diseases, transplant rejection, and malignancies [5]. Parallel advances in the understanding of the molecular biology of intestinal inflammation in animal models allow specific application to CD in humans. This article discusses infliximab (Remicade, Centocor, Malvern, PA), a chimeric monoclonal antibody (75% human, 25% mouse) that targets tumor necrosis factor (TNF), a potent proinflammatory cytokine pivotal in the initiation and promotion of intestinal inflammation. This novel biologic agent is now used extensively in the treatment of patients with moderate to severe luminal and fistulizing CD. An estimated 400,000 patients had been treated with infliximab worldwide by April 2003 [6]. To date, it has proved to be safe and effective for patients afflicted with CD.

Background Tumor necrosis factor is an important proinflammatory cytokine with a key role in several disease states. Interest in TNF as a possible therapeutic target began 20 years ago when its role in endotoxin-induced sepsis was investigated [3]. Elevated TNF concentrations have been found in inflamed tissues of patients with CD, rheumatoid arthritis, and multiple sclerosis [7]. Stool and mucosal concentrations of TNF in CD patients have been shown to correlate with clinical activity of disease [8]. Tumor necrosis factor is a 157–amino acid protein produced by T cells, monocytes, and macrophages; after secretion as an inactive precursor, it is rapidly proteolyzed to a 17-kd monomer. Three monomers rapidly combine to form the biologically active 51-kd trimeric cytokine that binds to either the 55- or 75-kd transmembrane TNF receptor located on the surface of a number of different cell types. These receptors are designated TNF-R p55 and TNF-R p75 [3,9]. Intracellular signaling events then occur by the NFkB and JNK pathways as a result of the binding of the ligand to the receptor. Transcription of genes involved in the inflammatory response is initiated. Induction of apoptosis by proteins called caspases occurs [3,7]. This interaction causes up-regulation of endothelial cell adhesion molecules; proliferation of fibroblast; induction of metalloproteinases critical to tissue destruction; induction of other inflammatory mediators, such as interferonc, platelet activating factor, nitric oxide synthase, and cyclooxygenase; activation of the coagulation cascade; and formation of granulomas. Increased intestinal permeability is a consequence [9–14]. Given the role of TNF in the inflammatory cascade, considerable research has been focused on studying the effects of blocking this cytokine with novel biologic agents. Animal models of colitis, arthritis, and myelin

L.W. Comerford, S.J. Bickston / Gastroenterol Clin N Am 33 (2004) 387–406

389

destruction show clinical and histologic improvement with inhibition of TNF [3]. Investigators postulated because TNF was involved in granuloma formation, there might be a role for an anti-TNF agent in the treatment of granulomatous bowel disease, such as CD [15]. Recombinant technology allowed the development of monoclonal antibodies that could serve as these anti-TNF agents. Preliminary open-label trials showed mucosal healing and clinical improvement in CD patients treated with these monoclonal antibodies; the drug, formerly called cA2, is now named infliximab [15]. The name reflects standard nomenclature with ‘‘mab’’ denoting monoclonal antibody, ‘‘xi’’ conveying its chimeric nature, and ‘‘infli’’ showing its target is the inflammatory cascade. Infliximab is configured by linking the constant regions of the human immunoglobulin G1k (IgG1k) to the variable antigen-binding regions of a murine anti–human TNF antibody, resulting in a chimeric antibody that is 25% mouse and 75% human protein [11,16]. Infliximab neutralizes the biologic activity of TNF by binding to both the soluble and transmembrane forms of this cytokine and inhibiting binding of TNF with its receptors [16,17]. Binding to transmembrane or cell-bound TNF causes antibodydependent cell-mediated cytotoxicity or complement fixation and lysis of cells bearing TNF on their surface [17]. The IgG1 Fc portion of the antibody causes apoptosis of T lymphocytes [18]. Blocking TNF also results in decreased expression of interleukins-1 and -6, interferon-c, and other proinflammatory cytokines. Additionally, acute-phase proteins, adhesion molecules, and inducible nitric oxide synthetase are down-regulated [19,20].

Pharmacology Infliximab is produced by a recombinant cell line, which contains the genomic construct for the cA2 monoclonal antibody. The medication is intravenously administered, usually 5 mg/kg over a period of at least 2 hours. Data collected from clinical trials using single infusions of infliximab at doses of 5, 10, and 20 mg/kg revealed a linear and direct relationship between the dose administered and the maximum serum concentration and area under the concentration-time curve. Volume of distribution at steady state was determined to be independent of dose, indicating that infliximab was primarily distributed within the vascular compartment [3,14]. Based on infusions of 3 and 5 mg/kg, the terminal half-life of infliximab is 8 to 10 days. After a single infusion, detectable levels of infliximab were present for 8 to 12 weeks. Patients given up to four infusions of infliximab at 4- or 8week intervals with doses as high as 10 mg/kg did not show any systemic accumulation. Currently, it is not known how the drug is metabolized or excreted. Additionally, it is not known how gender and severe renal or hepatic dysfunction affect the clearance or volume of distribution of infliximab [3,21].

390

L.W. Comerford, S.J. Bickston / Gastroenterol Clin N Am 33 (2004) 387–406

Approved gastrointestinal indications The evidence to date supports the use of infliximab as induction therapy for the following indications as approved by the US Food and Drug Administration: reduction in signs and symptoms and induction of clinical remission in patients with moderately to severely active inflammatory CD where there is an inadequate response to conventional therapy; and reduction in the number of draining enterocutaneous fistulas in patients with fistulizing CD [22]. Off-label but clinically accepted indications for induction therapy include avoidance of initiating steroid therapy, using infliximab as a rapidly acting induction therapy, followed by maintenance treatment with azathioprine, 6-mercaptopurine, or methotrexate; and steroid-sparing in steroid-treated patients. Improvement of nutritional status in sick, malnourished patients with active disease may also be a reasonable indication [22]. Infliximab is now approved by the FDA for maintenance of remission as well, in both refractory and fistulizing CD. The rationale for using this novel medication was initially based on uncontrolled studies, but now there is evidence from well-designed clinical trials to support its use. Derkx et al [23] reported clinical improvement in a CD patient after treatment with infliximab. Subsequently, in an open pilot study, van Dullemen et al [15] provided direct evidence that a single infusion of infliximab caused remission in 8 of 10 patients; the infusions significantly decreased Crohn’s disease activity index (CDAI), and improved colonoscopic and histopathologic findings within 4 weeks of infusion. Sedimentation rates and C-reactive protein levels fell within days of treatment. The positive results of these initial studies led to a multicenter, randomized, placebo-controlled, double-blind trial of 108 patients with active CD [24]. Patients received a single infusion of infliximab (5 mg/kg, 10 mg/kg, 20 mg/kg, or placebo). At 4 weeks, 22 (81%) of 27 patients given the 5 mg/kg dose had a clinical response, which was the primary end point of the study and defined as a reduction of 70 or more points in the CDAI score. A total of 14 (50%) of 28 patients given the 10 mg/kg dose achieved clinical response, whereas 18 (64%) of 28 patients infused with 20 mg/kg improved their CDAI at least 70 points. Overall response in the infliximab group was 65%. Only 4 (17%) of 24 patients given placebo responded at 4 weeks (P \ .001). Thirty-three percent of the patients infused with infliximab achieved complete remission, defined as a CDAI score less than 150, compared with only 4% of patients given placebo (P = .005). Forty-eight percent of the patients who received 5 mg/kg infliximab achieved complete remission. At 12 weeks, 34 (41%) of 83 patients in the infliximab group maintained their clinical response compared with 3 (12%) of 25 in the placebo group (P = .008). The investigators concluded a single infusion of infliximab was an effective short-term treatment in patients with moderateto-severe CD. Although a landmark study in the clinical investigation of

L.W. Comerford, S.J. Bickston / Gastroenterol Clin N Am 33 (2004) 387–406

391

infliximab, constructive criticisms of the study include an unusually low placebo response rate, a lower mean concentration of C-reactive protein at baseline in the placebo group, and significantly more patients with ileal disease alone in the placebo group compared with the three treatment groups. Approximately one third of CD patients develop fistula; the efficacy of infliximab in closing these fistula has been studied [25]. In a multicenter, randomized, placebo-controlled, double-blind trial, a total of 94 adults with active draining perianal or abdominal fistulae were given either placebo, 5 mg/kg of infliximab, or 10 mg/kg of infliximab intravenously at 0, 2, and 6 weeks [26]. Fifty-five percent of patients who received 5 mg/kg and 38% of patients who received 10 mg/kg had closure of all fistulas, compared with only 13% of patients who received placebo (P = .001 and P = .04, respectively). In addition, 68 percent of the patients receiving 5 mg/kg and 56% of the patients receiving 10 mg/kg achieved closure of at least half of their fistulae compared with 26% of the placebo group (P = .002 and P = .02, respectively). The median length of time the fistulas remained closed was 3 months. The clinical effect after a single infusion of infliximab wanes with time and relapses are common [27]. Patients often require retreatment with infliximab. There is evidence from clinical trials to support using infliximab as maintenance therapy. The Food and Drug Administration–approved indication for infliximab as maintenance therapy is maintenance of clinical improvement and clinical remission in patients who previously had moderately to severely active inflammatory CD with an inadequate response to conventional therapy who responded to initial induction therapy with infliximab. Infliximab is now also indicated for maintenance in fistulizing CD. Clinically accepted indications for maintenance therapy include maintenance of fistula improvement (reduction in the number of draining perianal or enterocutaneous fistulas) and complete fistula response (no draining fistulas) in patients with fistulizing CD who responded to initial induction therapy with infliximab; and steroid sparing in patients with steroid-treated CD who have failed an attempt at steroid sparing with one or more of the immunosuppressive agents including azathioprine, 6mercaptopurine, or methotrexate [22]. Rutgeerts et al [28] conducted a follow-up study to determine if response could be maintained with repeated infusions in patients who responded to an initial infusion. Seventy-three patients were randomized to receive 10 mg/kg doses of infliximab or placebo at 8-week intervals through week 36 with follow-up through week 48. Fifty-three percent of patients receiving infliximab maintained remission through week 44 compared with 20% of placebotreated patients. Most infliximab-treated patients eventually relapsed 8 to 12 weeks after the final infliximab dose administered at week 36, suggesting the duration of benefit for infliximab in patients is approximately 8 weeks [18]. Median values for CDAI, inflammatory bowel disease questionnaire

392

L.W. Comerford, S.J. Bickston / Gastroenterol Clin N Am 33 (2004) 387–406

(a quality of life measurement), and serum C-reactive protein concentrations were maintained at remission levels with infliximab retreatment. The ACCENT I trial was conducted to determine whether maintenance infliximab therapy provides better long-term efficacy than no further treatment for CD patients who respond to a single dose of infliximab [2]. This study included 573 patients with active CD in a multicenter, randomized, placebo-controlled, double-blind trial. All patients received an open-label dose of 5 mg/kg infliximab at week 0. Responders at week 2 (335 [59%] of 573) were then randomized into one of three groups. Group 1 received infusions of placebo at weeks 2 and 6 and then every 8 weeks until week 46. Group II received infusions of 5 mg/kg of infliximab at the same time points. Group III received infusions of 5 mg/kg at weeks 2 and 6 followed by 10 mg/ kg every 8 weeks until week 46. Study end points were the proportion of patients who responded at week 2 and were in remission (CDAI \ 150) at week 30 and the time to loss of response up to week 54. At week 30, 23 (21%) of 110 patients of the placebo group were in remission, compared with 44 (39%) of 113 group II patients (P = .003), and 50 (45%) of 112 group III patients (P = .0002). These results show that retreatment with infliximab every 8 weeks in initial responders is more effective than placebo in maintaining remission. Analysis of a nested study at week 10 showed that a three-dose induction regimen with infliximab (dosing at 0, 2, and 6 weeks) was more effective at inducing remission than a single induction dose. Forty percent achieved remission after a three-dose induction compared with 28% remission after a single-dose induction [18,29]. Other regimens have also been advocated as improving response or decreasing adverse events. One study suggests that a single second infusion within 8 weeks is beneficial [30]. The efficacy of infliximab as maintenance therapy for fistulizing disease was evaluated over 54 weeks in ACCENT II, a multicenter randomized placebo-controlled trial. Patients were infused with 5 mg/kg infliximab at 0, 2, and 6 weeks. Of the 282 patients who completed the study through week 14, 195 patients (69%) were responders with closure of at least 50% of draining fistulas sustained over 1 month. These patients were then randomized to receive either 5 mg/kg infliximab (96 patients) or placebo (99 patients) every 8 weeks. Sands et al [31] reported significantly greater rates for fistula improvement (reduction in the number of draining fistulas) and fistula remission (no draining fistulas) in the infliximab-treated group. Specifically, almost half (48%) of the infliximab-treated patients maintained fistula remission at week 30 compared with 27% of the placebo group. At week 54, 36% of the infliximab-treated group maintained fistula remission compared with 19% of the placebo group. The median time to loss of response was more than 40 weeks in the infliximab-treated group compared with 14 weeks in the placebo group. Mucosal healing from infliximab treatment was evaluated in a multicenter randomized placebo-controlled trial. A total of 30 patients underwent colonoscopy with terminal ileum intubation before treatment with

L.W. Comerford, S.J. Bickston / Gastroenterol Clin N Am 33 (2004) 387–406

393

infliximab at doses of 5 mg/kg, 10, mg/kg, 20 mg/kg, or placebo. Endoscopy was repeated 4 weeks after infusion of either placebo or infliximab. Mucosal lesions were scored using a validated Crohn’s Disease Endoscopic Index of Severity (CDEIS). Biopsy specimens were taken from 9 of 30 patients pretreatment and posttreatment. CDEIS scores decreased significantly in most infliximab-treated patients, although no dose response was noted. In contrast, placebo patients did not exhibit any endoscopic improvement. The inflammatory infiltrate observed on initial biopsies resolved after treatment in the infliximab group but not the placebo group [32]. Rutgeerts et al [33] showed mucosal healing documented on endoscopy correlated with improved outcomes; specifically, fewer hospitalizations and surgeries occurred in the group with mucosal healing compared with the group with no mucosal healing. The findings of this small study are provocative but require validation in larger trials. A sub study of 99 patients in the ACCENT I trial evaluated endoscopic mucosal healing in patients receiving episodic retreatment with infliximab compared to maintenance therapy every 8 weeks. At week 54, only 7% of the episodic retreatment patients had achieved mucosal healing compared to 50% of the patients receiving maintenance therapy. Improvements in CDEIS and CDAI scores were positively correlated in the maintenance therapy group [34]. Infliximab is an option for patients who are intolerant of, resistant to, or dependent on steroids [35]. Of the first 100 patients treated with infliximab at Mayo Clinic, a total of 29 (73%) of 40 patients were able completely to withdraw from steroids [27]. Cohen et al [36] reported corticosteroid tapering was achieved in more than 90% of patients with luminal disease, with complete withdrawal of steroids in 54% of patients after the second infusion of infliximab. This study included 81 patients with luminal disease and 48 patients with fistulizing disease who received at least one infusion of infliximab. In the ACCENT I trial, more than half of patients were taking corticosteroids at study entry. One third of patients receiving maintenance infliximab both discontinued steroids and achieved clinical remission [2]. Other reported uses Refractory ulcerative colitis (UC) has two main presentations: severe illness requiring hospitalization and the more common ‘‘working wounded’’ that have persistent mild-to-moderate disease. Although infliximab is not approved for treatment of UC, there are studies that suggest a future role for this therapy in refractory UC. Unfortunately, the available data come from studies that are small, uncontrolled, or retrospective. In a retrospective case series, 16 patients with varying levels of active UC received a single 5 mg/kg infusion of infliximab [37]. Clinical, endoscopic, and histologic improvements were observed in 88% (14 of 16) of patients after initial treatment. Clinical remission was maintained in these patients for at least 4 months. Surgery was avoided in 86% (six of seven) of patients who were

394

L.W. Comerford, S.J. Bickston / Gastroenterol Clin N Am 33 (2004) 387–406

surgical candidates. Most of the treated patients were completely withdrawn from corticosteroid therapy. In a placebo-controlled trial, 11 patients with active severe, steroidrefractory UC were randomized to receive a single infusion of infliximab or placebo [38]. The study was appropriately designed and powered to clarify whether infliximab might serve in this presentation in like manner to the more established use of cyclosporine, but was aborted for lack of enrollment. Four (50%) of the eight patients receiving infliximab experienced a clinical response at 2 weeks. Improvement in sedimentation rates and C-reactive proteins correlated with clinical response. None of the three placebo patients improved. Infusion with infliximab produced no significant adverse events. A retrospective analysis of clinical experience in four medical centers was conducted to assess the effectiveness of infliximab in UC [39]. A total of 27 patients with UC received single or multiple infusions of infliximab. Twelve patients (44%) achieved remission and six patients (22%) had a partial response, whereas nine patients (33%) had no response. Five patients who did not respond subsequently underwent total colectomy. The median time to achieve response and remission was 4 days; the median duration of response was 8 weeks. Steroid-responsive patients were more likely to respond to infliximab than steroid-refractory patients (83% versus 33%; P = .03). Of the 18 patients who responded, 9 experienced 19 relapses; 18 of these relapses (95%) were successfully retreated with further infusions of infliximab. One death occurred. One placebo-controlled trial evaluating infliximab in 42 patients with steroid-refractory UC showed no clinical benefit [40]. This comparative trial only had 42 patients, underpowering the study to detect a difference. These small studies show promise, but larger controlled trials are required. The use of infliximab for UC remains investigational until efficacy and safety for this indication are demonstrated in controlled trials, such as the two phase III placebo-controlled trials currently in progress. Infliximab has been reported to treat other gastrointestinal-related conditions, including CD of the ileoanal pouch. Medical records of seven patients with CD who underwent an ileal pouch anal anastomosis for an original diagnosis of presumed UC were reviewed at Mayo Clinic. The patients received one to four doses of infliximab at 5 mg/kg for active inflammatory or fistulizing disease after they had no improvement in their symptoms with conventional therapies. All patients improved clinically, with six of seven obtaining a complete response and one patient achieving a partial response. Six of the seven patients received concurrent treatment with immunomodulators [41]. Patients with CD often experience extraintestinal manifestations of their disease, which are often debilitating and difficult to manage. There is evidence infliximab may have a role in treating these conditions, which include ankylosing spondylitis, peripheral arthritis, pyoderma gangrenosum, and erythema nodosum [42–45].

L.W. Comerford, S.J. Bickston / Gastroenterol Clin N Am 33 (2004) 387–406

395

Infliximab may also improve bone mineral density in CD patients both directly, through inhibition of TNF and indirectly through steroid sparing. CD patients are at increased risk for low bone mineral density; prevalences of osteopenia and osteoporosis as high as 50% and 10%, respectively, have been reported. The etiology for low bone mineral density is multifactorial; low body mass index through poor nutrition, corticosteroid use, decrease intake of calcium and vitamin D, and malabsorption of nutrients secondary to inflamed or resected bowel may all play a role. The systemic inflammatory disorder of CD may also cause bone loss through the action of cytokines, including TNF. Osteoclast function, stimulated by these cytokines, affects bone resorption, which has been demonstrated in numerous in vitro and in vivo studies. Abreu et al [46] conducted a prospective study evaluating the effect of infliximab on surrogate markers of bone turnover in 38 CD patients. The results showed bone synthesis markers were increased in the infliximab-treated patients. Longer-term studies are needed to clarify the effect of infliximab on bone mineral density.

Toxicity Although an effective medication for CD, serious side effects have been reported including acute infusion reactions, delayed hypersensitivity reactions, infections including reactivation of tuberculosis (TB), autoantibody formation, and a lupus-like syndrome. Clinicians need to be aware of these potential outcomes to diagnose and manage correctly the complications. Candidates for therapy should be counseled about these toxicities before infusions. Acute infusion reactions are adverse events occurring during the infusion or within 2 hours after the infusion is complete. They are common, occurring in approximately 22% of treated patients compared with 9% of patients receiving placebo according to the manufacturer’s drug insert [21]. Mayo Clinic, however, reported a much lower incidence in their clinical experience; only 19 (3.8%) of 500 patients who received infusions experienced an acute infusion reaction [47]. These events are non-IgE mediated anaphylactoid events. These include but are not limited to headache, nausea, dyspnea, urticaria, and chest tightness. Generally, these reactions can be managed easily by first slowing or temporarily stopping the infusion, then treating with oral acetaminophen and serial doses of intravenous diphenhydramine, 25 to 50 mg, if symptoms persist. At the authors’ institution, they have also found intravenous famotidine to be helpful for the H2 component of the allergic response. After symptoms resolve, recommencing the infusion at a slower rate and then titrating upward as tolerated is usually successful. Most patients are able to complete their infusion. Patients with a history of infusion reactions should be considered for premedication with these medications approximately 30

396

L.W. Comerford, S.J. Bickston / Gastroenterol Clin N Am 33 (2004) 387–406

minutes before the infusion. There is no evidence that routine premedication in patients without a history of infusion reaction is necessary [22]. At times, prednisone may be required as a premedication in patients who have symptoms with infusions not alleviated with diphenhydramine and acetaminophen or those who are at risk because of a long interval (greater than 4 months) since last infusion. Any patient who has had prior infusion reaction should be considered for premedication with prednisone. Delayed hypersensitivity or serum-sickness–like reactions several days after the infusion can also occur. Symptoms include severe pruritus; headaches; hand, facial, or lip swelling; myalgias; rash; sore throat; or dysphagia. One study of 40 CD patients showed a 25% incidence rate, with 6 patients requiring hospitalization [48]. These patients had initially received an investigational liquid formulation of the drug, which is no longer in use with a follow-up infusion 2 to 4 years later with the commercialized formulation (lyophilized powder). These events occur much less frequently in clinical practice with retreatment intervals up to 1 year; in ACCENT I, where patients received repeated infusions every 8 weeks, the frequency of delayed hypersensitivity reaction was 2% [2]. In Mayo Clinic’s experience with 500 patients, only 14 patients (2.8%) had serum sickness related to infliximab [47]. Infections requiring treatment have been associated with infliximab therapy during clinical trials; specifically, 36% of infliximab-treated patients compared with 26% of patients receiving placebo [21]. In postmarketing experience, infections have been observed with pathogens including viral, bacterial, fungal, and protozoal organisms. Most infections involved the respiratory (pharyngitis, sinusitis, bronchitis) and urinary tract. Serious and even fatal infections have been reported including abscess, sepsis, pneumonia, cellulitis, TB, disseminated coccidioidomycoses, Pneumocystis carinii pneumonia, histoplasmosis, listeriosis, and aspergillosis. During trials, no statistically significant increase in serious infections or sepsis was seen in infliximab-treated patients compared with placebo-treated patients [22]. Mayo Clinic reported 41 (8.2%) of 500 patients developed an infection related to infliximab [47]. Twenty patients had a serious infection: two lethal sepsis; eight pneumonias, of which two were lethal; six viral infections, including three varicella-zoster virus infections; two abdominal abscesses requiring surgery; one arm cellulites; and one histoplasmosis. No cases of TB were observed. Because there was no control group in the Mayo series, it is difficult to know what proportion, if any, of these infections were caused by infliximab. Over 85% of the patients in this cohort were taking additional concomitant immunosuppressive medications. The overall mortality rate was not different from the background rate in CD [49–52]. Active or suspected infections should be treated before infusing infliximab. Reactivation of latent TB after infusion with infliximab has been observed, mandating screening of patients for TB before infusions. This likely reflects the impact of infliximab on the TNF-driven apoptosis of cells within

L.W. Comerford, S.J. Bickston / Gastroenterol Clin N Am 33 (2004) 387–406

397

granulomas. Over 70 cases have been reported; 48 of the cases developed TB after three or fewer infusions [53]. Most cases occurred within the first 2 months after initiation of therapy with infliximab suggesting activation of latent disease rather than new infection. Most cases (64 of 70) were from countries with a low incidence of TB. Forty of 70 patients had extrapulmonary disease. Interestingly, most cases involved patients being treated with infliximab for rheumatoid arthritis; only 22% of patients had CD [22]. A purified protein derivative should be placed on all patients being considered for infliximab infusion with the results interpreted according to the risk strata adapted from the American Thoracic Society [21,54]. Patients with negative readings and no risk factors for previous exposure obtained on history and physical examination can receive infliximab therapy. Patients with a positive purified protein derivative should undergo a chest radiograph. If the radiograph is normal, patients should begin treatment for latent TB according to American Thoracic Society guidelines before beginning infliximab therapy [22,55]. A 9-month course of isoniazid is the preferred treatment. If the radiograph is abnormal, infliximab should not be given until the active TB is adequately treated. Chronically ill patients taking corticosteroids and immune modulators may be anergic [56]. For this reason, the criteria used when screening inflammatory bowel disease patients should be that a positive purified protein derivative is greater than or equal to 5-mm induration. It cannot be overemphasized that a thorough history for risk factors should also be taken. A chest radiograph should be performed if warranted by the medical history, despite a negative purified protein derivative in these patients. The authors’ pharmacy confirms clearance for TB before releasing vials of infliximab, a practical fail-safe mechanism. Although the safety of infliximab in reproduction and pregnancy is unclear, there are accumulating data to show patients are delivering healthy children after exposure to the drug. Currently a pregnancy category B drug, animal reproduction studies have not been conducted because infliximab does not bind TNF in species other than humans and chimpanzees [21]. A toxicity study in mice was conducted using an analogous antibody that selectively inhibits the functional activity of mouse TNF. No evidence of maternal toxicity, embryotoxicity, or teratogenicity was observed. There are case reports of patients delivering healthy babies after being infused with infliximab during their pregnancy. Katz et al [57] recently queried the infliximab safety database maintained by the manufacturer (Centocor, Malvern, PA) for pregnancy outcomes in 133 female patients and 14 male partners exposed to infliximab. Pregnancy outcome data were available for approximately 50% (65 of 133) of patients. Fifty-six percent (74 of 133) of female patients were exposed to the drug within 3 months before conception; 45% (33 of 74) of these patients received infliximab before conception and during the first trimester. Results showed live births in 65% (42 of 65); miscarriages in 17% (11 of 65); and therapeutic terminations in 22% (14 of 65). These were not different from expected outcomes in the

398

L.W. Comerford, S.J. Bickston / Gastroenterol Clin N Am 33 (2004) 387–406

general pregnant United States population. Of the 14 male partners, there were 7 live births, 1 miscarriage, 3 ongoing pregnancies, and 3 unknown outcomes. The available data suggest inadvertent exposure does not cause harm to the fetus. It should probably only be administered knowingly to pregnant patients when a flare uncontrolled by other medications poses a greater health risk to the mother and unborn child than the risk of infliximab. Although immunoglobulins and many medications are secreted in breast milk, it is unknown if infliximab is excreted in breast milk [21]. It is also unknown if infliximab is absorbed systematically after oral administration. Because there is a theoretical risk for adverse reactions in nursing infants, patients should make a decision either to discontinue infliximab therapy before breast-feeding, or discontinue breast-feeding if the medication is required. Infliximab is contraindicated in patients with moderate to severe congestive heart failure (NYHA class III to IV). Higher incidences of mortality and hospitalization caused by worsening heart failure were observed in a phase II study comparing infliximab with placebo in 150 congestive heart failure patients treated with three infusions over 6 weeks. In follow-up at 38 weeks, nine infliximab-treated patients had died compared with one placebo patient [21]. Despite this evidence that infliximab may worsen pre-existing congestive heart failure, there is no evidence that infliximab causes congestive heart failure.

Special considerations Infliximab contains exogenous proteins that can prompt treated individuals to form antibodies to these proteins, called antibodies-to-infliximab (ATIs). The clinical implications of ATIs are currently a topic of research. From the ACCENT I trial, 442 patients were assessed up to week 54 for the presence of ATIs [2]. A total of 64 (14.5%) of 442 developed antibodies, whereas 173 (39%) of 442 did not form antibodies. Approximately half of the patients (46%) had inconclusive results concerning formation of ATIs because infliximab was detected in their serum, which can compete for the detection of antibodies to infliximab in the immunoassay. When followed longer, most of these inconclusive patients were found to be negative for ATIs. These results are similar to previous studies. Patients receiving a single dose of infliximab followed by either placebo or episodic infliximab retreatment had higher incidence of ATI formation than patients receiving scheduled maintenance regimens of 5 or 10 mg/kg (28% of patients compared with 9% and 6% of patients, respectively). Patients had similar rates of clinical response independent of their antibody status. Sixty-four percent of patients with ATIs responded clinically to infliximab (decrease in CDAI of [70 points from baseline and [25 points reduction in total CDAI

L.W. Comerford, S.J. Bickston / Gastroenterol Clin N Am 33 (2004) 387–406

399

score) compared with 62% who did not form ATIs. The rate of infusion reactions was slightly higher in the ATI positive group. Thirty-eight percent of patients with ATIs had one or more infusion reactions compared with 24% of patients without ATIs. Only a small minority of infusions in the ATI group, however, experienced an infusion reaction: 16% of infusions in the ATI-positive group compared with 8% of infusions in the ATI-negative group. Most of the infusion reactions were mild to moderate. Severe reactions and serum sickness–like reactions were rare and not increased in the ATI-positive group. Baert et al [58] conducted a study of 125 CD patients who received ‘‘on demand’’ (episodic) infliximab therapy; patients with luminal disease received a single 5 mg/kg infusion, whereas patients with fistulizing disease received three infusions of 5 mg/kg infliximab at 0, 2, and 6 weeks [58]. Responders were retreated ‘‘as needed’’ when symptoms recurred. Sixty-one percent of patients developed ATIs, much higher than the 14% detected in ACCENT I. Of these patients, only 37% had clinically significant levels of infliximab (>8 lg/mL). There was a higher risk of infusion reactions in the ATI-positive group (relative risk 2.4), but the association of high ATI levels with loss of response is clearly the more important finding. Patients with high ATI levels had a substantially shorter duration of response (35 days) compared with the patients who did not form antibodies (71 days). This impact on durability of response is reshaping treatment strategies. Three approaches have been examined to date: (1) premedication-concomitant steroids, (2) concomitant antimetabolite therapy, and (3) regular rather than episodic infusions. The development of ATIs has generally been lower in patients receiving concomitant immunosuppressants. Rheumatoid arthritis patients given methotrexate in addition to infliximab had lower antibody formation. In ACCENT I, only 4 (6%) of 64 patients developed ATIs who were receiving corticosteroids plus immunomodulator therapy [2]. Seventeen percent of patients receiving steroids alone and 10% of patients receiving immunomodulators alone formed ATIs. In comparison, 18% of patients receiving no additional immunomodulators formed ATIs. The lowest incidence of infusion reactions in the ACCENT I trial occurred in patients receiving both steroids and immunomodulators (8%), as compared with patients receiving neither (32%). In the Baert et al [58] study, patients receiving concomitant immunomodulator therapy had less antibody formation, higher concentrations of infliximab, reduced incidence of infusion reactions, and increased duration of response, prompting the authors to recommend their use. In their randomized trial of 53 consecutive patients receiving 199 ‘‘on demand’’ infusions, Farrell et al [30] also showed that loss of initial response and infusion reactions postinfliximab were strongly related to ATI formation and level. Administering a second infusion within 8 weeks of the first and concurrent immunosuppressant therapy significantly reduced ATI formation. They also found that premedication with intravenous hydrocortisone significantly reduced ATI levels but did not eliminate ATI formation or

400

L.W. Comerford, S.J. Bickston / Gastroenterol Clin N Am 33 (2004) 387–406

infusion reactions. Based on the results of these studies, most authorities now recommend that infliximab be administered on a regular maintenance schedule and that strong consideration be given to the administration of concomitant immunomodulators. There was initial concern over a possible link between infliximab and lymphoma, but early analyses and subsequent regulatory data show that malignancies are no more common in treated patients than in matched controls [59]. Nineteen new or recurrent malignancies were observed in 18 of 1372 patients treated with infliximab for up to 102 weeks in clinical trials over 1430 patient-years of follow-up [21]. These included non-Hodgkin’s Bcell lymphoma; breast cancer; rectal adenocarcinoma; and melanoma, squamous cell, and basal cell skin cancers. The observed rates and incidences were similar to those expected for the populations studied. Patients with CD are probably more likely to develop lymphomas irrespective of concomitant infliximab therapy. Data are insufficient to determine whether infliximab contributed to the development of these malignancies. Mayo Clinic reported 3 of 500 patients treated with infliximab developed a malignancy (two lung cancers and one non-Hodgkin lymphoma) in a time frame that cannot exclude a relationship to the infliximab therapy [47]. Patients treated with infliximab may develop autoantibodies; in clinical trials, antinuclear antibodies and anti-double–stranded DNA antibodies developed in 44% and 22% of patients, respectively [21]. Most of these patients remain asymptomatic and infliximab retreatment is not contraindicated in these patients [22]. Three CD patients developed signs of druginduced lupus [21]. All of these patients recovered without sequelae on discontinuation of infliximab.

Cost Infliximab is an expensive medication costing over $2000 US per infusion, raising the question whether or not it is a cost-effective therapy for CD patients, especially in the current health care climate. To answer this question, one needs first to study the cost of CD in general on society. Hay and Hay [60] provided landmark economic analysis of this disease. They found the lifetime direct medical cost of the illness per case in 1990 dollars was significant ($18,000–178,000). For comparison, heart disease was estimated costing $10,000 to 60,000. The estimated annual average medical cost per patient was approximately $9500 [60,61]. The estimated direct total annual cost of CD in 1996 dollars was $1.4 to 1.7 billion. As expected, surgery and hospitalizations accounted for most of the direct cost, approximating 80% of the total bill, compared with medications, outpatient resources, complications, and diagnostic testing, which accounted for the remaining 20%. Indirect costs were also significant with 5% to 10% of

L.W. Comerford, S.J. Bickston / Gastroenterol Clin N Am 33 (2004) 387–406

401

patients out of work and receiving disability benefits annually. The average number of workdays missed per month because of CD among full-time workers is 3.3 days [62]. In the United States, the proportion of patients not working because of their disease was estimated to be one in six. In their study of insurance claims for over 600 patients with CD over a 1year period, Feagan et al [63] found results similar to Hay and Hay [60]. Patients were stratified into three disease-severity groups: group 1 required hospitalization, group 2 required chronic steroids or immunomodulator therapy, group 3 included all remaining patients. Group 1 consumed the most health care dollars; specifically $37,135 per patient-year compared with $10,033 and $6277 for groups 2 and 3 patients, respectively. Hospitalization accounted for 57% of all direct care costs in CD. A minority of patients was responsible for most of the costs: approximately 25% of patients requiring 80% of the cost. New therapies could reduce overall costs if the need for hospitalization could be reduced. Cohen et al [64] reviewed the computer database for all hospitalizations at the University of Chicago during a 1-year period with a primary diagnosis of CD. The major charge during hospitalization was for surgery, accounting for nearly 40% of the hospital charges. The authors concluded more effective medical therapies could result in an overall decrease in medical costs if they reduce the need for hospitalization and surgery. Finally, a study was conducted by Rubenstein et al [65] to determine if infliximab decreased health care use of CD patients. The investigation included an electronic and paper chart review up to 3 years before infusion and 1 year following the initial infusion. Patients served as their own controls; use rates were compared pre and post first infliximab infusion. Some health care resource uses were decreased by a statistically significant percentage following infliximab infusion including gastrointestinal surgeries (
18%); emergency room visits (
66%); endoscopies (
43%); radiology examinations (
12%); and all outpatient visits (
16%). Patients treated for fistulas had decreases in hospitalizations (
59%) and gastrointestinal surgeries (
59%). Rutgeerts et al [61] reviewed the ACCENT I data comparing CD patients treated with infliximab episodically versus scheduled treatment strategies and evaluated the rate of hospitalizations and surgeries. In the infliximab 5 and 10 mg/kg scheduled treatment groups, significantly fewer CD-related hospitalizations were required (23 and 24 per 100 patients, respectively) compared with patients in the infliximab episodic treatment group (38 per 100 patients) (P ¼ .047, P ¼ .023 respectively for each comparison). Additionally, significantly fewer patients in the scheduled treatment group required CD-related surgery compared to the episodic treatment group. Scheduled therapy patients required hospitalization or surgery at approximately half the rate required by episodic therapy patients. Although these studies indicate cost savings can be accrued by attempting to reduce hospitalizations and surgical procedures, possibly with infliximab, further cost-effectiveness studies that factor in medication costs of infliximab

402

L.W. Comerford, S.J. Bickston / Gastroenterol Clin N Am 33 (2004) 387–406

with its direct and indirect cost savings, including improvement in quality of life aspects, are needed. Summary Hundreds of thousands of patients have been treated with infliximab since its approval in 1998. Clinical trials and practice have shown it to be safe, effective, and generally well tolerated. On its debut as the earliest effective biologic agent for CD, infliximab was considered the first truly novel therapy for CD in half a century. Thus far, complement activation and destruction of effector cells distinguish it from agents like CDP571, other humanized monoclonal antibodies, and other anti-TNF products. Are these the critical differences? Drug factors aside, what about patient characteristics? Parsi et al [66] showed nonsmoking and the concurrent use of immunomodulators are predictors of response to infliximab. One study showed that neither NOD2-CARD15, ASCA, nor ANCA were predictive of outcome with infliximab treatment for CD [67,68]. What other factors could identify patients more likely to accrue benefit from this drug? Other topics for future investigation include the role of infliximab after surgical resection of disease to prevent recurrence; assessment of a possible synergy in combining immunomodulators and infliximab; and finally, infliximab as a possible first-line drug in the treatment of CD. Because it is a relatively new medication, expensive, and novel in its mechanism of action, clinicians need to continue to refine the strategy for using this drug. In 1998 there were substantial concerns over the safety and cost of infliximab, very similar to the gastroenterology community’s response to 6mercaptopurine decades ago. Most clinicians have grown comfortable with 6-mercaptopurine over the years and are gaining experience with biologic therapy. As clinicians become more comfortable with infliximab, more than 70 new biologic agents are upstream in the development pipeline. The speed of process from concept-to-drug is far faster than in the days when antimetabolites were newcomers: it is prudent to continue to examine infliximab closely for lessons in therapeutic success.

References [1] Loftus EV, Sandborn WJ. Epidemiology of inflammatory bowel disease. Gastroenterol Clin North Am 2002;31:1–20. [2] Hanaeur SB, Feagan BG, Lichtenstein GR, Mayer LF, Schreiber S, Colombel JF, et al. Maintenance infliximab for Crohn’s disease: the ACCENT I randomized trial. Lancet 2002;359:1541–9. [3] Valle E, Gross M, Bickston SJ. Infliximab. Expert Opin Pharmacother 2001;2:1015–25. [4] Breedveld FC. Therapeutic monoclonal antibodies. Lancet 2000;355:735–40. [5] Gura T. Therapeutic antibodies: magic bullets hit the target. Nature 2002;417:584–6. [6] Data on file, Centocor, Inc. April 2003 (unpublished data).

L.W. Comerford, S.J. Bickston / Gastroenterol Clin N Am 33 (2004) 387–406

403

[7] Ksontini R, MacKay SLD, Moldawer LL. Revisiting the role of tumor necrosis factor a and the response to surgical injury and inflammation. Arch Surg 1998;133:558–67. [8] van Deventer SJ. Review article: targeting TNF alpha as a key cytokine in the inflammatory processes of Crohn’s disease–the mechanisms of action of infliximab. Aliment Pharmacol Ther 1999;13(Suppl 4):3–8. [9] Beutler BA. The role of tumour necrosis factor in health and disease. J Rheumatol 1999; 26(Suppl 57):16–21. [10] Yacyshyn BR. Novel manipulations of inflammatory mediator pathways. In: Bayless TM, Hanauer SB, editors. Advanced therapy of inflammatory bowel disease. London: BC Decker; 2001. p. 165–9. [11] Sandborn WJ. Transcending conventional therapies: the role of biologic and other novel therapies. Inflamm Bowel Dis 2001;1(Suppl 7):s9–16. [12] van Deventer SJ. Tumour necrosis factor and Crohn’s disease. Gut 1997;40:443–8. [13] Kalogeris T, Grisham MB. Mode of action of anti-inflammatory agents. In: Bayless TM, Hanauer SB, editors. Advanced therapy of inflammatory bowel disease. London: BC Decker; 2001. p. 63–7. [14] Mouser JF, Hyams JS. Infliximab: a novel chimeric monoclonal antibody for the treatment of Crohn’s disease. Clin Ther 1999;21:932–42. [15] van Dullemen HM, van Deventer SJ, Hommes DW, Bijl HA, Jansen J, Tytgat GN, et al. Treatment of Crohn’s disease with anti-tumor necrosis factor chimeric monoclonal antibody (cA2). Gastroenterology 1995;109:129–35. [16] Knight DM, Trinh H, Le J, Siegel S, Shealy D, McDonough M, et al. Construction and initial characterization of a mouse-human chimeric anti-TNF antibody. Mol Immunol 1993;30:1443–53. [17] Scallon BJ, Moore MA, Trinh H, Knight DM, Ghrayeb J. Chimeric anti-TNF-alpha monoclonal antibody cA2 binds recombinant transmembrane TNF-alpha and activates immune effector functions. Cytokine 1995;7:251–9. [18] Sandborn WJ, Targan SR. Biologic therapy of inflammatory bowel disease. Gastroenterology 2002;122:1592–608. [19] Eigler A, Sinha B, Hartmann G, Endres S. Taming TNF: strategies to restrain this proinflammatory cytokine. Immunol Today 1997;18:487–92. [20] Sands BE. Crohn’s disease. In: Feldman M, Friedman LS, Sleisenger MH, editors. Sleisenger & Fordtran’s gastrointestinal and liver disease. 7th edition. Philadelphia: WB Saunders; 2002. p. 2028–9. [21] Remicade (infliximab) for IV injection. Package insert. Malvern, PA: Centocor; 2002. [22] Sandborn WJ, Hanauer SB. Infliximab in the treatment of Crohn’s disease: a user’s guide for clinicians. Am J Gastroenterol 2002;97:2962–72. [23] Derkx B, Taminiau J, Radema S, Stronkhorst A, Wortel C, Tytgat G, et al. Tumournecrosis-factor antibody treatment in Crohn’s disease. Lancet 1993;342:173–4. [24] Targan SR, Hanauer SB, van Deventer SJH, Mayer L, Present DH, Braakman T, et al. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor a for Crohn’s disease. N Engl J Med 1997;337:1029–35. [25] Williams DR, Collier JA, Corman ML, Nugent FW, Veidenheimer MC. Anal complications in Crohn’s disease. Dis Colon Rectum 1981;24:22–4. [26] Present DH, Rutgeerts P, Targan S, Hanauer SB, Mayer L, van Hogezand RA, et al. Infliximab for the treatment of fistulas in patients with Crohn’s disease. N Engl J Med 1999;340:1398–405. [27] Ricart E, Panaccione R, Loftus E, Tremaine W, Sandborn W. Infliximab for Crohn’s disease in clinical practice at the Mayo Clinic: the first 100 patients. Am J Gastroenterol 2001;96:722–9. [28] Rutgeerts P, D’Haens G, Targan S, Vasiliauskas E, Hanauer SB, Present DH, et al. Efficacy and safety of retreatment with anti-tumor necrosis factor antibody (infliximab) to maintain remission in Crohn’s disease. Gastroenterology 1999;117:761–9.

404

L.W. Comerford, S.J. Bickston / Gastroenterol Clin N Am 33 (2004) 387–406

[29] Mayer L, Han C, Bala M, Keenan G, Olson A, Hanauer SB, et al. Three dose induction regimen of infliximab (Remicade) is superior to a single dose in patients with Crohn’s disease (CD). Am J Gastroenterol 2001;96:S303. [30] Farrell RJ, Alsahli M, Jeen YT, Falchuk KR, Peppercorn MA, Michetti P. Intravenous hydrocortisone premedication reduces antibodies to infliximab in Crohn’s disease: a randomized controlled trial. Gastroenterology 2003;124:917–24. [31] Sands B, van Deventer S, Bernstein C, Kamm M, Rachmilewitz D, Chey W, et al. Longterm treatment of fistulizing Crohn’s disease: response to infliximab in the ACCENT II trial through 54 weeks. Gastroenterology 2002;122:A81. [32] D’Haens G, van Deventer S, van Hogezand R, Chalmers D, Kothe C, Baert F, et al. Endoscopic and histologic healing with infliximab anti-tumor necrosis factor antibodies in Crohn’s disease: a European multicenter trial. Gastroenterology 1999;116:1029–34. [33] Rutgeerts P, Malchow H, Vatn MH, Yan S, Bala M, van Deventer S, et al. Mucosal healing in Crohn’s disease patients is associated with reduction in hospitalizations and surgeries. Gastroenterology 2002;123:M2138. [34] Rutgeerts P, Colombel JF, van Deventer S, Vatn M, Loftberg R, Schreiber S, et al. Endoscopic healing induced by infliximab maintenance therapy correlates with long-term clinical response in patients with active Crohn’s disease. Results of endoscopic sub study of ACCENT I. Am J Gastroenterol 2002;97:S260. [35] Lichtenstein GR. Approach to corticosteroid-dependent and corticosteroid-refractory Crohn’s disease. Inflamm Bowel Dis 2001;7:S23–9. [36] Cohen RD, Tsang JF, Hanauer SB. Infliximab for Crohn’s disease: first anniversary clinical experience. Am J Gastroenterol 2000;95:3469–77. [37] Chey WY. Infliximab for patients with refractory ulcerative colitis. Inflamm Bowel Dis 2001;7:S30–3. [38] Sands BE, Tremaine WJ, Sandborn WJ, Rutgeerts PJ, Hanauer SB, Mayer L, et al. Infliximab in the treatment of severe, steroid-refractory ulcerative colitis: a pilot study. Inflamm Bowel Dis 2001;7:83–8. [39] Su C, Salzberg BA, Lewis JD, Deren JJ, Kornbluth A, Katzka DA, et al. Efficacy of antitumor necrosis factor therapy in patients with ulcerative colitis. Am J Gastroenterol 2002; 97:2577–84. [40] Probert CSJ, Hearing SD, Schrieber S, Kuhbacher T, Ghosh S, Forbes A, et al. Infliximab in steroid-resistant ulcerative colitis: a randomized controlled trial. Gastroenterology 2002; 122:A99. [41] Ricart E, Panaccione R, Loftus EV, Tremaine WJ, Sandborn WJ. Successful management of Crohn’s disease of the ileoanal pouch with infliximab. Gastroenterology 1999;117:429–32. [42] Braun J, Brandt J, Listing J, Zink A, Alten R, Golder W, et al. Treatment of active ankylosing spondylitis with infliximab: a randomized controlled multicenter trial. Lancet 2002;359:1187–93. [43] Parsi MA, Achkar JP, Brzezinski A, Shen B, Lashner B. Extraintestinal manifestations of Crohn’s disease respond to infliximab. Am J Gastroenterol 2002;97:S265. [44] Tan MH, Gordon M, Lebwohl O, George J, Lebwohl MG. Improvement of pyoderma gangrenosum and psoriasis associated with Crohn’s disease with anti-tumor necrosis factor alpha monoclonal antibody. Arch Dermatol 2001;137:930–3. [45] Su CG, Judge TA, Lichtenstein GR. Extraintestinal manifestations of inflammatory bowel disease. Gastroenterol Clin North Am 2002;31:307–27. [46] Abreu MT, Kam LY, Vasiliauskas EA, Vora P, Yang H, Ying-Chao L, et al. Treatment with infliximab is associated with increased markers of bone synthesis in patients with Crohn’s disease. Am J Gastroenterol 2002;97:S269. [47] Colombel JF, Loftus EV, Tremaine WJ, Egan LJ, Harmsen WS, Schleck CD, et al. The safety profile of infliximab for Crohn’s disease in clinical practice: the Mayo Clinic experience in 500 patients. Gastroenterology 2003;124:A7.

L.W. Comerford, S.J. Bickston / Gastroenterol Clin N Am 33 (2004) 387–406

405

[48] Hanauer SB, Rutgeerts PJ, D’Haens G, Targan SR, Kam L, Present DH, et al. Delayed hypersensitivity to infliximab (Remicade) re-infusion after a 2–4 year interval without treatment. Gastroenterology 1999;116:A731. [49] Jess T, Winther KV, Munkholm P, Langholz E, Binder V. Mortality and causes of death in Crohn’s disease: follow-up of a population-based cohort in Copenhagen County, Denmark. Gastroenterology 2002;122:1808–14. [50] Loftus EV, Silverstein MD, Sandborn WJ, Tremaine WJ, Harmsen WS, Zinsmeister AR. Crohn’s disease in Olmsted County, Minnesota, 1940–1993: incidence, prevalence, and survival. Gastroenterology 1998;114:1161–8. [51] Farmer RG, Whelan G, Fazio VW. Long-term follow-up of patients with Crohn’s disease. Relationship between the clinical pattern and prognosis. Gastroenterology 1985;88: 1818–25. [52] Ekbom A, Helmick CG, Zack M, Holmberg L, Adami HO. Survival and causes of death in patients with inflammatory bowel disease: a population-based study. Gastroenterology 1992;103:954–60. [53] Keane J, Gershon S, Wise RP, Mirabile-Levens E, Kasznica J, Schweiterman WD, et al. Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent. N Engl J Med 2001;345:1098–104. [54] Diagnostic standards and classification of tuberculosis in adults and children. Official Statement of the American Thoracic Society and the Centers for Disease Control and Prevention, adopted by the American Thoracic Society Board of Directors, July 1999. Endorsed by the Council of the Infectious Diseases Society of America, September 1999. Am J Respir Crit Care Med 2000;161:1376–95. [55] Targeted tuberculin testing and treatment of latent tuberculosis infection. Official Statement of the American Thoracic Society, adopted by the American Thoracic Society Board of Directors, July 1999. Joint Statement of the American Thoracic Society and the Centers for Disease Control and Prevention, endorsed by the Council of the Infectious Diseases Society of America, September 1999. Am J Respir Crit Care Med 2000;161:S221–47. [56] Mow WS, Abreu MT, Papadakis KA, Targan SR, Vasiliauskas EA. High incidence of anergy limits the usefulness of PPD screening for tuberculosis (TB) prior to Remicade in inflammatory bowel disease (IBD). Gastroenterology 2002;122:A100. [57] Katz JA, Keenan GF, Snith DE, Lichtenstein GR. Outcome of pregnancy in patients receiving infliximab for the treatment of Crohn’s disease and rheumatoid arthritis. Gastroenterology 2003;124:A63. [58] Baert F, Noman M, Vermeire S, Van Assche G, D’ Haens G, Carbonez A, et al. Influence of immunogenicity on the long-term efficacy of infliximab in Crohn’s disease. N Engl J Med 2003;348:601–8. [59] Bickston SJ, Lichtenstein GR, Arseneau KO, Cohen RB, Cominelli F. The relationship between infliximab treatment and lymphoma in Crohn’s disease. Gastroenterology 1999; 117:1433–7. [60] Hay JW, Hay AR. Inflammatory bowel disease: costs-of-illness. J Clin Gastroenterol 1992; 14:309–17. [61] Rutgeerts P, Feagan B, Lichtenstein G, Mayer L, Schreiber S, Colombel J, et al. Comparison of scheduled and episodic treatment strategies of infliximab in Crohn’s disease. Gastroenterology 2004;126:402–13. [62] The TREAT Registry Report, September 2000. [63] Feagen BG, Vreeland MG, Larson LR, Bala MV. Annual cost of care for Crohn’s disease: a payor perspective. Am J Gastroenterol 2000;95:1955–60. [64] Cohen RD, Larson LR, Roth JM, Becker RV, Mummert LL. The cost of hospitalization in Crohn’s disease. Am J Gastroenterol 2000;95:524–30. [65] Rubenstein JH, Chong RY, Cohen RD. Infliximab decreases resource use among patients with Crohn’s disease. J Clin Gastroenterol 2002;35:151–6.

406

L.W. Comerford, S.J. Bickston / Gastroenterol Clin N Am 33 (2004) 387–406

[66] Hanauer SB, Cohen RD, Becker RV, Larson LR, Vreeland MG. Advances in the management of Crohn’s disease: economic and clinical potential of infliximab. Clin Ther 1998;20:1009–28. [67] Parsi MA, Achkar JP, Richardson S, Katz J, Hammel JP, Lashner BA, et al. Predictors of response to infliximab in patients with Crohn’s disease. Gastroenterology 2002;123:707–13. [68] Vermeire S, Louis E, Rutgeerts P, De Vos M, Van Gossum A, Belaiche J, et al. NOD2/ CARD15 does not influence response to infliximab in Crohn’s disease. Gastroenterology 2002;123:106–11.