Use of biological molecules in the treatment of inflammatory bowel disease

Transcription

1 Review doi: /j x Use of biological molecules in the treatment of inflammatory bowel disease O. H. Nielsen 1, J. B. Seidelin 1,L.K.Munck 2 &G.Rogler 3 From the 1 Department of Gastroenterology, Medical Section, Herlev Hospital; and 2 Division of Gastroenterology, Department of Internal Medicine, Køge Hospital, University of Copenhagen, Copenhagen, Denmark; and 3 Department of Gastroenterology and Hepatology, University Hospital of Zürich, Zürich, Switzerland Abstract. Nielsen OH, Seidelin JB, Munck LK, Rogler G (Herlev Hospital, University of Copenhagen, Copenhagen; Køge Hospital, University of Copenhagen, Copenhagen, Denmark; and University Hospital of Zürich, Zürich, Switzerland). Use of biological molecules in the treatment of inflammatory bowel disease (Review). JInternMed2011; 270: The introduction of biological agents (i.e. antitumour necrosis factor-a and anti-integrin treatments) for the treatment of inflammatory bowel disease (IBD) [i.e. Crohn s disease (CD) and ulcerative colitis] has led to a substantial change in the treatment algorithms and guidelines, especially in CD. However, many questions still remain about the true efficacy and the best treatment regimens. Thus, a need for further treatment options still exists as up to 40% of IBD patients treated with the presently available biologicals do not have positive clinical responses. Better patient selection might maximize the clinical benefit for those in most need of an effective therapy to avoid disabling disease whilst also minimizing the complications associated with therapy. Further, the trough-level strategy may help clinicians to optimize therapy and to avoid loss of response and or immunogenicity. The idea behind this dosage regimen is that correct dosing must ensure that the patient s lowest level of drug concentration (i.e. the trough level) occurring just before the next drug administration is high enough for the full effect to be seen. Controversy continues regarding the appropriate use of biologicals; therefore, in this review, we focus on considerations that might lead to a more rational strategy for antitumour necrosis factor-a agents in IBD, emphasizing the situations in which the risks may outweigh the benefits. Finally, the need for an appropriate strategy for stopping biological treatment is discussed. Keywords: biologicals, Crohn s disease, inflammatory bowel disease, therapy, ulcerative colitis. Introduction The introduction of biological agents antitumour necrosis factor (TNF)-a and anti-integrin therapy represents a new treatment paradigm for inflammatory bowel disease (IBD). Treatment goals have been discussed and partially redefined by gastroenterologists and their societies globally from focusing on clinical remission to focusing on mucosal healing and alteration of the clinical course of the diseases [1]. Biologicals have been shown to reduce the need for both hospitalization and surgery in IBD patients [2 4]; however, this is accompanied by a significant increase in the cost of treatment [5]. Biologicals are amongst the most thoroughly investigated agents prescribed by gastroenterologists, yet crucial questions persist regarding their true efficacy, when to use them and the treatment-associated risks. Randomized, controlled trials provide only a narrow view of the true effects of any agent and may raise new questions. Furthermore, the anti-tnf-a compounds have only rarely been evaluated in true clinical settings, which are compared with the best conventional therapy available, largely because of a regulatory requirement of a placebo arm in registration studies. As a result of rigid selection and inclusion criteria, the various clinical trials mimic imperfectly the highly variable nature of the conditions seen in patients in a real-world clinical setting. Thus, we are left with a limited understanding of the optimal use of anti-tnf-a compounds including combination with other therapies. The main biological therapies for IBD are TNF-a antibodies and also anti-a 4 integrin monoclonal antibodies. Initially, a chimeric (25% murine sequence and 75% human sequence) immunoglobulin (Ig)G1j ª 2011 The Associationfor the Publication ofthe Journal ofinternal Medicine 15

2 subclass antibody (infliximab) was shown to be beneficial for patients with Crohn s disease (CD) (Table 1) [6, 7]. In an attempt to reduce immunogenic responses induced by chimeric antibodies, all murine sequences were removed to create a fully human monoclonal antibody [8]. This fully human IgG1 anti- TNF-a monoclonal antibody, adalimumab, was shown to be efficacious too (Table 1) [9 12], as was a pegylated humanized antibody fragment conjugated with a 40-kDa polyethylene glycol molecule (certolizumab pegol) (Table 1) [13, 14]. Selected CD patients who have lost response to or have become intolerant of anti-tnf-a therapy have access to natalizumab, a humanized anti-a 4 integrin monoclonal antibody that inhibits leucocyte adhesion and migration into inflamed tissue. However, this agent is not approved by the European Medicines Agency (EMA) for treatment of CD because of serious side effects, including the rare but serious brain disease progressive multifocal leucoencephalopathy (PML) [15, 16]. Natalizumab is available in the USA but it carries a black box warning [the highest-level warning from the Food and Drug Administration (FDA)] about PML. Infliximab, adalimumab and certolizumab pegol are all efficacious in patients with moderate to severe CD who have inadequate responses to standard medications [17]. Recent trials have also addressed their use as first-line therapy [18]. Whereas biologicals are now a mainstay of treatment for refractory CD, results from clinical trials in acute ulcerative colitis (UC) have been variable and less convincing for infliximab [19] and adalimumab [20]; in particular, studies are required to determine whether infliximab can prevent colectomy in the long term [19]. Controversy persists regarding the appropriate use of biologicals in IBD. In this article, we will focus on how to optimize the selection of patients for treatment with anti-tnf-a agents and how immunogenicity and trough-level issues should be addressed in the treatment strategy of IBD with these drugs. Search strategy and selection criteria A search of English language publications between 1995 and November 2010 was performed using PubMed, the Cochrane Library and the EMA and FDA databases. The following search terms were applied: CD or IBD or UC and biologicals or biological therapy, combined with adverse events, hypersensitivity, immunogenicity, immunosuppression, infections, malignancy, smoking or trough levels. Therapeutic goals Traditionally, the therapeutic goals in both UC and CD have included (i) induction of a rapid response, (ii) maintenance of glucocorticoid-free remission, (iii) minimization of complications and surgery, (iv) prevention of disease-related mortality, (v) improvement in patients quality of life and (vi) minimization of the adverse effects of treatment. A new therapeutic goal, mucosal healing, has been introduced in recent years. However, at present, it is known only that patients who achieve mucosal healing have a better long-term disease course. This is to some extend a self-fulfilling prophecy, as better response is likely to confer better long-term outcome. The really important question of whether one should escalate therapy to achieve mucosal healing has not yet been answered. Another new therapeutic goal considered by leading gastroenterologists that goes even beyond mucosal healing is the so-called deep remission (i.e. simultaneous clinical, biological and endoscopic remission) [21]. Both mucosal healing and deep remission need, however, to be evaluated for their prediction of long-term outcome and benefit risk ratio if treatment escalation becomes necessary. Table 1 Administration of biological agents in inflammatory bowel disease Infliximab Adalimumab Certolizumab pegol Dosage 5 mg kg )1 40 mg 400 mg Route of administration i.v. s.c. s.c. Dosing intervals 8 weeks 2 weeks (e.o.w) 4 weeks Induction 5 mg kg )1 weeks0,2, mg (FDA) or mg (EMA) 400 mg weeks 0, 2, 4 Dose escalation 10 mg kg )1 or every 4 6 weeks 40 mg e.w. 400 mg e.o.w. i.v., intra venous; s.c., subcutaneous; e.w., every week; e.o.w., every other week; EMA, European Medicines Agency; FDA, Food and Drug Administration. 16 ª 2011 TheAssociationfor the Publication ofthe JournalofInternal Medicine Journal ofinternalmedicine 270; 15 28

3 Selecting the right patients for biological therapy Even though biological therapies hold significant promise for the treatment of IBD, anti-tnf-a agents are not the definitive treatment for all patients with CD, and a need for other treatment options continues. Up to 40% of CD patients treated do not have a clinically relevant response to currently available anti-tnf-a agents (i.e. primary failures or primary nonresponders ) [6, 7, 11 13], which may in part be attributed to the fact that IBD has a complex polygenic origin and might be regarded as more than one disease [22, 23]. Only approximately a third to half of all patients achieve complete remission after 6 months of treatment, as assessed by various clinical scoring systems in different clinical studies [7, 11 13], and only about one-third maintain a response for 12 months during continuous treatment (Fig. 1) [11, 14, 24]. Although the use of a second or even a third agent within the same class may be beneficial in some patients [25], both post hoc analyses and prospective clinical trials have shown that patients failing a first anti-tnf-a antibody may be less likely to achieve remission with standard dosages of a second anti-tnf-a agent [26]. Because of safety concerns, a third anti-tnf-a agent should be considered only after careful case-by-case assessment [25]. In a randomized trial, 21% of patients who experienced treatment failure with infliximab were in remission after 4 weeks of treatment with adalimumab at the mg induction dose at time 0 and 2 weeks as opposed to 7% in the placebo group; 52% of patients responded to adalimumab versus 34% in the placebo group [26]. These values should be compared with a Fig. 1 Comparative efficacy of anti-tnf-a biological agents. Data are extracted from different clinical studies with different inclusion criteria and are consequently not directly comparable. remission rate of 36% in patients naïve to biologicals treated with mg adalimumab [10]. A similar decrease in response rate to certolizumab pegol used as a second or third anti-tnf-a agent has been reported recently [27]. Thus, there is a need for methods to guide patient selection for both early and continuous use of biological therapy to maximize the clinical benefit for patients at risk of disabling disease whilst minimizing the complications associated with these therapies in individuals who have a more benign disease course. Smoking is harmful for patients with CD [28 30], and interventions to stop smoking do reduce the risk of recurrence and the need for surgery [31]. However, data regarding the influence of smoking on the efficacy of anti-tnf-a therapy are conflicting [32]. The best studies with regard to methodology have demonstrated that smoking has a strong adverse effect on response rates and maintenance of a beneficial response to infliximab [32 34], whereas other studies were not able not show an influence of tobacco use on the infliximab response [35 37]. Although smoking should not disqualify patients from receiving anti- TNF-a treatment, supportive action to help patients to stop smoking must be included in any treatment of CD, and perhaps this effort should include the use of smoking cessation medications such as varenicline or bupropion. Responders to infliximab therapy were younger (median age 33 years) than nonresponders (median age 40 years) [37], suggesting that age may affect the treatment response, and CD patients with isolated ileitis and a history of surgery for their bowel disorder were also less likely to respond to infliximab [37]. However, age and history of surgery could also simply reflect a more complicated disease course with a longer duration and need of surgery rather than a reduced response to infliximab per se. For UC, it seems that the response to infliximab is restricted to patients with moderate-stage disease rather than those with more severe disease [38]. Post hoc analysis of UC studies [Active Ulcerative Colitis Trials (ACT) 1 and 2] showed that infliximab reduced the risk of colectomy after 1 year from 17% in the placebo group to 10% in the infliximab group [4]. When used as rescue therapy for severe UC, glucocorticoids plus a single infusion of infliximab (5 mg kg )1 )versus glucocorticoids plus placebo reduced the number of colectomies from (67%) to 7 24 (29%) within the first 90 days of infliximab treatment [39]; after 2 years, the values were (76%) and ª 2011The Association forthe Publication of thejournalof InternalMedicine JournalofInternal Medicine 270;

4 (46%), respectively [40]. Gender and race have not been shown to be predictive of the response to biologicals in IBD patients. Effects of biologicals on extraintestinal manifestations of IBD Extraintestinal complications occur in more than 25% of IBD patients [41]. Some precede the diagnosis of IBD, and some run an independent course (e.g. colectomy in UC does not affect the clinical course of ankylosing spondylitis, uveitis or primary sclerosing cholangitis). However, the activity of peripheral arthritis (in larger joints), erythema nodosum and episcleritis usually mirrors the activity of the bowel disease [41]. Treatment with biologicals has a beneficial effect on some extraintestinal manifestations of IBD, including IBD-associated spondyloarthropathy [42], erythema nodosum [43], pyoderma gangrenosum [44, 45], Sweet s syndrome [46, 47] and uveitis [48, 49]. Arthralgia without clear signs of joint inflammation, which is a frequent extraintestinal symptom of IBD, also improves during infliximab treatment [50]. Adverse effects of biologicals Clinicians treating IBD patients must consider the benefits and risks of biological therapy in the context of the risks of the disease, other or concomitant medical therapies and surgery. The cumulative probability of surgery in patients with a new diagnosis of CD has been reported to approach 80% 20 years after diagnosis [51 54], although a significant decline in the surgery rate in CD, but not in UC, has been reported recently prior to the extensive use of biologicals and might reflect an earlier diagnosis and increased use of immunosuppressants (e.g. azathioprine and 6-mercaptopurine) [55]. Many patients require multiple operations, which might lead to a permanent stoma and or development of short bowel syndrome. Assessment of benefit requires demonstration of efficacy not only in controlled trials but also from comparative effectiveness data. Major concerns regarding the use of biological agents include hypersensitivity reactions, loss of effect and continued treatment of patients without disease activity, serious infections and malignancy [56, 57]. The frequency per 100 patient-years of serious infections and malignancy is shown in Fig.2. Acute delayed hypersensitivity complications Acute injection-site reactions of the skin (i.e. rash with or without oedema), anaphylactic reactions and Fig. 2 Frequency of serious infections and malignancies per 100 patient-years. Serious infections are defined as those leading to or prolonging hospitalization, fatal or life-threatening infections or those causing significant disability and opportunistic infections. Data regarding patients with inflammatory bowel disease for infliximab are extracted from the TREAT study [128], adalimumab from global clinical trials (Crohn s disease only) [129] and certolizumab pegol from UCB (data on file). delayed hypersensitivity associated with such symptoms as fever, hypotension, muscle aches and even shock occur during and following administration of biologicals [58]. These reactions may require treatment with glucocorticoids, paracetamol and antihistamines, which generally leads to resolution of symptoms [59, 60]. Rarely, treatment may induce serum sickness and leucocytoclastic vasculitis, which are typical delayed immune-mediated adverse drug reactions with varying degrees of symptoms from very mild to potentially life-threatening [61 63]. In the case of hypersensitivity reactions, patients can be switched to another biological agent, given the lack of cross-reactivity between the anti-tnf-a biologi- 18 ª 2011 TheAssociationfor the Publication ofthe JournalofInternal Medicine Journal ofinternalmedicine 270; 15 28

5 cals. To our knowledge, no direct comparative studies have been conducted to determine the relative risk of allergic reactions to the different anti-tnf-a biologicals in IBD, but a recent study to assess the reasons for discontinuation of these drugs in rheumatoid diseases revealed a significantly higher contribution of acute systemic reactions with infliximab than with adalimumab or etanercept (hazard ratio = 2.11; 99% confidence interval ) [64]. Infections Biological therapy increases the risk of infections (some fatal), including sepsis, pneumonia, histoplasmosis, listeriosis and other opportunistic infections and may reactivate latent tuberculosis (TB), hepatitis B and other viral infections [65, 66]. The rate of serious infections, however, appears to remain fairly constant at approximately 2% over subsequent years of therapy in both patients with early disease [17, 18, 67] and those with late disease that is refractory to conventional therapy [65]. All patients should be carefully informed about the high risk of reactivation of latent TB [66, 68] and hepatitis B, [66, 69, 70] and it is strongly recommended that patients are screened for these diseases prior to exposure to anti-tnf-a biologicals. A tuberculin skin test (Mantoux test) might give false-negative results in patients with IBD as it is negatively affected by immunosuppressive therapy, and false-positive results may follow bacille Calmette-Guérin (BCG) vaccination. In addition to taking a good clinical history, both an in vitro T-cell interferon-c release assay (TIGRA) and a chest X-ray should be performed because latent TB infections can affect the abdominal and mesenteric area; a chest X-ray alone is insufficient for excluding TB. TIGRAs are minimally affected (Quantiferon-TB Gold) or unaffected (T-Spot.TB) by immunosuppressive therapy [71]. Only patients with a negative screening test result for TB and hepatitis B should receive biologicals. There is no evidence to suggest that hepatitis C is reactivated by these drugs [66, 72]. Neurological complications Neurological events (e.g. new onset or exacerbation of demyelinizing neuropathy, including optic neuritis and multiple sclerosis) are rare but serious adverse effects of biological administration, but the prognosis is usually good if the event is diagnosed immediately and the anti-tnf-a treatment is discontinued [73]. The treatment in such patients should be discussed on a case-by-case basis by the treating gastroenterologist and a neurologist. However, it should be emphasized that the risk of demyelinating disorders may be elevated even in IBD patients who are not treated with biological agents [74, 75]. Malignancy Combinations of glucocorticoids, immunosuppressive drugs and anti-tnf-a agents may be associated with an increased risk of malignancies [e.g. non- Hodgkin s lymphoma (including hepatosplenic T-cell lymphoma), lung cancer, skin cancer and other (pre-) malignancies, including cervical dysplasia] [76, 77]. This matter has been thoroughly investigated in clinical trials, retrospective analyses, case control studies, case reports and postmarketing surveillance studies [78]. An increased risk of malignancies, in particular lymphomas, has been reported in some studies, but no causal associations between biologicals and malignancy have been demonstrated [78]. The general population of IBD patients has a slightly increased cancer risk, especially for colorectal cancer [78], although this was not found in a Danish epidemiological study in which selection bias (e.g. data from tertiary referral centres) was eliminated [79]. Inflammatory bowel disease patients receiving biologicals may be a subgroup of the general population with severe, chronically active, refractory disease on long-term concomitant immunosuppression. Whether the slightly elevated cancer risk is associated with the biological agent, the disease, concomitant immunosuppression (which might also lead to the development of hepatosplenic T-cell lymphoma or lymphomas in general [80 83]) or a combination of these variables is currently unknown and needs further examination [78]. However, lymphomas do occur in excess amongst these patients [84] and, as a consequence, biologicals (and immunosuppressives) should be reserved for IBD patients with a genuine need. The risk for patients of overtreatment can be similar to or greater than that of undertreatment. The use of biologicals in patients with previous malignancies or at high risk of developing cancer is not recommended, but in properly selected patients, the benefits of biological therapy clearly outweigh the risk of malignancy [78, 85]. Concomitant immunosuppression There is no consensus as to whether or how antimetabolites should be combined with anti-tnf-a agents. ª 2011The Association forthe Publication of thejournalof InternalMedicine JournalofInternal Medicine 270;

6 Long-term use of anti-tnf-a monoclonalantibodies is associated with immunogenicity that interferes with efficacy and adds to the risk of infusion-related complications [86]. Concomitant administration of azathioprine may to some degree prevent the development of antibodies [87]. The results of an open-label study showed that early coadministration of infliximab and azathioprine was superior to steroid alone with addition of azathioprine and infliximab as needed with respect to induction and maintenance of remission for up to 1 year, after which the proportion of patients in remission, however, did not differ between the groups [18]. This finding was similar to that ofthe Grouped Etudes Thérapeutiques des Affections Inflammatoires dutubedigestif(getaid) study[88]. However, the value of concomitant treatment with immunosuppressives and biologicals remains contentious given the contrasting results of the Study of Biologic and Immunomodulator Naïve Patients in Crohn s disease (SONIC) [67] and the Combination of Maintenance Methotrexate-Infliximab Trial (COM- MIT) [89] studies. In the SONIC study [67], CD patients naïve to immunosuppressives and biologicals were randomly assigned to azathioprine, infliximab or a combination therapy. Steroid-free (but not necessarily budesonide-free) clinical remission at week 26 was obtained by 30% of patients on azathioprine, 44% on infliximab and 57% on combination therapy. The results obtained at week 50 in the extension study were 55%, 61% and 72%, respectively [67]. The superior benefits of infliximab and combination therapy for the end-point of mucosal healing were similar. The COMMIT study, however, compared the efficacy and safety of infliximab plus methotrexate to infliximab alone at weeks 14 and 50 for the control of signs and symptoms of CD necessitating administration of glucocorticoids. Amongst 126 CD patients included in the study, both medication groups achieved approximately 75% glucocorticoid-free remission rates at week 14, whereas only approximately 40% in each group maintained glucocorticoid-free remission at week 50. Thus, the results of the COMMIT study supported a lack of synergy between infliximab and methotrexate [89]. A randomized clinical trial of withdrawal of immunosuppressives in CD patients on scheduled maintenance therapy with biologicals also demonstrated that more than 6 months of azathioprine cotherapy had no benefit compared with infliximab monotherapy, although C-reactive protein levels and the proportion of patients with antibodies to infliximab (ATIs) were greater in those who discontinued azathioprine [67, 90]. However, a recent study has shown that in CD patients who are in clinical remission under azathioprine infliximab combination therapy, withdrawal of azathioprine is associated with a high risk of relapse in those with a duration of combination therapy of <27 months and or the presence of biological inflammation [91]. Safety issues should be taken into consideration before deciding whether to give combined therapy with azathioprine and scheduled infliximab in patients with CD, although this combination might be preferable for episodic infliximab administration [65]. Thus, for episodic biological therapy, immunosuppressives may be considered to decrease immunogenicity and a secondary loss of response [92]. In adalimumab-treated patients, concomitant immunosuppressive therapy at baseline did not affect treatment outcome, adalimumab trough serum concentrations or development of antibodies against serum adalimumab and had no impact on side effects [93]. Hence, adalimumab can be used as monotherapy [93]. Immunogenicity All exogenous proteins have the potential to induce immunogenicity, and chimeric antibodies such as infliximab induce human antichimeric antibodies (HACAs; also referred to as ATIs). It should be stressed that there are several examples in diseases other than IBD of antibody formation against therapeutic proteins (e.g. recombinant human insulin in diabetes [94] and factor VIII in haemophilia A [95, 96]). Concerns about immunogenicity to infliximab led to the development of humanized human biologicals. The degree of humanness of any biological agent is, however, not the sole determinant of immunogenicity. Thus, data from clinical trials of adalimumab and certolizumab pegol confirm that antidrug antibodies are produced despite any success in decreasing their incidence by reducing the murine component of the drug [90, 97 99]. Several potential mechanisms may account for the progressive loss of response to biologicals, amongst which the most important are drug-related mechanisms, including immunogenicity and tolerance. When considering the efficacy of the two treatment strategies episodic versus scheduled it should not be forgotten that intermittent or episodic dosing allows blood antibody concentrations to drop to undetectable levels. Results emerging from an earlier study [100] demonstrate that the formation and concentration of ATIs correlated with lower postinfu- 20 ª 2011 TheAssociationfor the Publication ofthe JournalofInternal Medicine Journal ofinternalmedicine 270; 15 28

7 sion serum infliximab concentrations as well as with an increase in severe infusion reactions and serum sickness-like reactions. Patients undergoing induction treatment followed by a scheduled maintenance regimen showed reduced ATI formation and a greater clinical benefit than those receiving a single dose followed by episodic treatment [100, 101]. Limited data are available on the development of antibodies to adalimumab in patients with CD, whereas more data have been generated by rheumatoid arthritis studies [102, 103]. Whereas ATIs are directed against the murine sequences in infliximab as well as the variable binding region, anti-adalimumab antibodies are directed against the variable binding region of the antibody against adalimumab (anti-idiotype antibodies) [98]. Apart from this, antiallotype antibodies may play a role in immunogenicity for both infliximab and adalimumab [104]. The results of one observational study demonstrated that the existence of ATIs in CD patients who had become secondary failures (i.e. acute or delayed hypersensitivity reactions or a lost response as judged by the treating physician) to infliximab was associated with neither a higher incidence of antibodies against adalimumab nor an effect of or reaction to adalimumab [93]. When antibodies against adalimumab did develop, these antibodies and low trough levels were associated with a loss of efficacy [93]. Guided therapy using trough levels, binding capacity and antibodies Clinicians should consider optimizing therapy with biologicals to avoid loss of response and or immunogenicity, as well as to re-establish response when a biological agent begins to fail. Switching to the next biological has become an option for patients and clinicians, but this should not always be the first intervention when a loss of response is encountered. Optimal use of biological agents involves ensuring that the patient s lowest level of drug concentration (i.e. the trough level), which should be high enough that the full effect of the drug is seen, occurs just before the periodically administered drug is taken. On the other hand, peak levels and average levels should not exceed concentrations associated with an increased risk of toxicity. Therapeutic monitoring of trough levels at regular intervals is carried out routinely for treatments involving small molecules with a narrow therapeutic window (e.g. cyclosporin), but a similar approach to therapeutic monitoring has not yet been incorporated routinely into treatment with monoclonal antibodies in IBD. It is generally accepted that the clearance of monoclonal antibodies is fairly predictable. The terminal halflife of infliximab is 9.5 days, with a low clearance rate of 9.8 ml h )1 [105], and for adalimumab, these values are 14 days and 12 ml h )1, respectively [106]. The prolonged bioavailability of infliximab, together with its high affinity for TNF-a, should result in an effective and prolonged blockade of TNF-a with administration of 5 mg kg )1 every 8 weeks. However, clearance of infliximab is greatly increased in the presence of ATIs [87], and rapid clearance is also observed in a minority of patients without such antibodies. Recently, investigator-initiated clinical cohort studies have revealed the problem of immunogenicity of anti-tnf-a agents and the importance of achieving sufficiently high trough levels. UC patients with a detectable serum infliximab concentration compared to those with an undetectable serum trough level have a higher rate of clinical remission (69% vs. 15%, P < 0.001) irrespective of antibody status [107]. A significant predictor for colectomy in active UC was an undetectable serum infliximab level, which carried a ninefold increased risk of surgery (55% vs. 7%, P < 0.001) [107]. It has been hypothesized that early formation of immune complexes in acute UC might result in rapid clearance of the drug and, in patients with loss of response to infliximab, a dose adjustment might restore the treatment effect [107]. By contrast, secondary loss of response to infliximab in CD patients was associated with high levels of infliximab antibodies and low levels of TNF-a-binding capacity, and primary response failure may be seen despite high levels of functionally active TNF-a binding [108]. Further, a recent investigator-initiated retrospective study has shown that measurement of ATIs and infliximab concentrations had a bearing on treatment decisions in 130 of 177 clinical situations (74%) and that such tests are a useful adjunct to clinical and endoscopic radiological assessment [109]. Table 2 shows how to apply the trough-level strategy in IBD patients who are losing their response to a biological agent [110]. One would expect dosage escalation to be more successful in patients displaying no or low ATI titres compared with patients with high titres, but this matter remains uninvestigated. Dosage escalation amongst CD patients with a failing response to infliximab was successful in 80 90% in the A CD Clinical Trial Evaluating Infliximab in a New Long-term Treatment Regimen (ACCENT 1) study [111]. Further as mentioned earlier, immunosuppressives decreased the immunogenicity of infliximab, and concomitant administration of azathioprine or methotrexate ª 2011The Association forthe Publication of thejournalof InternalMedicine JournalofInternal Medicine 270;

8 resulted in higher long-term trough levels in CD patients [67, 90]. Administering a higher drug dosage to all patients is not only ineffective from a cost perspective, but it may also lead to a higher rate of complications [112]. Therefore, patients in need of a higher drug dosage because of rapid clearance must be identified, and measurement of trough levels and antibodies before scheduled administrations of biologicals to guide the treatment may be considered for patients with failing responses. Unfortunately, the optimal trough levels for infliximab and adalimumab remain unknown and may vary significantly amongst individuals, but levels should at least be measurable before the next infusion. In patients without measurable trough levels and no antibodies, the first step would be to administer a higher dose or to shorten the interval between doses. If antibodies are present, an alternative treatment (e.g. another anti-tnf-a agent) should be considered (see Table 2). Optimizing therapy with infliximab and other monoclonal antibodies by measuring trough levels of the drug thus might be of benefit to IBD patients and could improve the long-term outcome and optimize resource usage. Serum infliximab and ATI levels can be measured by either enzyme-linked immunosorbent assay (ELISA) or radioimmunoassay (RIA) [113] techniques. ATI concentration has been reported as negative when it was below 1.69 lg ml )1 and the serum infliximab concentration was below 1.40 lg ml )1 and positive when the ATI concentration exceeded 1.69 lg ml )1 and the serum infliximab concentration was below 1.40 lg ml )1 using the ELISA technique [107]. An inconclusive result is reported if the serum infliximab level is higher than 1.40 lg ml )1 because infliximab interferes with the ATIs in the assay, and antibody formation in such a case cannot be determined. It is not clear whether antibodies measured with ELISA have clinical importance; for example, by preventing anti-tnf-a agents from reaching inflamed tissues, by interfering with the bioactivity of the drugs and or by being associated with issues of clinical efficacy and safety. A sandwich ELISA technique may give false-positive results because of nonspecific binding to Igs other than biologicals, whereas a functional RIA technique that directly assesses antibodies, and their effect on TNF-a binding to serum IgG (one epitope only) may be superior for determining bioavailability (i.e. TNF-a binding to serum IgG) and for measurement of ATIs (Fig. 3) [108, 110]. Thus, it was recently shown that an ATI concentration of 10 U ml )1 or more and a serum infliximab concentration of 0.5 lg ml )1 or less measured by RIA had a sensitivity and specificity of loss of response in CD patients of 79% and 89%, respectively [114]. For adalimumab, the ELISA technique was found to have a detection limit of lg ml )1, and the lower and upper limits of quantification were 0.1 and 4.8 lg ml )1, respectively [93]. Serum samples were diluted 1 : 10 if the upper limit of quantification was exceeded. Serum concentrations of antibodies against adalimumab were analysed, but because of interference by circulating adalimumab, adalimumab antibodies could not be measured if the adalimumab concentration was >0.094 lg ml )1. The cut-off value (i.e. resulting in a false-positive indication of antibodies against adalimumab) determined using untreated samples from CD patients was lg ml )1 [93]. Table 2 Algorithm for interpretation of trough levels in inflammatorybowel disease patients who cease to respond to biological treatment (see text) Antidrug antibody level Low High Drug trough level binding capacity Low Either dose intensification or decreased intervals between dosages is recommended or switch to another anti-tnf-a drug A switch to another biological agent is recommended High The therapeutic regimen is not sufficient. Check for an alternate aetiology of symptoms or switch to another anti-tnf-a drug or different therapeutic mechanism of action It is unknown how to handle this combination, but it is recommende to repeat the test for antidrug antibodies 22 ª 2011 TheAssociationfor the Publication ofthe JournalofInternal Medicine Journal ofinternalmedicine 270; 15 28

9 Fig. 3 Methods of assessing anti-tnf-a drug levels: difference between drug level determination and TNF-a-binding capacity. (a) An example of an enzyme-linked immunosorbent assay (ELISA). The anti-tnf-a drug level is determined by binding of the drug to TNF-a coated to the well. Subsequent addition of enzyme-linked anti-human IgG-Fc antibodies and addition of substrate to the enzyme allow quantification of the drug level by a colour reaction. (b) Determination of TNF-a-binding capacity is another way of determining drug levels. This method is based on the binding of radioactively labelled TNF-a to the anti-tnf-a drug (b1.). Subsequent cross-binding with anti-human IgG-Fc antibodies and centrifugation separates the bound labelled TNF-a from the unbound TNF-a and the binding capacity can be assessed using a gamma counter (b2.). The latter method is superior to the first as it is considered to be functional by measuring the actual binding capacity of TNF-a, whereas the former method could also quantify nonfunctional anti-tnf-a drug. Measurements of anti-tnf-a drug antibodies are based on similar methods. Patients who develop antibodies against adalimumab frequently have low trough serum concentrations, and in those with a serum concentration below the threshold for detection at least once, antibodies against adalimumab were detected, indicating that antibodies against adalimumab may lead to a more rapid elimination of the drug (low trough serum concentrations) and to treatment failure [93]. In a long-term observational study in which trough serum concentrations and antibodies against adalimumab were monitored at predefined time-points (weeks 2, 4, 12, 24 and 54) with subsequent dosage adjustments, up to 70% of CD patients treated with infliximab who presented with secondary failure demonstrated a response to adalimumab, with 61.5% maintaining clinical benefit during a median followup of almost 2 years [93]. Evidence for application of the trough-level approach to the use of certolizumab pegol and natalizumab is lacking. When should biological therapy be stopped? This question has not yet been explored in prospective clinical trials. If induction therapy fails to achieve a response or if serious and or allergic reactions occur, the anti-tnf-a agent should be stopped [115]. Relapse during continued maintenance therapy should trigger clinical reassessment and in some cases include assays for anti-tnf-a antibodies and levels of the active substance. The long-term treatment outcome with infliximab in 614 patients with CD in a large tertiary and highly specialized European centre was recently reported [116]. A sustained clinical benefit, defined as a lasting control of disease activity during follow-up (median 55 months), with persistent improvement in the symptoms, was observed in 63% of 547 patients who experienced an initial response. Of these, 43% continued therapy and had a sustained clinical benefit. Another 20% stopped infliximab treatment (the majority after initial episodic treatment) and stayed in remission for a median of 47 months. In this retrospective study, 89% ( ) had initial clinical improvement, but the clinical benefit was not defined further. Despite the lack of a clear definition of efficacy, the impressive series does demonstrate that biological therapy can be stopped. In most clinical studies, the Crohn s Disease Activity Index (CDAI) has been used to judge efficacy [117, 118]. It has been suggested that biological therapy should be stopped when response ceases (i.e. nonresponse). In clinical studies, a nonresponse was defined as a decrease in CDAI of <70 (100) points from baseline after a full induction, on average 6 10 weeks after the first injection. However, it is difficult to apply the CDAI in clinical practice. The Harvey Bradshaw ª 2011The Association forthe Publication of thejournalof InternalMedicine JournalofInternal Medicine 270;

10 Index seems to correlate with the CDAI in assessing CD severity [119]. In addition, it is useful in daily clinical assessments and can be used to assess lack of response [120]. Results of blood examinations, particularly markers of inflammation (e.g. C-reactive protein, orosomucoid or ferritin), are nonspecific. Likewise, even though a change in faecal calprotectin level has shown promise as a marker of luminal activity [121], as yet there is insufficient evidence to suggest that it can replace C-reactive protein or orosomucoid as a surrogate marker of inflammation [122], and it does not distinguish between infectious and noninfectious aetiologies. Recent data from the GETAID consortium [the Stop Infliximab in Crohn s disease (STORI) study] indentified predictors for a relapse after stopping infliximab therapy. If more than one of these predictors haemoglobin level 14.5 g dl )1, Crohn s Disease Endoscopic Index of Severity 2 [123],C-reactive protein 5 mgl )1, infliximab trough levels <2 lg ml )1 was positive, the likelihood of a relapse was high [124]. Further, endoscopy is recommended to evaluate mucosal healing, and magnetic resonance imaging to confirm fistula closure [125] prior to stopping biological therapy. It has been proposed that episodic treatment with anti-tnf-a drugs increases the risk of HACA formation and thereby loss of response and increased risk of adverse reactions. This should be taken into account when considering stopping treatment. Data on the treatment response after reintroduction of infliximab to prior responders are lacking, but in one study, 36 of 37 patients went into remission on reintroduction of infliximab treatment, indicating that a flare on stopping therapy may not be harmful for these patients [124]. Further studies are needed, however, to address this issue. These and other data indicate that biological therapy can be stopped after 1 year without a high risk of relapse in patients with complete remission (or deep remission). In all other patients, especially those with ongoing signs of inflammation, a relapse after cessation of biological therapy is relatively common. Most patients do not want to risk a relapse or flare after having been without symptoms for a year. On the other hand, such patients can be retreated successfully if necessary. Therefore, this should be discussed with patients. Their willingness to accept a low or high risk of relapse and the side effects of therapy have to be taken into account when one is considering stopping biological therapy. Conclusions To address the issue of the risks and benefits of biological therapy with various anti-tnf-a agents in IBD, the clinician must balance the following factors: the expected natural history of the disease in any particular patient, the risks and efficacy of medical and surgical therapies, and any comparative efficacy data. The clinician must also take into consideration that the efficacy of the anti-tnf-a agents is high, the absolute risk of infection and cancer development is low, the alternative medical therapies also have risks, there are risks from the IBD itself and surgery has risks and results in significant morbidity. Thus, in the context of important risks from all possible treatment strategies, efficacy can be the dominant factor in selecting therapy. Certainly, undertreatment should be avoided. However, whether top-down or accelerated step-up strategies are useful or places patients not in need of biological treatment at unnecessary risk is still a matter of debate. There is no evidence that glucocorticoid treatment changes the long-term course of IBD, and neither is there evidence that early biological treatment changes the long-term disease course in IBD patients, in contrast to patients with the chronic inflammatory condition rheumatoid arthritis [126]. The new treatment goals, such as mucosal healing in CD and deep remission, may change this situation but need to be further evaluated. An attempt to do this will be assessed in a forthcoming study [127]. In the absence of robust cost-effectiveness and utility data, it is probably reasonable at present to practice on the basis of comparative effectiveness data. However, a disadvantage of many sponsored trials is their problematic inclusion criteria and designs, which do not reflect routine clinical situations. Biological therapy with infliximab, adalimumab, certolizumab pegol and natalizumab has revolutionized the treatment of IBD patients refractory to conventional treatment and most dramatically for fistulizing CD [125]. Although biologicals should not remain third-line therapy and may even become a first-line therapy in selected patient subgroups, they are most likely to be indicated only in a proportion of IBD patients, some of whom have been identified and only at certain stages of the disease course. The use of biologicals must become more intelligent and better integrated coordinated with other aspects of treatment to optimize the risk benefit ratio and economic expenditure. In particular, much stronger 24 ª 2011 TheAssociationfor the Publication ofthe JournalofInternal Medicine Journal ofinternalmedicine 270; 15 28

11 emphasis should be put on active help for current smokers with CD to help them to quit smoking. Knowledge of trough level and antibody status may help clinicians to optimize therapy and minimize loss of response and or immunogenicity; that is, a more optimal dosage regimen will be more likely to engender a therapeutic response in individual IBD patients. Unfortunately, the interest of manufacturers in providing clinicians with the resources to test for trough levels or neutralizing antibodies is limited for commercial reasons. The optimal duration of biological treatment for individual IBD patients is still unknown. However, concomitant immunosuppression should not be given beyond the time necessary for bridging or with episodic biological therapy. Future randomized, controlled studies focusing on trough levels and ATIs in routine clinical situations may result in a more rational treatment algorithm for IBD patients. Conflict of interest statement Gerhard Rogler received grant support from Novartis. Acknowledgements This study was supported by grants from Fonden til Lægevidenskabens Fremme (the A. P. Møller Foundation), the Family Erichsen Memorial Foundation, the Axel Muusfeldts Foundation, the Foundation of Aase and Ejnar Danielsen, the Swiss National Science Foundation, the Swiss IBD Cohort and the Zurich Center for Integrative Human Physiology of the University of Zurich. References 1 D Haens GR, Panaccione R, Higgins PD et al. The London Position Statement of the World Congress of Gastroenterology on BiologicalTherapyforIBDWiththeEuropeanCrohn sand Colitis Organization: When to Start, When to Stop, Which Drug to Choose, and How to Predict Response? Am J Gastroenterol 2011; 106: [Epub aheadofprint]. 2 Feagan BG, Panaccione R, Sandborn WJ et al. Effects of adalimumab therapyon incidence of hospitalization and surgery in Crohn s disease: results from the CHARM study. Gastroenterology 2008; 135: Rutgeerts P, Feagan BG, Lichtenstein GR et al. Comparison of scheduled and episodic treatment strategies of infliximab in Crohn s disease. Gastroenterology 2004; 126: Sandborn WJ, Rutgeerts P, Feagan BG et al. Colectomy rate comparison after treatment of ulcerative colitis with placebo or infliximab. Gastroenterology 2009; 137: Cohen RD. The pharmacoeconomics of biologic therapy for IBD. Nat Rev GastroenterolHepatol2010; 7: Present DH, Rutgeerts P, Targan S et al. Infliximab for the treatment of fistulas in patients with Crohn s disease. N Engl J Med 1999; 340: Targan SR, Hanauer SB, van Deventer SJ et al. A short-term study of chimeric monoclonal antibody ca2 to tumor necrosis factor alpha for Crohn s disease. Crohn s Disease ca2 Study Group. N Engl J Med 1997; 337: Breedveld FC. Therapeutic monoclonal antibodies. Lancet 2000; 355: Colombel JF, Schwartz DA, Sandborn WJ et al. Adalimumab for the treatment of fistulas in patients with Crohn s disease. Gut 2009; 58: Schreiber S, Sandborn WJ. CLASSIC-I study the efficacy of adalimumab. Gastroenterology 2006; 130: Colombel JF, Sandborn WJ, Rutgeerts P et al. Adalimumab for maintenance ofclinical response and remission in patients with Crohn s disease: the CHARM trial. Gastroenterology 2007; 132: Hanauer SB, Sandborn WJ, Rutgeerts P et al. Human antitumor necrosis factor monoclonal antibody (adalimumab) in Crohn s disease: the CLASSIC-I trial. Gastroenterology 2006; 130: Sandborn WJ, Feagan BG, Stoinov S et al. Certolizumab pegol for the treatment of Crohn s disease. N Engl J Med 2007; 357: Schreiber S, Khaliq-Kareemi M, Lawrance IC et al. Maintenance therapy with certolizumab pegol for Crohn s disease. NEnglJ Med 2007; 357: Yousry TA, Major EO, Ryschkewitsch C et al. Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalopathy. N Engl J Med 2006; 354: Edula RG, Picco MF. An evidence-based review of natalizumab therapy in the management of Crohn s disease. Ther Clin Risk Manag 2009; 5: Peyrin-Biroulet L, Deltenre P, de SN, Branche J, Sandborn WJ, Colombel JF. Efficacyandsafetyoftumornecrosisfactorantagonists in Crohn s disease: meta-analysis of placebo-controlled trials. Clin GastroenterolHepatol2008; 6: D Haens G, Baert F, van AG et al. Early combined immunosuppression or conventional management in patients with newly diagnosed Crohn s disease: an open randomised trial. Lancet 2008; 371: Lawson MM, Thomas AG, Akobeng AK. Tumour necrosis factor alpha blocking agents for induction of remission in ulcerative colitis. CochraneDatabaseSystRev 2006; 3: CD Reinisch W, Sandborn W, Hommes D et al. Adalimumab for induction of clinical remission in moderately to severely active ulcerative colitis. Gut 2011; 60: [Epub ahead of print]. 21 OussalahA, DaneseS, Peyrin-Biroulet L. Efficacy oftnf antagonists beyond one year in adult and pediatric inflammatory bowel diseases: a systematic review. Curr Drug Targets 2010; 11: Kaser A, Zeissig S, Blumberg RS. Inflammatory bowel disease. AnnuRevImmunol 2010; 28: Schmidt KJ, Buning J, Jankowiak C, Lehnert H, Fellermann K. Crohn s targeted therapy: myth or real goal? Curr Drug Discov Technol 2009; 6: Sands BE, Anderson FH, Bernstein CN et al. Infliximab maintenance therapy for fistulizing Crohn s disease. N Engl J Med 2004; 350: Allez M, Vermeire S, Mozziconacci N et al. The efficacy and safety of a third anti-tnf monoclonal antibody in Crohn s ª 2011The Association forthe Publication of thejournalof InternalMedicine JournalofInternal Medicine 270;

12 disease after failure of two other anti-tnf antibodies. Aliment Pharmacol Ther 2010; 31: Sandborn WJ, Rutgeerts P, Enns R et al. Adalimumab induction therapy for Crohn disease previously treated with infliximab: a randomized trial. Ann Intern Med 2007; 146: Schoepfer AM, Vavricka SR, Binek J et al. Efficacy and safety of certolizumab pegol induction therapy in an unselected Crohn s disease population: results of the FACTS survey. Inflamm BowelDis 2010; 16: Lindberg E, Jarnerot G, Huitfeldt B. Smoking in Crohn s disease: effect on localisation and clinical course. Gut 1992; 33: Reese GE, Nanidis T, Borysiewicz C, Yamamoto T, Orchard T, Tekkis PP. The effect of smoking after surgery for Crohn s disease: a meta-analysis of observational studies. Int J Colorectal Dis 2008; 23: Seksik P, Nion-Larmurier I, Sokol H, Beaugerie L, Cosnes J. Effects of light smoking consumption on the clinical course of Crohn s disease. Inflamm Bowel Dis 2009; 15: Cosnes J, Beaugerie L, Carbonnel F, Gendre JP. Smoking cessationand thecourse ofcrohn s disease: anintervention study. Gastroenterology 2001; 120: Parsi MA. Does smoking decrease the response to infliximab in patients with Crohn s disease? Inflamm Bowel Dis 2008; 14(Suppl 2): S ArnottID, McNeill G, SatsangiJ. Ananalysis offactors influencing short-term and sustained response to infliximab treatment for Crohn s disease. Aliment Pharmacol Ther 2003; 17: Parsi MA, Achkar JP, Richardson S et al. Predictors of response to infliximabin patients with Crohn s disease. Gastroenterology 2002; 123: Fefferman DS, Lodhavia PJ, Alsahli M et al. Smoking and immunomodulators do not influence the response or duration of response to infliximab in Crohn s disease. Inflamm Bowel Dis 2004; 10: Orlando A, Colombo E, Kohn A et al. Infliximab in the treatment of Crohn s disease: predictors of response in an Italian multicentric open study. Dig LiverDis2005; 37: VermeireS, LouisE, Carbonez A et al. Demographic and clinical parameters influencing the short-term outcome of anti-tumor necrosis factor (infliximab) treatment in Crohn s disease. Am J Gastroenterol 2002; 97: Rutgeerts P, Sandborn WJ, Feagan BG et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med 2005; 353: Jarnerot G, Hertervig E, Friis-Liby I et al. Infliximab as rescue therapy in severe to moderately severe ulcerative colitis: a randomized, placebo-controlled study. Gastroenterology 2005; 128: Halfvarson J, Jarnerot G. Treatment of choice for acute severe steroid-refractory ulcerative colitis is remicade. Inflamm Bowel Dis 2009; 15: Larsen S, Bendtzen K, Nielsen OH. Extraintestinal manifestations of inflammatory bowel disease: epidemiology, diagnosis, and management. Ann Med 2010; 42: Sieper J, Rudwaleit M, Baraliakos X et al. The Assessment of SpondyloArthritis international Society (ASAS) handbook: a guide to assess spondyloarthritis. Ann Rheum Dis 2009; 68(Suppl 2): ii Agrawal D, Rukkannagari S, Kethu S. Pathogenesis and clinical approach to extraintestinal manifestations of inflammatory bowel disease. Minerva Gastroenterol Dietol 2007; 53: Traczewski P, Rudnicka L. Adalimumab in dermatology. Br J ClinPharmacol 2008; 66: Brooklyn TN, Dunnill MG, Shetty A etal. Infliximab for the treatment of pyoderma gangrenosum: a randomised, double blind, placebocontrolled trial. Gut 2006; 55: Cohen PR. Sweet s syndrome a comprehensive review of an acute febrile neutrophilic dermatosis. Orphanet J Rare Dis 2007; 2: Foster EN, Nguyen KK, Sheikh RA, Prindiville TP. Crohn s disease associatedwithsweet s syndromeand Sjogren ssyndrome treatedwith infliximab. ClinDevImmunol 2005; 12: Ally MR, Veerappan GR, Koff JM. Treatment of recurrent Crohn s uveitis with infliximab. Am J Gastroenterol 2008; 103: Barrie A, Regueiro M. Biologic therapy in the management of extraintestinal manifestations of inflammatory bowel disease. InflammBowel Dis2007; 13: Herfarth H, Obermeier F, Andus T et al. Improvement of arthritis and arthralgia after treatment with infliximab (Remicade) in a German prospective, open-label, multicenter trial in refractory Crohn s disease. AmJ Gastroenterol 2002; 97: Peyrin-Biroulet L, Loftus EV Jr, Colombel JF, Sandborn WJ. The natural history of adult Crohn s disease in populationbased cohorts. AmJ Gastroenterol2010; 105: Bernell O, Lapidus A, Hellers G. Risk factors for surgery and postoperative recurrence in Crohn s disease. Ann Surg 2000; 231: Lapidus A, Bernell O, Hellers G, Lofberg R. Clinical course of colorectal Crohn s disease: a 35-year follow-up study of 507 patients. Gastroenterology 1998; 114: Oriuchi T, Hiwatashi N, Kinouchi Y et al. Clinical course and longterm prognosis of Japanese patients with Crohn s disease: predictive factors, rates of operation, and mortality. JGastroenterol 2003; 38: Jess T, Riis L, Vind I et al. Changes in clinical characteristics, course, and prognosis of inflammatory bowel disease during the last 5 decades: a population-based study from Copenhagen, Denmark. Inflamm Bowel Dis 2007; 13: Bachmann F, Nast A, Sterry W, Philipp S. Safety and efficacy of the tumor necrosis factor antagonists. Semin Cutan Med Surg 2010; 29: Stallmach A, Hagel S, Bruns T. Adverse effects of biologics used for treating IBD. Best Pract Res Clin Gastroenterol 2010; 24: Campi P, Benucci M, Manfredi M, Demoly P. Hypersensitivity reactions to biological agents with special emphasis on tumor necrosis factor-alpha antagonists. Curr Opin Allergy Clin Immunol 2007; 7: The diagnosis and management of anaphylaxis. Joint Task Force on Practice Parameters, American Academy of Allergy, Asthma and Immunology, American College of Allergy, Asthma and Immunology, and the Joint Council of Allergy, Asthma and Immunology. J Allergy Clin Immunol 1998; 101(6 Pt 2): S Sandborn WJ, Hanauer SB. Infliximab in the treatment of Crohn s disease: a user s guide for clinicians. Am J Gastroenterol 2002; 97: Gamarra RM, McGraw SD, Drelichman VS, Maas LC. Serum sickness-like reactions in patients receiving intravenous infliximab. J Emerg Med 2006; 30: ª 2011 TheAssociationfor the Publication ofthe JournalofInternal Medicine Journal ofinternalmedicine 270; 15 28

13 62 McIlwainL, Carter JD, Bin-SagheerS, VaseyFB, NordJ. Hypersensitivity vasculitis with leukocytoclastic vasculitis secondary to infliximab. J ClinGastroenterol 2003; 36: Vermeire S, van AG, Rutgeerts P. Serum sickness, encephalitis and other complications of anti-cytokine therapy. Best Pract Res Clin Gastroenterol 2009; 23: Du Pan SM, Dehler S, Ciurea A, Ziswiler HR, Gabay C, Finckh A. Comparison of drug retention rates and causes of drug discontinuation between anti-tumor necrosis factor agents in rheumatoid arthritis. Arthritis Rheum 2009; 61: Toruner M, Loftus EV Jr, Harmsen WS et al. Risk factors for opportunistic infections in patients with inflammatory bowel disease. Gastroenterology 2008; 134: Papa A, Mocci G, Bonizzi M et al. Use of infliximab in particular clinical settings: management based on current evidence. Am J Gastroenterol 2009; 104: Colombel JF, Sandborn WJ, Reinisch W et al. Infliximab, azathioprine, or combination therapy for Crohn s disease. NEnglJ Med 2010; 362: Keane J, GershonS, Wise RPet al. Tuberculosisassociatedwith infliximab, a tumor necrosis factor alpha-neutralizing agent. N Engl J Med 2001; 345: del VG-S, Gomez-Camacho F, Poyato-Gonzalez A, Iglesias-Flores EM, de Dios-Vega JF, Sancho-Zapatero R. Infliximab therapy in a patient with Crohn s disease and chronic hepatitis B virus infection. InflammBowelDis 2004; 10: Esteve M, Saro C, Gonzalez-Huix F, Suarez F, Forne M, Viver JM. Chronic hepatitis B reactivation following infliximab therapy in Crohn s disease patients: need for primary prophylaxis. Gut 2004; 53: Lalvani A. Diagnosing tuberculosis infection in the 21st century: new tools to tackle an old enemy. Chest 2007; 131: Chevaux JB, Nani A, Oussalah A et al. Prevalence of hepatitis B and C and risk factors for nonvaccination in inflammatory bowel disease patients in Northeast France. Inflamm Bowel Dis 2010; 10: Lozeron P, Denier C, Lacroix C, Adams D. Long-term course of demyelinating neuropathies occurring during tumor necrosis factor-alpha-blocker therapy. Arch Neurol 2009; 66: Benavente L, Moris G. Neurologic disorders associated with inflammatory bowel disease. Eur J Neurol 2011; 18: Boisse L, Chisholm SP, Lukewich MK, Lomax AE. Clinical and experimental evidence of sympathetic neural dysfunction during inflammatory bowel disease. Clin Exp Pharmacol Physiol 2009; 36: Marehbian J, Arrighi HM, Hass S, Tian H, Sandborn WJ. Adverse events associated with common therapy regimens for moderate-to-severe Crohn s disease. Am J Gastroenterol 2009; 104: Jones JL, Loftus EV Jr. Lymphoma risk in inflammatory bowel disease: is it the disease or its treatment? Inflamm Bowel Dis 2007; 13: Biancone L, Calabrese E, Petruzziello C, Pallone F. Treatment with biologic therapies and the risk of cancer in patients with IBD. Nat ClinPractGastroenterolHepatol2007; 4: Winther KV, Jess T, Langholz E, Munkholm P, Binder V. Longterm risk of cancer in ulcerative colitis: a population-based cohort studyfrom Copenhagen County. ClinGastroenterol Hepatol 2004; 2: Beaugerie L, Brousse N, Bouvier AM et al. Lymphoproliferative disorders in patients receiving thiopurines for inflammatory bowel disease: a prospective observational cohort study. Lancet 2009; 374: Shale M, Kanfer E, Panaccione R, Ghosh S. Hepatosplenic T cell lymphoma in inflammatorybowel disease. Gut 2008; 57: Kandiel A, Fraser AG, Korelitz BI, Brensinger C, Lewis JD. Increased risk of lymphoma among inflammatory bowel disease patients treated with azathioprine and 6-mercaptopurine. Gut 2005; 54: Navarro JT, Ribera JM, Mate JL et al. Hepatosplenic T-gammadelta lymphoma in a patient with Crohn s disease treated with azathioprine. Leuk Lymphoma 2003; 44: Hemminki K, Li X, Sundquist J, Sundquist K. Cancer risks in Crohn disease patients. Ann Oncol 2009; 20: D Haens G. Risks and benefits of biologic therapy for inflammatory bowel diseases. Gut 2007; 56: Vermeire S, Noman M, van AG, Baert F, D Haens G, Rutgeerts P. Effectiveness of concomitant immunosuppressive therapy in suppressing the formation of antibodies to infliximab in Crohn s disease. Gut 2007; 56: Baert F, Noman M, Vermeire S et al. Influence of immunogenicity on the long-term efficacy of infliximab in Crohn s disease. N Engl J Med 2003; 348: Lemann M, Mary JY, Duclos B et al. Infliximab plus azathioprine for steroid-dependent Crohn s disease patients: a randomized placebo-controlled trial. Gastroenterology 2006; 130: Fergan BG, McDonald JW, Panaccione R et al. Arandomised trial of methotrexate in combination with infliximab for the treatment of Crohn s disease. Gastroenterology 2008; 135: van Assche G, Magdelaine-Beuzelin C, D Haens G et al. Withdrawal of immunosuppression in Crohn s disease treated with scheduled infliximab maintenance: a randomized trial. Gastroenterology 2008; 134: Oussalah A, Chevaux JB, Fay R, Sandborn WJ, Bigard MA, Peyrin-Biroulet L. Predictors of infliximab failure after azathioprine withdrawal in Crohn s disease treated with combination therapy. AmJ Gastroenterol2010; 105: ShahSB, Hanauer SB. Risks andbenefits oftheuse ofconcomitant immunosuppressives and biologics in inflammatory bowel disease. Rev GastroenterolDisord2008; 8: Karmiris K, Paintaud G, Noman M et al. Influence of trough serum levels and immunogenicity on long-term outcome of adalimumab therapy in Crohn s disease. Gastroenterology 2009; 137: Fineberg SE, Galloway JA, Fineberg NS, Rathbun MJ, Hufferd S. Immunogenicity of recombinant DNA human insulin. Diabetologia 1983; 25: Bray GL, Gomperts ED, Courter S et al. A multicenter study of recombinant factor VIII (recombinate): safety, efficacy, and inhibitor risk in previously untreated patients with hemophilia A. The Recombinate StudyGroup. Blood 1994; 83: Schellekens H. Immunogenicity of therapeutic proteins: clinical implications and future prospects. Clin Ther 2002; 24: Lichtenstein GR, Diamond RH, Wagner CL et al. Clinical trial: benefits and risks of immunomodulators and maintenance infliximab for IBD-subgroup analyses across four randomized trials. Aliment Pharmacol Ther 2009; 30: ª 2011The Association forthe Publication of thejournalof InternalMedicine JournalofInternal Medicine 270;

14 98 Cassinotti A, Ardizzone S, Porro GB. Adalimumab for the treatmentofcrohn s disease. Biologics 2008; 2: Rivkin A. Certolizumab pegol for the management of Crohn s disease in adults. Clin Ther 2009; 31: Hanauer SB, Wagner CL, Bala M et al. Incidence and importance of antibody responses to infliximab after maintenance or episodic treatment in Crohn s disease. Clin Gastroenterol Hepatol 2004; 2: Maser EA, Villela R, Silverberg MS, Greenberg GR. Association of trough serum infliximab to clinical outcome after scheduled maintenance treatment for Crohn s disease. Clin Gastroenterol Hepatol 2006; 4: Bartelds GM, Wijbrandts CA, Nurmohamed MT et al. Clinical response to adalimumab: relationship to anti-adalimumab antibodies and serum adalimumab concentrations in rheumatoid arthritis. Ann RheumDis2007; 66: Radstake TR, Svenson M, Eijsbouts AM et al. Formation of antibodies against infliximab and adalimumab strongly correlates with functional drug levels and clinical responses in rheumatoid arthritis. Ann RheumDis2009; 68: Magdelaine-Beuzelin C, Vermeire S, Goodall M et al. IgG1heavy chain-coding gene polymorphism (G1m allotypes) and development of antibodies-to-infliximab. Pharmacogenet Genomics 2009; 19: Rutgeerts P, Vermeire S, van Assche G. Predicting the response to infliximabfrom troughserum levels. Gut 2010; 59: Plosker GL, Lyseng-Williamson KA. Adalimumab: in Crohn s disease. BioDrugs 2007; 21: Seow CH, Newman A, Irwin SP, Steinhart AH, Silverberg MS, Greenberg GR. Trough serum infliximab: a predictive factor of clinical outcome for infliximab treatment in acute ulcerative colitis. Gut 2010; 59: Ainsworth MA, Bendtzen K, Brynskov J. Tumor necrosis factoralpha binding capacity and anti-infliximab antibodies measured byfluid-phase radioimmunoassaysaspredictors ofclinical efficacy of infliximab in Crohn s disease. Am J Gastroenterol 2008; 103: Afif W, Loftus EV Jr, Faubion WA et al. Clinical Utility of Measuring Infliximab and Human Anti-Chimeric AntibodyConcentrations in Patients With Inflammatory Bowel Disease. Am J Gastroenterol 2010; 105: Bendtzen K, Ainsworth M, Steenholdt C, Thomsen OO, Brynskov J. Individual medicine in inflammatory bowel disease: monitoring bioavailability, pharmacokinetics and immunogenicity of anti-tumour necrosis factor-alpha antibodies. Scand J Gastroenterol 2009; 44: Hanauer SB, Feagan BG, Lichtenstein GR et al. Maintenance infliximab for Crohn s disease: the ACCENT I randomised trial. Lancet 2002; 359: Bongartz T, Sutton AJ, Sweeting MJ, Buchan I, Matteson EL, Montori V. Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials. JAMA 2006; 295: Svenson M, Geborek P, Saxne T, Bendtzen K. Monitoring patients treated with anti-tnf-alpha biopharmaceuticals: assessing serum infliximab and anti-infliximab antibodies. Rheumatology (Oxford) 2007; 46: Steenholdt C, Thomsen OØ, Brynskov J, Bendtzen K, Ainsworth MA. Discriminating between response types in infliximab-treated patients with Crohn s disease: sensitivity and specificity of combined assessment of infliximab trough levels and anti-drug antibodies. Gastroenterology 2010; 138(suppl. 1): Louis E, Belaiche J, Reenaers C. Anti-TNF and Crohn s disease: when shouldwe stop? CurrDrugTargets 2010; 11: Schnitzler F, Fidder H, Ferrante M et al. Long-term outcome of treatment with infliximab in 614 patients with Crohn s disease: results from a single-centre cohort. Gut 2009; 58: SandbornWJ, FeaganBG, Hanauer SB et al. A review of activity indices and efficacy endpoints for clinical trials of medical therapy in adults with Crohn s disease. Gastroenterology 2002; 122: Best WR, Becktel JM, Singleton JW, Kern F Jr. Development of a Crohn s disease activity index. National Cooperative Crohn s Disease Study. Gastroenterology 1976; 70: Vermeire S, Schreiber S, Sandborn WJ, Dubois C, Rutgeerts P. Correlation between the Crohn s disease activity and Harvey- Bradshaw indices in assessing Crohn s disease severity. Clin Gastroenterol Hepatol 2010; 8: Best WR. Predicting the Crohn s disease activity index from the Harvey-Bradshaw Index. InflammBowelDis 2006; 12: Gisbert JP, McNicholl AG. Questions and answers on the role of faecal calprotectin as a biological marker in inflammatory bowel disease. Dig Liver Dis 2009; 41: von Roon AC, Karamountzos L, Purkayastha S et al. Diagnostic precision of fecal calprotectin for inflammatory bowel disease and colorectal malignancy. Am J Gastroenterol 2007; 102: D Haens G, van DS, Van HR et al. Endoscopic and histological healing withinfliximab anti-tumor necrosis factor antibodies in Crohn s disease: a European multicenter trial. Gastroenterology 1999; 116: Louis E, Vernier-Massouille G, Grimaud J et al. Infliximab discontinuation in Crohn s disease patients in stable remission on combined therapy with immunosuppressors: interim analysis of a prospective cohort study. 16th United European Gastroenterology Week2008; Vienna, October Nielsen OH, Rogler G, Hahnloser D, Thomsen OO. Diagnosis and management of fistulizing Crohn s disease. Nat Clin Pract Gastroenterol Hepatol 2009; 6: Klareskog L, Catrina AI, Paget S. Rheumatoid arthritis. Lancet 2009; 373: Colombel JF, Rutgeerts P, Sandborn WJ et al. Deep remission for adalimumab-treated patients with moderate to severe ileocolonic Crohn s disease. ECCO 2010; Prague, February Lichtenstein GR, Cohen RDFBG, Salzberg B et al. Safety of infliximab and other Crohn s disease therapies: TREAT registry data with 27,762 patient-years of follow-up. Gastroenterology 2010; 138(suppl. 1): S Burmester GR, Mease P, DijkmansBA et al. Adalimumab safety and mortality rates from global clinical trials of six immunemediated inflammatory diseases. Ann Rheum Dis 2009; 68: Correspondence: Ole H. Nielsen, Department of Gastroenterology D112M, Herlev Hospital, University of Copenhagen, Herlev Ringvej 75, DK-2730 Herlev, Denmark. (fax: ; ohn@dadlnet.dk). 28 ª 2011 TheAssociationfor the Publication ofthe JournalofInternal Medicine Journal ofinternalmedicine 270; 15 28