Inf lammatory bowel disease (IBD), which includes both Crohn’s disease (CD) and ulcerative colitis (UC), affects approximately 1.4 million people in the USA [1] and results from a complex interaction between innate and adaptive immunity [2]. It is believed that aber-rant innate immune responses to commensal flora play an important role in IBD patho-genesis [3]. Patients with IBD develop strong immune responses to common bacterial anti-gens that do not trigger an immune response in a normal host [3]. Controlling inflammatory responses to commonly encountered antigens presents a challenge to the mucosal immune system of patients with IBD. The basal state of mucosal immune suppression observed in healthy people is important to prevent a patho-logic response to the constant presence of com-mensal flora and dietary antigens. While the immunologic tone of mucosa-associated lym-phoid tissue in a normal host is that of hypore-sponsiveness or suppression, the immunologic tone of the mucosa-associated lymphoid tissue in an IBD patient is that of activation [3]. The mechanisms responsible for the healthy tone of hyporesponsiveness in a normal host involve
complex interactions between the intestinal epithelial cell of the GI tract and the underly-ing T lymphocyte in the lamina propria [3]. Intercellular communication in the gut mucosa occurs via a broad array of cytokines, some of which, such as TNF-α, IL-12 and IL-23, have been demonstrated to play a key role in foster-ing gut inflammation in patients with CD [4,5]. TNF-α is also found in increased concentra-tions in the blood, colonic tissue and stools of patients with UC [6,7]. TNF-α is a potent proinflammatory cytokine with pleiotrophic effects on cells of the innate and adaptive immune system. It promotes the production of additional proinflammatory cytokines (IL-1 and IL-6), upregulates the expression of adhe-sion molecules on vascular endothelial cells (vascular cell adhesion molecule and intercel-lular adhesion molecule-1) and mediates the secretion of tissue-altering enzymes (matrix metalloproteinases, collagenase and elastase) that alter tissue architecture [8].
Medical therapies that block TNF have changed the clinical management of chronic inflammatory disorders, including IBD. Since the initial report of the first successful use of
Vera Kandror Denmark*1 and Lloyd Mayer1
Mount Sinai School of Medicine, One Gustave L Levy Place, Box 1069, New York, NY 10029-6574, USA*Author for correspondence: Tel.: +1 212 659 9266 Fax: +1 212 987 5593 [email protected]
Inflammatory bowel diseases Crohn’s disease and ulcerative colitis are complex multifactorial diseases that involve the interaction between innate and adaptive immunity. TNF-α is a potent proinflammatory cytokine with pleiotrophic effects on cells of the innate and adaptive immune system. Medical therapies that block TNF have changed the clinical management of inflammatory bowel disease. This review will discuss the new recommendations for the use of anti-TNF agents in the treatment of inflammatory bowel disease, as well as insights into immunogenicity and the safety of these agents. In addition, new biologic therapies that inhibit various elements in the leukocyte infiltration process and others that target proinflammatory cytokines will be addressed. This review will cover key studies examining the use of biologic agents in the treatment of Crohn’s disease and ulcerative colitis.
TNF-α blockade in patients with moderate-to-severe CD in 1997 [9], many studies have focused on the delineation of the mechanisms of action of anti-TNF-α mAbs. Accumulating evi-dence suggests that not only soluble TNF-α, but also its precur-sor form, membrane TNF-α, is involved in the inflammatory response [10]. Membrane TNF-α acts both as a ligand by binding to TNF-α receptors, and a receptor that transmits outside-to-inside (reverse) signals back into the TNF-α-producing cells [10]. The newly recognized biological activities of membrane TNF-α as a receptor have been demonstrated in T cells, monocytes/macrophages and NK cells in humans [11,12]. Recent studies have suggested that different anti-TNF-α agents have variable effects against membrane TNF-α, possibly explaining their different biological efficacy in IBD. Thus, infliximab and adalimumab, but not etanercept, induce apoptosis and cell cycle G0/G1 arrest upon binding to membrane TNF-α-expressing Jurkat T cells, a T-cell leukemia-derived cell line [13]. In addition, IL-10 produc-tion is induced by infliximab but not etanercept in membrane TNF-α expressing Jurkat T cells [13]. Despite these differences, clinical efficacy profiles of anti-TNF agents are unlikely to be solely dependent on their activity against the membrane TNF-α and other effects on the inflammatory network that are dif-ferent between anti-TNF agents may determine their overall effectiveness in treating IBD.
A new approach to biologic therapy has been the development of inhibitors of various elements in the leukocyte adhesion process. The main targets of these new agents are the integrins α4β1 and α4β7, which interact with VCAM-1 and MAdCAM-1, respec-tively, to mediate interactions between leukocytes and endothelial cells [14]. Monoclonal antibodies, natalizumab and MLN0002 (vedolizumab), bind to and antagonize α4 and α4β7, respectively. These new therapies have provided another medical option for IBD patients who are unresponsive to conventional therapies and anti-TNF agents.
In the following sections, the authors will discuss key studies pertaining to the efficacy and safety of biological agents used in the treatment of CD and UC. They will also discuss new insights into the appropriate dosing and monitoring parameters of these drugs that may help achieve and preserve a sustained response to these agents.
Anti-TNF therapyCrohn’s diseaseInfliximabInflammatory CDInfliximab (Remicade®, Centocor, CA, USA) is a IgG1 (murine [25%] and human [75%]) chimeric mAb targeted against TNF-α [15] and is given as an intravenous infusion. It was the first biologic approved for the treatment of CD. Studies over the past 15 years have documented the efficacy of infliximab (IFX) in inducing and maintaining remission in steroid-refractory, steroid-dependent and immunomodulator-refractory inflamma-tory CD, healing of complex fistula and preventing postoperative recurrence. In 1997, Targan et al. reported that a single infusion of IFX provided significant clinical and endoscopic benefit for
patients with treatment-refractory moderate-to-severe CD [9]. Other early studies have shown similar success with IFX for the treatment of refractory CD disease (Hungary: 46.0% and Milan: 31.3%) [16,17].
Subsequent studies have demonstrated efficacy of IFX in the maintenance of remission in CD. The ACCENT I trial showed that maintenance therapy with either 5 or 10 mg/kg of IFX was more effective than placebo in sustaining clinical remis-sion and sparing patients steroid use [18]. A separate analysis of the ACCENT I study revealed that scheduled IFX treatment resulted in a greater improvement in CDAI and mucosal healing at 54 weeks, fewer surgeries and hospitalizations, and a lower proportion of antibody formation, as compared with episodic treatment [19]. A subsequent study from Belgium showed that 68% of patients who responded to IFX achieved mucosal healing while on long-term maintenance IFX. In addition, mucosal heal-ing was associated with an improved long-term outcome of the disease, such as a decreased need for hospitalizations and major abdominal surgeries [20]. It has been shown in a population-based cohort before the era of biologic therapy that mucosal healing at 1 year after diagnosis is predictive of reduced subsequent dis-ease activity; however, to date, IFX is the most potent inducer of mucosal healing [21].
Although IFX is an effective drug for the induction and maintenance of remission in CD, a significant proportion of patients experience loss of response (LOR) and flare of symp-toms. Definitions of LOR vary: a recent ECCO workshop defined LOR as a 70-point elevation of CDAI, whereas others define LOR as the need for IFX dose escalation, IFX cessation or surgery [22,23]. In the ACCENT I trial, the median time to LOR was 38 weeks for IFX-treated patients. A subsequent study of prolonged IFX therapy from a single center in Belgium revealed that after a median follow-up of 55 months, 63% of patients had sustained benefit and 22% experienced LOR despite an increase in dose and shortening of dose intervals [24]. A more recent study from a single center in Spain reported the annual risk of LOR to IFX to be 12% per patient-year of treatment (n = 309; mean follow-up: 41 months) [25]. A meta-analysis by the same group evaluating LOR for IFX in 16 studies with a total of 2236 patients found that 37% lost IFX response with an annual risk for LOR to IFX of 13% per patient-year [26].
The administration of IFX leads to highly variable serum con-centrations [16]. This variability may influence clinical response in CD. The ACCENT I trial has reported that 50% of patients who receive a single dose of 5 mg/kg IFX have undetectable levels at week 14. It has also been shown in a cohort of 105 CD patients that the rates of clinical remission and endoscopic improvement are higher in patients with a detectable trough serum IFX level compared with patients in whom serum IFX was undetectable [27]. Despite the association between low trough levels and LOR, routine measurements of IFX drug levels to guide dosing are not yet being performed, as prospective controlled trials for this prac-tice are lacking. Possible reasons for low trough levels and LOR to IFX will be discussed in the ‘Antibodies to monoclonal drugs’ section of this review.
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Fistulizing CDThe presence of fistulae in CD is a common complication, affecting between 10 and 33% of patients [28]. In a randomized, placebo-controlled trial, which examined the effect of IFX on 94 patients with abdominal or perianal fistulae, Present et al. showed that 62% of patients who received 5 or 10 mg/kg of IFX at 0, 2 and 6 weeks reached the primary end point of a 50% reduction in draining fistulas from baseline (compared with 26% of placebo patients) [29]. A similar response rate of 50% following IFX treatment was observed in a smaller cohort study of 26 patients with perianal fistulizing disease [30]. A more recent study of 99 patients with perianal CD also showed that 32.3% of patients with draining fistula had a complete response to IFX [31]. The ACCENT II study demonstrated the absence of draining fistula at a 54-week follow-up period in 36% of patients in the IFX group compared with 19% in the placebo group [32].
Recent studies using magnetic resonance have evaluated fistula healing and compared it to the clinical assessment of response in patients treated with IFX for perianal fistulizing CD. A prospective study from Belgium examined 59 patients treated with IFX for perianal CD with serial MRI examinations over a course of 36 weeks [33]. This study showed that MRI detected persistent fistula tracks in 79% of patients, with an improvement in inflammation in only 50%, although 77% of the patients reported clinical benefit from IFX therapy. These results suggest different healing rates for cutaneous and internal soft tissue structures of the fistula tracks and question the con-cept of complete fistula healing as assessed on clinical grounds. This and other studies pointing to the persistence of fistula tracks despite apparent clinical response may justify the need for long-standing therapy with IFX in patients with perianal fistulizing CD [34,35].
Postoperative CD recurrenceMore recently, a small study assessed the role of IFX in post-operative recurrence in CD patients undergoing an ileocolic resection (n = 24) who either received IFX or placebo induction followed by an every 8-week infusion [36]. The primary end point was endoscopic recurrence at 1 year. There was endoscopic recur-rence in 9.1% (one of 11) of IFX patients compared with 84.6% in the placebo group. Clinically, 0% in the IFX group versus 38.5% in the placebo group had a recurrence as measured by CDAI. A subsequent prospective randomized open-label trial from Japan assessed the efficacy of scheduled maintenance IFX monotherapy 5 mg/kg (without induction) in 31 CD patients following ileocolic resection [37]. The primary end point was remission rates at 12 and 36 months defined as CDAI <150 and CRP <0.3 mg/dl. This study found 100 and 93% remission rates in the IFX group at 12 and 36 months, respectively, versus 69 and 56% in the control group. Furthermore, the IFX group achieved higher endoscopic remission rates at 12 months (78.6 vs 18.8%). The challenge remains to identify patients at high risk for postoperative recur-rence in order to spare low-risk patients the side effects and cost of anti-TNF therapy.
AdalimumabAdalimumab (ADA; Humira®, Abbott Labs, IL, USA) is a fully human anti-TNF mAb that is given subcutaneously [38]. The CLASSIC-I trial demonstrated that ADA can be used for the induction of remission in patients with moderate-to-severe CD [39]. The maintenance trial for ADA in luminal CD, the CHARM trial, randomized patients who responded to the ADA induction regimen (80 mg at week 0 and 40 mg at week 2) to ADA 40 mg every other week, ADA 40 mg every week or placebo [40]. Both maintenance doses were effective at weeks 26 and 56. Remission rates at week 26 and 56 were 17 and 12%, respectively, on placebo, 40 and 36% on ADA 40 mg every other week and 47 and 41% on ADA 40 mg every week. Fewer hospitalizations and surgeries occurred in the continuous versus induction/re-initiation group [41]. The CHARM study also demonstrated the efficacy of ADA in fistulizing CD: at week 26 and 56, 30 and 33% of patients, respectively, exhibited fistula closure. A 3-year open-label extension of the CHARM trial, ADHERE, evaluated the steroid-sparing efficacy of long-term ADA use [42]. Of the 313 patients who were receiving corticosteroids at the beginning of the CHARM trial, 206 were randomized to ADA. The rates of steroid-free remission in the ADA group at 1 and 3 years were 26 and 23%, respectively.
With ADA approved in 2007, clinicians hoped to use this medi-cation in those patients who were IFX primary nonresponders, secondary nonresponders or who experienced intolerable infu-sion reactions. Short-term response to ADA in primary IFX non-responders and anti-TNF-naive patients was documented in the CARE study, which showed a remission rate of 52% at week 20 in both subgroups. Results at week 4 (49%) and week 20 (61%) were better in the TNF antagonist-naive group compared with those with prior IFX exposure.
The GAIN study, a 4-week, randomized, double-blind placebo- controlled trial of 325 patients, evaluated the use of ADA in sec-ondary nonresponders to IFX [43]. In this study, 21% of ADA patients achieved remission compared with 7% of the placebo group patients. In addition, 52% of ADA patients had a decrease in CDAI of 70 points, a decrease in median CRP and an improve-ment in the IBDQ. The GAIN study showed that ADA could pro-vide a viable therapeutic option to IFX patients who experienced infusion reactions or lost response to IFX.
A subsequent observational multicenter cohort study followed 168 CD patients who lost response to IFX (secondary non-responders) and were re-induced and maintained on ADA therapy 40 mg every other week with a median follow-up of 20 months [44]. The indication for ADA therapy was luminal CD in 95% of patients. A total of 7% discontinued ADA by week 4 owing to pri-mary nonresponse and adverse events. Of the ones who continued therapy past week 4, 61.5% showed sustained clinical benefit to ADA at week 20. Escalation to 40 mg every week was needed in 65.4% of patients. The probability of dose escalation was compa-rable with what was shown in the CHARM trial. A total of 50% of patients who followed-up for 120 weeks lost clinical benefit and 80% needed dose escalation. Early discontinuation of therapy correlated with a lower ADA trough serum concentration.
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An important randomized open-label single-center 1-year study from Belgium evaluated the impact of elective switching from IFX to ADA in patients under complete remission on a stable IFX dose for at least 6 months [45]. A total of 73 patients were randomly allocated to either continue IFX 5 mg/kg at the same time interval as before allocation or switch to ADA 80 mg at inclusion, fol-lowed by 40 mg every other week. The main end point was the proportion of patients who needed rescue therapy with steroids, intensification of anti-TNF dosing or termination of the assigned anti-TNF agent. The trial produced large differences in the dis-continuation of the assigned treatment between the two groups. Almost one in three patients who switched to ADA had to return to IFX within the time frame of 1 year despite a strong patient preference for a subcutaneously administered anti-TNF agent. Four of eight patients who returned to the IFX group needed IFX dose intensification within 1 year after restarting. This trial sug-gests that switching from IFX to ADA for reasons other than LOR or loss of tolerance may not be a successful therapeutic strategy. Since the number of approved biologics for CD is limited, it is beneficial to optimize the use of the first anti-TNF agent before switching to another one.
CertolizumabCertolizumab (Cimzia®, UCB Pharma, Belgium) is a humanized anti-TNF mAb [38]. Unlike the agents mentioned earlier, it does not have an Fc portion, and therefore has less in vitro complement activation, antibody-dependent cellular cytotoxicity or induction of apoptosis [46]. This drug is provided as a subcutaneous injec-tion: 400 mg given at 0, 2 and 4 weeks for induction, and every 4 weeks thereafter for maintenance.
The PRECISE 1 trial, which evaluated the certolizumab (CZP) induction protocol (400 mg at weeks 0, 2 and 4) for patients with moderate-to-severe CD (baseline CRP of at least 10 mg/l), resulted in a modest improvement in response rates compared with placebo (22 vs 12% at week 26); however, a statistically sig-nificant remission rate was not observed compared with placebo at 26 weeks [47]. A more recent multicenter, randomized, double-blind, placebo-controlled trial evaluated the efficacy of CZP as an induction agent for CD patients naive to anti-TNF therapy [48]. Patients were randomized to CZP 400 mg or placebo at weeks 0, 2 and 4 and the response was assessed at week 6. The differences between CZP and placebo did not reach statistical significance (32 vs 25%). The subgroup of patients who achieved significant differences in clinical remission with CZP included patients with a baseline CRP concentration >10 mg/l. The lack of a statistically significant difference between CZP and placebo induction groups might have reflected the relatively high proportion of patients with a baseline CRP concentration <5.
The PRECISE 2 trial examined maintenance with CZP follow-ing an open-label induction. Patients who responded to the induc-tion were randomized to placebo or 400 mg of CZP every 4 weeks [49]. A total of 48% of CZP patients, including those previously treated with IFX, were in remission at week 26 based on CDAI (compared with 29% placebo response). The PRECISE 3 trial reported results of the long-term use of CZP [50]. For patients with
no drug interruption, 62.1% were in remission at week 80 based on the Harvey–Bradshaw Scale. In addition, patients with drain-ing fistulas at the beginning of the PRECISE 2 trial (n = 108) received open-label induction with CZP and responders were randomized to CZP 400 mg (n = 28) or placebo (n = 30) every 4 weeks [51]. Fistula closure was observed in 36% of patients in the CZP group compared with 17% in the placebo group at week 26.
An important question of whether CZP is efficacious in patients who lose response to IFX was evaluated in an open-label trial [52]. At 6 weeks, CZP induced remission and response in 39 and 68% of patients, respectively. Those who achieved clinical response at week 6 were randomized to receive CZP 400 mg every 4 or 2 weeks for 24 weeks. At week 24 clinical remission and response rates were 29 and 40%, respectively. There was no difference between CZP 400 mg every 2 or 4 weeks for maintenance of response or remission.
A recent retrospective study evaluated the efficacy of a third anti-TNF in CD after failure/intolerance of two different anti-TNF agents [53]. Sixty seven patients were included, of which 40 patients received CZP as the third anti-TNF. Median dura-tion between the first and last anti-TNF was 18 months. Clinical response was observed in 61% at week 6 and 51% at week 20, with clinical response at week 6 being the only clinical predictor of response at week 20. The probability of retaining the third anti-TNF was 45% at 9 months. The subgroup analysis demonstrated similar benefits with CZP and ADA as a third-line anti-TNF.
In summary, anti-TNF agents are successful at inducing and maintaining remission in patients with moderate-to-severe lumi-nal CD, as well as fistulizing CD. Once response is lost to the first anti-TNF agent, remission can be induced and maintained with a second and even a third anti-TNF agent (albeit with a reduced response to additional anti-TNFs). However, elective switching between anti-TNF agents is not recommended, as it does not pro-duce satisfactory long-term results. It should be emphasized that the selection of patients for anti-TNF therapy should be based on the objective evidence of inflammation, such as elevated CRP lev-els, fecal biomarkers or imaging studies, to minimize un necessary biologic exposure and ensure optimal response to therapy.
Ulcerative colitisInfliximabTNF-α is a key proinflammatory cytokine in patients with CD, but is also found in increased concentrations in the blood, colonic tissue and stools of patients with UC [6,7]. Targeting the TNF-α pathway in the treatment of moderate-to-severe UC was shown to be effective by two multicenter, randomized, double-blind, placebo-controlled trials, ACT 1 and 2 [54]. Each study r andomized 364 patients to receive an induction regimen of either IFX 5 mg/kg, IFX 10 mg/kg or placebo at weeks 0, 2 and 6, followed by a maintenance regimen of IFX 5 mg/kg, IFX 10 mg/kg or placebo every 8 weeks for a total of 30 weeks (ACT 2) and 54 weeks (ACT 1). Both trials have demonstrated a statistically significant benefit of IFX as compared with placebo at inducing remission at each time interval evaluated. In addition, both trials resulted in mucosal healing rates of approximately 60%
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at 8 weeks in both dosage groups as compared with a 30% heal-ing rate in the placebo group. A significantly higher proportion of patients discontinued steroids in the IFX groups at week 30 than in the placebo groups. Thus, the ACT 1 and 2 trials have shown that IFX is effective in patients with moderate-to-severe UC in inducing clinical response, remission and mucosal healing.
The ACT-1 and -2 3-year long-term extension studies have been conducted to evaluate long-term efficacy and health-related qual-ity of life outcomes in patients who received IFX (not placebo) during the main studies [55]. Patients who enrolled in the 3-year extension study received open-label IFX every 8 weeks at their sta-ble dose. Efficacy measures were the physician’s global assessment scale and the IBD questionnaire. During the extension studies, patients maintained improved health-related quality of life meas-ures for up to 3 additional years of IFX therapy. Overall, 36% of patients either discontinued IFX due to intolerance or LOR (30%) or escalated the dose from 5 to 10 mg/kg.
Finally, IFX was evaluated as a rescue therapy in hospitalized patients with moderate-to-severe UC unresponsive to intrave-nous steroid therapy in a randomized, double-blind, single-center study [56]. Forty five patients were randomized to a single dose of IFX 5 mg/kg (n = 24) or placebo (n = 14). The primary out-come was colectomy rates at 3 months. Seven patients in the IFX group and 14 patients in the placebo group had a colectomy within 3 months of randomization. This study showed that IFX 5 mg/kg may be an effective rescue therapy in patients experienc-ing an acute severe attack of UC not responding to convention treatment. In addition, a recent multicenter, randomized, open-label trial evaluated the efficacy of cyclosporine versus infliximab as salvage therapy in severe UC refractory to steroid therapy [57]. Patients with steroid-refractory UC and a Lichtiger score of greater than 10 were randomized to receive either infliximab 5 mg/kg (n = 56) or cyclosporine 2 mg/kg (n = 55) and were followed for up to 98 days. The primary end point, treatment failure at the end of 98 days, was not statistically different between the treat-ment groups: 60% failed in the cyclosporine versus 54% in the infliximab arm. Secondary end points, such as early response at 7 days and mucosal healing, were also similar for the two groups and did not reach a statistically significant difference. Thus, this first randomized study comparing cyclosporine and infliximab for the treatment of severe, steroid-refractory UC found cyclosporine to be no more effective than infliximab in this population, sug-gesting that IFX is efficacious not just as maintenance, but also as rescue therapy in UC.
AdalimumabAt present, no subcutaneously administered anti-TNF agents are approved for patients with UC in the USA; however, adalimumab has recently been approved for the treatment of moderately-to-severely active UC in Europe. Two recent randomized, double-blind, placebo-controlled trials have been conducted to address the efficacy of ADA at inducing and maintaining remission in patients with moderate-to-severe UC. The first trial assessed the efficacy of two ADA dosing regimens (160/80/40/40 and 80/40/40/40 at weeks 0, 2, 4 and 6, respectively) for the
induction of clinical remission in patients with moderately-to-severely active UC naive to any biologic agents [58]. Patients with ulcerative proctitis were excluded. Approximately twice as many patients in the ADA 160/80 group achieved clinical remission at week 8 compared with patients in the placebo group. The propor-tion of patients in clinical remission at week 8 in the placebo and ADA 80/40 groups was similar. Interestingly, the rate of clinical remission for patients below 82 kg in the 160/80 group was more than double the rate of remission for patients above 82 kg. In addition, patients with high CRP levels at baseline (>10 mg/l) had reduced remission rates in the ADA 160/80 group. These results suggest that patients with a higher BMI and a greater inflam-matory burden may require a higher induction dose of ADA to achieve clinical remission.
A subsequent trial assessed the efficacy of ADA to induce and maintain remission in patients with moderate-to-severe UC through week 52 of treatment [59]. The ADA induction regi-men was 160/80 mg, followed by 40 mg every other week. Of 494 patients, 40% had previously received and discontinued an anti-TNF agent owing to intolerance or LOR. At week 8 and 52, 16.5 and 17.3% of patients in the ADA group were in clini-cal remission, respectively, compared with 9.3 and 8.5% in the placebo group. Among patients who were naive to anti-TNFs, 21.3 and 22% in the ADA group achieved clinical remission at weeks 8 and 52, respectively (with 11 and 12.4% response rates in the placebo arms), as compared with 9.2 and 10.2% at 8 and 52 weeks in the anti-TNF-experienced group (with 7 and 3% response rates in the placebo arms). However, this study was not powered to assess the efficacy of ADA in subgroups of patients who were either naive to anti-TNF therapy or who experienced anti-TNF therapy in the past. Overall, this study confirms the findings from the previous trial and shows that ADA 160/80 is an effective induction regimen for patients with UC and that ADA 40 mg every other week is superior to placebo in maintaining clinical remission in UC patients through week 52 of treatment. This study also suggests that the ideal patient population for ADA is outpatients with moderate-to-severe UC, failing conventional therapies who are anti-TNF naive. However, a statistically signifi-cant benefit for anti-TNF experienced patients was also observed and should be considered in those who fail IFX therapy. Large randomized, placebo-controlled trials are needed to address the long-term efficacy of ADA in this population.
GolimumabGolimumab is a human IgG1 anti-TNF-α monocloncal anti-body, which has a higher affinity for soluble TNF-α than either infliximab or adalimumab [60]. Golimumab (Simponi®) is approved for use in RA in conjunction with methotrexate. A new Phase III multicenter, randomized, double-blind, placebo-controlled trial, PURSUIT, evaluated the safety and efficacy of two sub cutaneous golimumab induction regimens at weeks 0 and 2 (200/100, 400/200 mg) versus placebo in adults with moder-ately-to-severely active UC who failed to respond to conventional therapies but were TNF inhibitor naive [61]. A total of 774 patients were randomized into the Phase III component of the study with
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a baseline Mayo score between 6 and 12 and an endoscopic score ≥2. The primary end point, clinical response at 6 weeks, defined as a decrease in the Mayo score of at least 30% or 3 points, was achieved in 52, 55 and 30% of patients in the 200/100, 400/200 and placebo groups, respectively. The secondary end points at 6 weeks (clinical remission, mucosal healing and a change in the quality of life) were also significantly in favor of golimumab. Clinical remission at 6 weeks, defined as a Mayo score of 2 or less, was measured at 19, 18 and 6% for the 200/100, 400/200 and placebo groups, respectively. Mucosal healing was observed in 43, 45 and 28% of patients in the three respective groups and a change in the quality of life as measured by a mean change from baseline in the IBD questionnaire score was detected in 27, 27 and 15% of patients in each respective group. Patients who responded to the induction treatment were eligible to continue in the Phase III PURSUIT maintenance study. There was no difference in frequency of adverse events between the treatment and the placebo groups. Of note, injection site reactions were uncommon. However, there was a single case of demyelination reported in the golimumab 400/200 group. Thus, golimumab appears to be a promising new anti-TNF agent with potentially fewer side effects related to immunogenicity.
In summary, both IFX and ADA have proven efficacious in inducing and maintaining clinical remission, as well as mucosal healing, in patients with moderate-to-severe UC refractory to conventional therapies. In addition, IFX is an effective rescue therapy for patients with an acute moderate-to-severe UC flare. ADA appears to induce and maintain remission in patients who have lost response to IFX; however, this conclusion comes from a subgroup analysis and a larger prospective randomized trial focusing on secondary IFX nonresponders is needed to further support this statement. Golimumab is a promising new human anti-TNF antibody, which appears to induce clinical response, remission and mucosal healing in the short term in patients with moderate and severe UC. Golimumab is currently undergoing investigation in a long-term Phase III trial (Tables 1 & 2).
General considerationsLOR, trough levels & antibody concentrationsRandomized controlled trials have shown that anti-TNF agents initially fail in 10–30% of patients. These patients are classified as primary nonresponders. Secondary nonresponders, on the other hand, are those patients who initially benefit from therapy but lose response over time: 30–40% of patients lose response to anti-TNF agents during the first year of therapy [22]. Central to the evaluation of the lack or loss of response is the assessment of factors unrelated to the drug, particularly the absence of active inflammation, con-current infection or a septic complication. Once objective evidence of inflammation has been established and infection has been ruled out, drug-related factors can be considered in the LOR, such as the presence of neutralizing antibodies, altered clearance of the drug or possibly biological escape mechanisms. Antibody formation was thought to be one of the most important causes of LOR to chimeric anti-TNF agents: it has been shown that high anti-drug antibody titers were correlated with low trough levels of IFX and secondary
LOR [24]. In addition, antibody formation may accelerate drug clearance due to the formation of immune complexes [62].
However, it appears that the antibody-dependent clearance of the drug may not be the sole mechanism for early drug elimina-tion, and the trough drug levels are better predictors of clinical response than the presence of antidrug antibodies. Interestingly, when the rate of antibody formation and its association with clini-cal response were studied in CD patients from the ACCENT 1 trial, it was found that the rate of clinical response was not related to the antibody status of the patient [63]. Up to 60% of patients with low IFX drug concentrations were not found to have detectable antidrug antibodies present, suggesting an acceler-ated clearance mechanism in some patients that is independent of antibody formation. In addition, higher rates of clinical remission and endoscopic improvement were observed in CD patients with detectable serum trough concentrations of IFX [27].
A recent study from Canada showed that the presence of IFX trough levels predicts clinical remission, whereas undetectable trough levels predict colectomy in patients with moderate-to-severe UC [64]. The study evaluated 115 patients with moderately severe (Mayo score between 6 and 10) to severe (Mayo score >10) UC treated with IFX 5 mg/kg at weeks 0, 2 and 6 followed by a maintenance dose every 8 weeks. Trough IFX levels and anti-IFX antibodies were measured immediately before an infusion and correlated with clinical and endoscopic remission rates as well as colectomy rates through week 54. An undetectable trough IFX level occurred in 61% of patients, of whom 41% had anti-IFX antibodies and 20% did not. Patients with a detectable serum IFX concentration had higher rates of clinical (69 vs 15%) and endoscopic remission (76 vs 28%) and a lower colectomy rate (7 vs 55%) than patients with undetectable trough IFX levels. The rates of clinical or endoscopic remission were no different between antibody-positive and antibody-negative patients (14 vs 18%). Because undetectable IFX levels occurred independently of the presence of anti-IFX antibodies, the authors concluded that the trough serum IFX concentration may provide a more useful guide for optimizing clinical outcomes.
Interestingly, a higher inflammatory burden in patients with UC may result in lower trough levels, suggesting an accelerated utilization of the drug. In the study described above, patients with moderately severe disease had higher remission rates at weeks 10 and 54 compared with patients with severe disease. In addition, the proportion of patients with detectable IFX levels tended to be lower with more severe disease activity (although the differ-ence did not reach statistical significance), suggesting a more rapid clearance of the drug in patients with a greater disease bur-den. Similarly, in the ULTRA 1 study (the ADA induction and maintenance trial), UC patients with high CRP levels at baseline (>10 mg/l) had reduced remission rates as compared with the lower CRP-patient group [59]. Thus, it is unclear whether a low drug level (as may occur in patients with a high inflammatory burden or in patients on intermittent infusion schedules) is a precursor for antibody production or whether the presence of antibodies causes an accelerated drug clearance resulting in lower trough levels.
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Table 1. Clinical response induction data for monoclonal antibodies for Crohn’s disease.
Study Treatment groups/induction dose
Response rate
Response definition Patient population
Comment Ref.
Infliximab
Targan et al.
Placebo 17% Decrease in CDAI by 70 points at week 4
Moderate-to-severe CD
This was the first biologic study, so patients were naive to biologic therapy by definition and were sicker overall (hence a very low placebo rate)
[74]
5 mg/kg 81%
10 mg/kg 50%
20 mg/kg 64%
65% overall
ACCENT-I Week 0 – all groups get 5 mg/kg
58% at 2 weeks
Decrease in CDAI by 70 points from baseline and 25% reduction in total score at week 2
Active CD with CDAI >220
This trial confirmed that IFX is an effective induction agent in CD and assessed its utility as a maintenance agent
[18]
Weeks 2, 6 and every 8 thereafter:
Group 1 – placebo
Group 2 – 5, 5, 5 mg/kg
Group 3 – 5, 5, 10 mg/kg
Adalimumab
CLASSIC-I Week 0/2: CDAI <150 at week 4 Moderate-to-severe CD naive to anti-TNFs
Remission rates were comparable to those achieved with IFX. 160/80 mg induction regimen was superior to others
[39]
Placebo 12%
40/20 mg 18%
80/40 mg 24%
160/80 mg 36%
GAIN Week 0 and 2: CDAI -70 vs CDAI -100
Decrease in CDAI by 70 or 100 points from baseline at week 4
Moderate-to- severe CD unresponsive to or intolerant of IFX
Showed that patients could be safely and effectively switched to adalimumab after losing response to IFX
[43]
Placebo 34 vs 25%
160/80 mg 52 vs 38%
Certolizumab
PRECISE-1 Week 0, 2, 4 and then every 4 weeks:
Decrease in CDAI by 100 points at week 6
Moderate-to-severe CD, CRP >10
High placebo rate obscured clinical effect
[47]
Placebo 27%
400 mg 35%
Sandborn et al.
Week 0, 2, 4: CDAI <150 at week 6
Moderate-to-severe CD naive to anti-TNFs
The difference between CZP and placebo did not reach statistical significance, except in the subgroup analysis of patients with CRP >10
[48]
Placebo 25%
400 mg 32%
Natalizumab
Gordon et al.
One infusion: Change in mean CDAI and remission (CDAI <150) at week 2
Mild-to-moderate CD
There was no difference in remission rates at week 12
Routine measurements of trough and antibody levels to guide biologic therapy have not yet been incorporated into clinical prac-tice. However, both measurements may become useful in deciding whether to escalate the dose of the existing anti-TNF or switch to another anti-TNF agent. A recent study from Mayo Clinic (MN, USA) has suggested that in antibody-positive patients, a change to another anti-TNF agent was associated with a complete or partial response in 92% of patients, whereas dose escalation had a response of only 17%. By contrast, in patients with subtherapeutic IFX con-centrations, dose escalation was associated with complete or partial clinical response in 86% of patients, whereas changing to another anti-TNF agent was associated with a response of only 33% [65].
Combination therapy with immunomodulators versus anti-TNF monotherapyAn additional concern is whether combination therapy with immunomodulators is more efficacious than anti-TNF mono-therapy in CD. The answer may depend on the patient popula-tion under study. For patients with active luminal CD despite immuno modulators post hoc analyses of the pivotal trials with IFX, ADA and CZP have not demonstrated superior efficacy of combination therapy. Subsequently, in an 18-month open-label study of 80 CD patients on combination therapy who failed immuno modulators before starting IFX, no benefit was found from continuing immunomodulators beyond 6 months [66].
However, the efficacy of combination therapy is different in anti-TNF and immunomodulator-naive patients. The most evi-dence for the superiority of combination therapy in this patient population comes from the SONIC trial, a randomized, double-blind trial, where anti-TNF and immunomodulator naive patients with moderate-to-severe CD were randomized to infliximab plus
placebo pills, azathioprine plus placebo infusion or combination therapy [21]. At week 26, 56.8% of combination therapy patients were in steroid-free remission compared with 44.4% in the inf-liximab-alone group and 30% in the azathioprine-alone group. Similar trends were noticed at week 50. The benefit was particu-larly evident in patients with objective evidence of inflammation (endoscopic lesions or elevated CRP).
Patients with moderate-to-severe UC often receive thio purines; however, it remains to be determined whether combination ther-apy in UC is superior to either thiopurines or IFX alone in the long run. A recently conducted double-blind, placebo-controlled trial to compare treatment with infliximab, azathioprine or both agents in combination, in patients with moderate to severe UC not responding to steroids, has shown superiority of combination therapy at 16 week [67]. The primary outcome of the study was steroid-free remission at 16 weeks, as defined by a Mayo score of 2 or less. A total of 239 UC patients were randomized to receive azathioprine/placebo, infliximab/placebo or infliximab/azathio-prine. All patients were biologic naive and either azathioprine naive or had stopped taking azathioprine more than 3 months prior to study entry. The results at 16 weeks indicated that com-bination therapy was superior to either agent alone in achieving steroid-free remission: 24% in the azathioprine group, 22% in the infliximab group and 40% in the combination group achieved the primary end point. In addition, secondary end points (clinical response and mucosal healing) were significantly higher in both IFX groups (IFX alone and combination therapy) as compared with the azathioprine group: clinical response was seen in 50% of patients in the AZA group, 69% in the IFX group and 77% in the combination group, while mucosal healing was observed in 37, 55 and 63%, respectively. These data suggest that combination
Table 1. Clinical response induction data for monoclonal antibodies for Crohn’s disease (cont.).
Study Treatment groups/induction dose
Response rate
Response definition Patient population
Comment Ref.
Natalizumab (cont.)
Ghosh et al. Two infusions 4 weeks apart:Placebo3 mg/kg + placebo3 mg/kg + 3 mg/kg6 mg/kg + 6 mg/kg
17%20%29%16%
CDAI <150 at week 6 Moderate-to-severe CD
At week 6 there was no difference in remission rates between the groups. At week 8 both natalizumab groups had significantly higher remission rates than placebo
[72]
ENACT-1 Week 0, 4, 8:
Placebo300 mg
Response vs remission:49 vs 30%56 vs 37%
Decrease in CDAI by 70 points from baseline and remission (CDAI <150) at week 10
Moderate-to-severe CD
Did not achieve primary end point. Post hoc analysis showed patients with an elevated CRP had a statistically significant response and remission rates at week 10
[73]
ENCORE Week 0, 4, 8:Placebo300 mg
32%48%
Decrease in CDAI by 70 points from baseline at week 8 and sustained at week 12
Moderate-to-severe CD with CRP >2.87 mg/l
Established that this agent was effective at maintaining remission in patients with objective evidence of inflammation
ReviewMonoclonal antibody therapy for the treatment of inflammatory bowel disease
therapy of thiopurines and IFX is superior to either agent alone in achieving steroid-free remission in the short term. More data are needed to evaluate this observation in the long term as well as to determine whether combination therapy provides additional benefit over IFX alone in achieving mucosal healing.
Stopping anti-TNF therapyCessation of anti-TNF therapy may need to be considered in various circumstances, such as where concerns exist about long-term safety and cost. To address whether CD patients in remission can stop IFX therapy and remain in remission was evaluated by a prospective multicenter cohort study from Europe, which followed 115 patients in stable steroid-free endo-scopic and clinical remission on combination therapy (an anti-metabolite and IFX) for over a year [68]. The median follow-up
was 28 months. The relapse rate was 57% in the first year. Predictors of relapse included smoking, previous steroid use, as well as elevated fecal calprotectin and CRP. The observed rate of relapse in this study supports the results of prior smaller retrospective and longitudinal single-center studies [69,70]. Although randomized controlled trials are needed to confirm these observations, it appears that there are parameters that can be used to identify patients at a low risk for relapse who may be able to stop IFX therapy.
Adhesion molecule antagonistsNatalizumabNatalizumab (Tysabri®, Elan Pharma, Dublin, Ireland) is a mono-clonal antibody against the integrin α4, which is 95% humanized and 5% murine derived. Natalizumab inhibits the migration of
Table 2. Long-term clinical remission for monoclonal agents in Crohn’s disease.
Study Agent Remission rate Remission definition Comments Ref.
Infliximab
ACCENT-I Week 0 – all groups get 5 mg/kg
CDAI <150 at week 30 Only those who responded to 5 mg/kg could advance in this trial. This trial confirmed that IFX is effective at maintaining remission but there is a gradual loss of response
[20]
Weeks 2, 6 and every 8 thereafter:
Week 30; Week 52 Time to loss of response at week 52
Group 1 – placebo 21%; 14%
Group 2 – 5, 5, 5 mg/kg
39%; 28%
Group 3 – 5, 5, 10 mg/kg
45%; 30%
Adalimumab
CHARM Week 0 – 80 mg CDAI <150 at weeks 26 and 52
Like IFX, ADA is effective at maintaining remission
[13]
Week 4 – 40 mg then: Week 26; Week 52
Placebo 17%; 12%
ADA 40 mg every other week
40%; 36%
ADA 40 mg weekly 47%; 41%
ADHERE 40 mg every other week or 40 mg weekly
23% Steroid-free remission at year 3
Open-label extension of CHARM: patients on steroids at the beginning of CHARM were randomized to ADA and followed up to 3 years. This study showed long-term steroid-sparing efficacy of ADA
[40]
Certolizumab
PRECISE-2 All; elevated CRP Remission at week 26 (CDAI <150)
Moderate-to-severe CD patients who responded to open-label induction with CZP were included
[48]
Placebo 28%; 26%
CZP 400 mg every 4 weeks
48%; 42%
PRECISE-3 CZP 400 mg every 4 weeks
41%; 12 months Remission (Harvey Bradshaw Index <4) up to 30 months
Continuation of PRECISE-2: only patients in the treatment arm were followed
lymphocytes into the brain and gut by blocking the interaction between the α4 integrin-containing heterodimers, α4β1 and α4β7, and their receptors, vascular cell adhesion molecule-1 and mucosal addressin cell adhesion molecule-1 [71].
The first study examining the use of natalizumab in mild-to-moderate CD by Gordon et al. did not detect any difference in remission rates or a change in CDAI between the natalizumab (a single 3 mg/kg infustion) and placebo groups at week 2 [71]. Neither was there a significant difference in remission rates at 6 weeks in the subsequent multicenter induction trial examining the use of different natalizumab doses in moderate-to-severe CD by Ghosh et al. [72]. However, despite no differences between the treatment and placebo groups at week 6, the natalizumab groups had statistically higher rates of remission and clinical response at week 8 compared with placebo (6 mg/kg: 43%; 3 mg/kg: 41%; and placebo: 16%).
Although the subsequent ENACT-1 trial again demonstrated no differences in remission rates between the natalizumab and the placebo groups (37 vs 30%) at week 10, a post hoc analysis showed that patients with an elevated CRP had a statistically signifi-cant response and remission rates as compared with placebo [73]. ENACT-2 randomized patients who responded to natalizumab at week 10 to either natalizumab or placebo every 4 weeks for a total of 56 weeks. This trial showed a statistically significant sustained clinical response in the natalizumab group as compared with placebo at 56 weeks (61 vs 28%) [73].
ENCORE examined the efficacy of natalizumab in patients with objective signs of inflammation. It enrolled 509 moderate-to-severe CD patients with elevated CRPs and CDAI between 220 and 450 [74]. In this multicenter, randomized, double-blind, placebo-controlled trial, clinical response by week 8 occurred in 48% of patients, whereas remission at week 12 occurred in 38% of treated patients (compared with 32 and 25% in the placebo group, respectively). Natalizumab is currently approved in the USA as monotherapy for moderate-to-severe CD for patients with biological evidence of disease activity who have failed to respond to conventional therapy and at least one anti-TNF agent.
VedolizumabAs opposed to the antibodies directed against α4 integrin, ved-olizumab is a humanized monoclonal antibody that specifi-cally blocks α4β7 integrin found on the cell surface of a small population of circulating T lymphocytes [75]. Since the major ligand for α4β7, mucosal addressin-cell adhesion molecule 1, is selectively expressed on the endothelium of the intestinal vasculature, blockade of this interaction is expected to reduce transmigration of pathogenic T cells into the gut, thereby reduc-ing mucosal inflammation. In addition, since vedolizumab is a selective inhibitor of α4β7, it does not impair lymphocyte trafficking to the brain and, therefore, may avoid the risk of JC virus reactivation. Two randomized, placebo-controlled, Phase II trials have demonstrated the efficacy of vedolizumab in inducing remission in patients with UC and CD. In the CD trial, 185 CD patients were randomized to receive 0.5 mg/kg
of the drug, 2 mg/kg of the drug or placebo on days 1 and 29 of the study [76]. The proportion of patients who achieved clini-cal remission at day 57 was 37, 30 and 21% in each respective group. In the UC trial, 181 patients were randomized to receive 0.5 mg/kg of the drug, 2 mg/kg of the drug or placebo on days 1 and 29 of the study [75]. The primary outcome was clinical remission at week 6. Remission rates were 33, 32 and 14% in the 0.5 mg/kg, 2 mg/kg and placebo groups, respectively. The rates of endoscopic remission were significantly greater in both drug groups as compared with placebo. Human anti-human antibodies (HAHA) developed in 44% of patients: 11% in the 2 mg/kg group and 38% in the 0.5 mg/kg group. Those patients who tested negative for HAHA or had lower antibody titers had higher remission rates (42%), which was associated with satu-rated α4β7 binding sites on T lymphocytes. Higher antibody titers were associated with unsaturated α4β7 binding sites and remission rates similar to placebo. These data suggest that the use of higher initial doses of vedolizumab may reduce the risk of sensitization.
In the original two studies, patients received an earlier ver-sion of vedolizumab derived from NS0 mouse myeloma cell line. In the attempt to reduce immunogenicity, a new formulation of vedolizumab was developed in a Chinese hamster ovary (CHO) cell line. This formulation was tested in UC patients in a Phase II randomized controlled trial [77]. This trial also tested higher doses of the drug: 2, 6 and 10 mg/kg. Forty six patients were enrolled in the study. HAHA antibodies were detected in four patients (11%), a rate of incidence that was significantly lower than observed with the older preparation. The three drug doses tested in this study were associated with maximally saturated α4β7 receptors over the tested dose range.
Recently, results from a multicenter, double-blind, randomized Phase III trial, GEMINI I, evaluating the efficacy of inducing and maintaining remission with vedolizumab in patients with moderate and severe UC who were both anti-TNF naive and anti-TNF failures, were presented [78]. The primary outcome of the induction phase was clinical response at 6 weeks. This end point was met by 47% of patients in the vedolizumab group versus 25% in the placebo group; clinical response was sustained in 57% of patients in the vedolizumab group at week 52 versus 24% in the placebo group. Clinical remission, a secondary end point of the induction phase and a primary end point of the maintenance phase, was achieved in 17% of patients in the vedolizumab group versus 5% in the placebo group and was sustained at 52 weeks in 42% of patients in the vedolizumab group versus 16% in the placebo group. Mucosal healing, another secondary end point, was observed in 41% of vedolizumab patients at 6 weeks and 52% of vedolizumab patients at 52 weeks (vs 25 and 20% placebo rates, respectively). Thus, it appears that vedolizumab is more effective than placebo in inducing and maintaining remission in patients with moderate-to-severe UC who are both anti-TNF exposed and naive. Of importance, no cases of demyelination have been reported with the use of vedolizumab to date. Therefore, it may become a first-line biologic therapy for UC in light of its efficacy and safety profile.
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Newer agentsAdhesion molecule antagonistsLymphocytes migrate to the gastrointestinal mucosa by utiliz-ing gastrointestinal homing receptors, integrin α4β7 and the chemokine receptor CCR9 [79]. In addition to vedolizumab, a selective inhibitor of α4β7, a human monoclonal anti-β7 integ-rin antibody, rhuMAb β7 or etrolizumab, was recently tested in a double-blind, randomized within cohort, placebo-controlled Phase I trial to evaluate its efficacy in patients with moderate-to-severe UC [80]. Patients were followed for 71 days: clinical response was observed in 12 out of 18 Etrolizumab and four out of five placebo patients, whereas remission was observed in three out of 18 Etrolizumab and one out of five placebo patients. The drug was well tolerated. Etrolizumab is currently under-going Phase II testing. In addition, a new human monoclonal antibody against α4β7, AMG 181, is undergoing a randomized, double-blind, placebo-controlled Phase I trial for patients with mild-to-moderate UC [79].
CCR9 is a chemokine receptor expressed during the process of homing in the small intestine [81]. Recently, a potent antagonist of CCR9, CCX282, was developed and tested in Phase II trials for moderate-to-severe CD patients [81]. CCX282, or Traficet-EN, is a small molecule that is orally bioavailable and is, therefore, an attractive alternative to other biologic agents that require either intravenous or subcutaneous administration. The largest multi-center, double-blind, placebo-controlled Phase II clinical trial, PROTECT-1, was conducted in 436 patients with moderate-to-severe CD. A 12-week induction period was followed by a 4-week open-label active period. Patients who had achieved response were re-randomized to drug and placebo for an additional 36-week maintenance period. Traficet-EN was effective in inducing clini-cal response (CDAI reduction of >70 points from baseline) over both, the induction and maintenance period; however, the results have not been fully published yet. Traficet-EN was well toler-ated and holds promise as a new effective oral biologic agent for CD. The PROTECT-1 trial is currently being followed by an open-label extension Phase III trial, SHIELD-3.
Proinflammatory cytokine blockadeOther biologic therapies aim to reduce pathogenic T-cell activa-tion and its effects by inhibiting the actions of proinflammatory cytokines. Ustekinumab is a recently developed fully human IgG1 monoclonal antibody against the p40 subunit shared by IL-12 and IL-23 [5]. IL-12 induces the differentiation of naive CD4+ T cells into Th1 cells, while IL-23 induces the differentiation of naive CD4+ T cells into Th17 cells [5]. Both IL-12 and IL-23 have been implicated in the pathogenesis of CD [4]. In a randomized, pla-cebo-controlled, Phase IIa induction trial, Sandborn et al. studied two populations of patients: population one consisted of mod-erately-to-severely active CD patients, both naive and previously exposed to infliximab therapy, while population two consisted exclusively of primary and secondary infliximab nonresponders [5]. The primary end point, clinical response at 8 weeks, defined as a reduction of 25% or more than 70 points from a baseline CDAI, was not achieved in population one. However, patients
in population two did achieve a statistically higher response rate at week 8 compared with placebo when the drug was adminis-tered via the intravenous route (54 vs 40%). A follow-up on this study, a Phase IIb trial on the efficacy and safety of ustekinumab in moderate-to-severe CD, was recently presented at Digestive Diseases Week [82]. Five hundred and twenty six patients, half of whom were anti-TNF failures, were randomized to receive 1, 3 or 6 mg/kg intravenous of ustekinumab or placebo. At week 8, 18% of patients in the 6 mg/kg group showed clinical response as defined by a 100-point decline in CDAI from baseline, as compared with a 10% response rate in the placebo group. The responders were then re-randomized to receive 270 mg subcutane-ously or placebo at week 8 and 90 mg subcutaneously or placebo at week 16. Patients were followed through week 22. At the end of the study period 69% in the treatment group versus 42% in the placebo group showed a clinical response and 41 versus 27%, respectively, were in remission. Adverse events were similar in the treatment and placebo groups. Thus, ustekinumab may become a therapeutic option for patients who fail anti-TNF therapy.
Recently, an oral inhibitor of Janus kinases 1, 2 and 3, tofaci-tinib, underwent testing in a double-blind, placebo-controlled Phase II trial and proved to be efficacious in inducing clini-cal response at 8 weeks in patients with moderately-to-severely active UC [83]. Tofacitinib is expected to block signaling involving gamma chain-containing cytokines, such as IL-2, IL-4, IL-15 and IL-21, thus interfering with lymphocyte activation, function and proliferation. A dose–response was observed in this Phase II trial: at 8 weeks, 78% of patients receiving the highest dose of 15 mg twice daily had a clinical response (a drop in the Mayo score by 3 points or a relative decrease from baseline of 30%) compared with a 42% placebo response rate, whereas clinical remission occurred in 41% of patients receiving the highest dose of the drug com-pared with a 10% placebo remission rate. Further studies are needed to assess the long-term efficacy and safety of tofacitinib.
In addition, monoclonal antibodies against the following pro-inflammatory cytokine targets have been developed: α-chain (CD25) of the IL-2 receptor, IFN-γ, IL-6, IL-6 receptor, IL-13, IL-17, IL-18 and IL-22. Unfortunately, antibodies against both IL-2R and IFN-γ failed to show benefit over placebo in inducing remission in patients with UC and CD, respectively [84,85]. The other monoclonal antibodies against proinflammatory cytokines are entering Phase I trials.
SafetySince biologic therapies target factors involved in immuno-surveillance, concerns over safety exist. The most important adverse events are infection, malignancy, infusion reactions, demyelinating disease and induction of autoimmunity. This sec-tion will briefly discuss the more commonly encountered adverse events and safety monitoring concerns. Substantial reviews of this topic exist in other publications [86].
InfectionWhile the rheumatology literature suggests a threefold increase in the risk of serious infections in patients receiving 10 mg/kg of
Expert Rev. Clin. Immunol. 9(1), (2013)88
Review Denmark & Mayer
IFX, serious infections were similar between the anti-TNF and control groups in a pooled analysis of 21 IBD trials [87]. Similarly, in placebo-controlled trials with natalizumab, no increase in seri-ous infections was observed [74]. The risk of opportunistic infec-tions, however, is significantly increased, particularly in patients on two or more immunosuppressive medications, such as biolog-ics, immunomodulators and steroids [88]. Much of the increased risk is driven by the use of corticosteroids. The risk of reactiva-tion of tuberculosis is significantly increased in patients receiving anti-TNF therapy and all patients should undergo screening for latent TB [89]. Invasive fungal infections and listeriosis have been reported following IFX, usually in the setting of concomitant immune suppression [90].
Reactivation of latent JC virus infection causes progressive multi focal leukoencephalopathy (PML), a demyelinating disorder associated with a blockade of lymphocyte trafficking in the brain [91]. PML was originally reported in three patients treated with natalizumab for CD or multiple sclerosis [92,93], with a resulting estimated risk of PML 1:1000 in patients treated with natali-zumab. A more recent review of patients with multiple sclerosis reported 212 cases of PML among 99,571 patients treated with natalizumab as of 29 February 2012 with a revised estimated risk of PML 2.1:1000 [94]. Only a single case of PML/JC virus reactiva-tion has been reported in the CD population to date [93]. Recently, a serologic test for JC virus has been developed: all cases of natal-izumab-associated PML were observed in patients with a positive JC serology [95]. A separate retrospective review of PML cases identified three risk factors for JC virus reactivation: the presence of anti-JC virus antibodies, prior use of immunosuppressants and an increased duration of natalizumab treatment (25–48 months) [94]. On the basis of these data, all patients who are being consid-ered for natalizumab therapy should undergo serological testing for anti-JC antibodies prior to therapy initiation.
Non-Hodgkin’s lymphomaIn a meta-analysis of 26 clinical trials, cohort studies or case series, the observed rate of non-Hodgkin’s lymphomas was three-fold higher in CD patients treated with anti-TNF agents than expected from cancer-registry data [96]. The majority of patients who developed non-Hodgkin’s lymphomas were receiving com-bination therapy with anti-TNF therapy and thiopurines. Thus, it is difficult to estimate the risk of non-Hodgkin’s lymphomas attributable to anti-TNF therapy alone.
Infusion reactions & autoimmunityInfusion reactions have been observed with IFX and NAT. Acute infusion reactions occur in 2–3% but are more common in those who develop anti-drug antibodies [18]. The ACCENT-I trial reported the rate of infusion reactions with IFX to be 16% among patients positive for anti-IFX antibodies, compared with 8% in those who were antibody negative. Even higher rates of infu-sion reactions in patients positive for anti-IFX anti bodies have been reported [24]. Infusion reactions have also been associated with antibodies to natalizumab (19–45% in antibody positive vs 7–9% in antibody negative group) [73,74]. In addition, numerous
autoimmune diseases are associated with anti-TNF therapy, such as cutaneous leukocytoclastic vasculitis, poly arteritis nodosa, lupus-like syndrome, systemic lupus erythematosus, peripheral neuropathy and antiphospholipid syndrome; however, these complications are very rare [97].
Skin lesionsEczematoid skin lesions, ranging from dry itchy skin to psoriasis-like eczema and palmoplantar pustulosis, are an emerging prob-lem in patients treated with anti-TNF agents, affecting up to 20% of patients. These can usually be helped by topical therapy, but drug discontinuation is occasionally required [88].
Expert commentary & five-year viewThe last 15 years have given rise to tremendous advances in the treatment for IBD. Currently, the field has a number of effica-cious monoclonal antibody treatments to help achieve a clinical response and induce and maintain remission. However, the opti-mal timing for the use of these medications in the treatment of IBD needs to be determined. Recent studies have indicated that starting biologic therapy early in the course of the disease and tar-geting the population of patients with the most aggressive disease phenotype is beneficial for long-term disease control. However, the clinical predictors of disease behavior are not always sensi-tive or specific markers of prognosis. Better pathogenesis-driven markers are needed to risk-stratify patients into the aggressive and nonaggressive phenotypes. Familial association studies with multiple affected family members may help identify genetic loci predisposing to an aggressive disease behavior. The identification of the dominant inflammatory pathway(s) prior to or at the time of diagnosis would allow for the individualized tailoring of thera-peutic options. In addition, new serologic and mucosal markers are likely going to identify postoperative CD patients at a high risk for disease recurrence, which would spare low-risk patients exposure to biologic therapies and afford high-risk patients the best available postoperative prophylaxis.
While biologic therapy provides the best chance at mucosal healing and long-term disease control, it is associated with high cost and potential side effects. It is still unclear whether stopping biologic therapy is a viable option for patients in remission and if it is, when it is safe to stop this therapy. Recent studies have indicated that in the select group of patients with no objective evidence of inflammation, stopping biologic therapy does not affect long-term remission rates. However, approximately half of patients in deep remission require reinstitution of biologic therapy after anti-TNF drug cessation. Therefore, new serologic and mucosal markers could help identify those patients who do not require long-term biologic therapy.
The future of biologic therapy in IBD lies not only in the dis-covery of new biological agents, but also in the refinement of use of the existing agents, thereby optimizing monitoring and dosing strategies, incorporating predictive markers into clinical practice and defining the appropriate end points of treatment in an attempt to maximize biologic efficacy and limit unnecessary exposure.
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Financial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes
employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
Key issues
• Anti-TNF monoclonal antibody treatment has been shown to be effective for the induction of clinical remission and endoscopic healing in patients with Crohn’s disease and ulcerative colitis as well as for the closure of fistulous tracts in Crohn’s disease patients.
• Patients with objective signs of inflammation (elevated CRP, mucosal lesions) have higher response rates to biologic agents than do patients without these signs.
• Anti-TNF trough drug levels predict clinical response and may be incorporated into clinical practice to guide drug dosing.
• A greater inflammatory burden in patients with ulcerative colitis may require higher induction and maintenance anti-TNF doses to achieve clinical response and remission.
• Patients who lose response to one anti-TNF agent often respond to a second and even a third anti-TNF agent (albeit with reduced response to additional anti-TNFs).
• Elective switching from one anti-TNF agent to another is not recommended as approximately half of these patients fail the second anti-TNF agent.
• Inhibitors of the leukocyte infiltration process have been found to induce clinical remission and response in Crohn’s disease and ulcerative colitis.
• It is still unclear whether biologic therapy can be stopped and if so, what the clinical parameters that should guide discontinuation of biologic therapy are.
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