The therapeutic approach in inflammatory bowel disease has evolved to target end-organ inflammation to heal intestinal mucosa and avoid structural damage. Objective therapeutic monitoring is required to achieve this goal. Earlier intervention with biologic therapy has been shown, indirectly, to be associated with higher clinical response and remission rates. A personalized approach to risk stratification with consideration of key clinical factors and inflammatory biomarker concentrations is recommended when deciding whether or not to start a patient on biologic therapy.
Key points
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The therapeutic approach in inflammatory bowel disease has evolved to target end-organ inflammation to heal intestinal mucosa and avoid structural damage. Objective therapeutic monitoring is required to achieve this goal.
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Earlier intervention with biologic therapy has been shown, indirectly, to be associated with higher clinical response and remission rates.
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A personalized approach to risk stratification with consideration of key clinical factors and inflammatory biomarker concentrations is recommended when deciding whether or not to start a patient on biologic therapy.
Background
Inflammatory bowel diseases (IBDs) are a group of incurable, complex, polygenic diseases of the gastrointestinal tract characterized by chronic, relapsing course of intestinal inflammation. IBD is thought to arise from an aberrant mucosal immune response to luminal antigens in the context of predisposing genetic risk factors and environmental exposures. A loss of tolerance to resident microbial flora is considered to be a central event, which triggers a complex cascade of innate and adaptive immune responses leading to intestinal damage. IBD is subclassified into 2 major diagnoses: Crohn disease (CD) and ulcerative colitis (UC). This classification is made on the basis of clinical, endoscopic, and pathologic criteria. Although this classification maintains relevance for purposes of clinical decision-making related to medical and surgical management of patients with IBD, it has become apparent that such a crude classification is an oversimplification of this complex disease process with overlapping genetic, and immunopathogenic, processes. These processes result in varied phenotypic expressions of disease. Immune mechanisms in UC and CD have been shown to be somewhat distinct and classified based on the type of T helper cells involved and the cytokines they produce. CD is generally considered to be a Th1 disease (with greater expression of interferon [IFN]-γ and interleukin [IL]-2, as well as the Th1-inducing cytokine IL-12), and UC an atypical disease with expression of both Th1 and Th2 cytokines (IL-5, IL-13, IFN-γ, and no upregulation of IL-4). The observed efficacy of anti–tumor necrosis factor-α (TNF-α) therapies in UC further erodes the traditional Th1/Th2 paradigms in IBD. Non-Th1/Th2 pathways also have been identified as being important in the pathogenesis of IBD, including Th17 cells, which produce large quantities of IL-17 (production is upregulated in both CD and UC ) and are induced by IL-23.
In the absence of adequate disease control, the chronic inflammatory process of IBD can lead to significant infectious, inflammatory, and structural complications. These complications could result in the need for hospitalizations and surgeries, impaired quality of life, and, in more severe instances, disease-related mortality. In the era before biologic therapy was available, a population-based cohort study of patients with CD demonstrated that the rate of hospitalization owing to medical complications, the need for surgery, or both was 194 admissions per 1000 patient-years, and the cumulative surgery rate in the first 10 years after a diagnosis was 40% to 50%. Recent population-based studies estimate colectomy rates in those with UC 20 years after diagnosis of 14.8%. At any time, extraintestinal manifestations can affect up to one-third of patients. In the case of CD, approximately 30% of patients will have a stricturing or penetrating complication at presentation and half of all patients will experience an intestinal complication within 20 years, often leading to the need for surgical intervention. Persistent and extensive colonic inflammation in UC or CD and ileal inflammation in CD also increase the risk of developing colorectal and small bowel carcinoma.
Background
Inflammatory bowel diseases (IBDs) are a group of incurable, complex, polygenic diseases of the gastrointestinal tract characterized by chronic, relapsing course of intestinal inflammation. IBD is thought to arise from an aberrant mucosal immune response to luminal antigens in the context of predisposing genetic risk factors and environmental exposures. A loss of tolerance to resident microbial flora is considered to be a central event, which triggers a complex cascade of innate and adaptive immune responses leading to intestinal damage. IBD is subclassified into 2 major diagnoses: Crohn disease (CD) and ulcerative colitis (UC). This classification is made on the basis of clinical, endoscopic, and pathologic criteria. Although this classification maintains relevance for purposes of clinical decision-making related to medical and surgical management of patients with IBD, it has become apparent that such a crude classification is an oversimplification of this complex disease process with overlapping genetic, and immunopathogenic, processes. These processes result in varied phenotypic expressions of disease. Immune mechanisms in UC and CD have been shown to be somewhat distinct and classified based on the type of T helper cells involved and the cytokines they produce. CD is generally considered to be a Th1 disease (with greater expression of interferon [IFN]-γ and interleukin [IL]-2, as well as the Th1-inducing cytokine IL-12), and UC an atypical disease with expression of both Th1 and Th2 cytokines (IL-5, IL-13, IFN-γ, and no upregulation of IL-4). The observed efficacy of anti–tumor necrosis factor-α (TNF-α) therapies in UC further erodes the traditional Th1/Th2 paradigms in IBD. Non-Th1/Th2 pathways also have been identified as being important in the pathogenesis of IBD, including Th17 cells, which produce large quantities of IL-17 (production is upregulated in both CD and UC ) and are induced by IL-23.
In the absence of adequate disease control, the chronic inflammatory process of IBD can lead to significant infectious, inflammatory, and structural complications. These complications could result in the need for hospitalizations and surgeries, impaired quality of life, and, in more severe instances, disease-related mortality. In the era before biologic therapy was available, a population-based cohort study of patients with CD demonstrated that the rate of hospitalization owing to medical complications, the need for surgery, or both was 194 admissions per 1000 patient-years, and the cumulative surgery rate in the first 10 years after a diagnosis was 40% to 50%. Recent population-based studies estimate colectomy rates in those with UC 20 years after diagnosis of 14.8%. At any time, extraintestinal manifestations can affect up to one-third of patients. In the case of CD, approximately 30% of patients will have a stricturing or penetrating complication at presentation and half of all patients will experience an intestinal complication within 20 years, often leading to the need for surgical intervention. Persistent and extensive colonic inflammation in UC or CD and ileal inflammation in CD also increase the risk of developing colorectal and small bowel carcinoma.
The evolution of biologic therapy for IBD
Until fairly recently, the only biologics available for use for the treatment of IBD belonged to the anti–TNF-α class. The first anti–TNF-α therapy demonstrated to be efficacious for the treatment of IBD was infliximab (a chimeric monoclonal antibody that specifically binds TNF-α and was initially evaluated in CD). Over time, attempts to humanize the monoclonal antibody to reduce immunogenicity led to the development of second-generation, third-generation, and fourth-generation anti–TNF-α agents (including adalimumab, certolizumab pegol, and golimumab). All of these anti–TNF-α agents have been demonstrated to be efficacious for the induction of clinical response, remission, maintenance of clinical remission, corticosteroid sparing, and mucosal healing in subjects with moderate to severely active IBD, including CD (infliximab, adalimumab, and certolizumab pegol) and UC (infliximab, adalimumab, and golimumab). Infliximab also has been shown to be efficacious for the therapy of fistulizing CD, and both infliximab and adalimumab for the prevention of early postoperative endoscopic and histologic recurrence. Post hoc analyses also have suggested that infliximab reduces the 1-year colectomy rate in UC from 17% in the placebo group to 10% in the infliximab-treated group. Despite the proven benefit of these therapies, a significant number of patients with CD (ie, 10% to 40%) will not respond to this class of biologic; this is otherwise referred to as primary treatment failure. Among patients with UC, this number could be as high as 50%. Additionally, only one-third to one-half of patients will have a complete remission, and two-thirds of patients will fail to maintain their response during 12 months of sustained therapy. The inability to maintain response to a biologic is termed secondary treatment failure. Despite these observed limitations in primary and durable response to anti–TNF-α therapies, they remain one of the most well tolerated and effective therapies at our disposal for the therapy of IBD.
The most recent biologic class to demonstrate efficacy and safety in phase 3 clinical trials are the lymphocyte trafficking inhibitors. Natalizumab (a humanized immunoglobulin G4 anti–α4-integrin monoclonal antibody that inhibits both α4β7-integrin/MAdCAM-1 interaction and α4β1-integrin/VCAM-1 binding) was the first in this class to be developed. Natalizumab was shown to be effective for induction and maintenance of clinical remission in the Efficacy of Natalizumab as Active Therapy of CD (ENACT-1 and ENACT-2) trials. Its efficacy as a corticosteroid-sparing agent was made evident because all subjects in the ENACT-2 study were able to be withdrawn from corticosteroid therapy. Natalizumab has been demonstrated in randomized controlled clinical trials to be efficacious for the therapy of multiple sclerosis (MS) as well. Despite these early and encouraging results, it was discovered, after natalizumab came to market, that it increased the risk of the development of a serious central nervous system infection called progressive multifocal leukoencephalopathy (PML). PML is a potentially fatal opportunistic infection that arises as a result of reactivation of the clinically latent John Cunningham (JC) polyomavirus. Two patients with MS and 1 patient with CD exposed to natalizumab developed PML within the context of the original clinical trials. These cases, as well as cases reported through postmarketing surveillance after release of the medication, lead the Food and Drug Administration (FDA) to withdraw the medication from the market temporarily. It has since been approved for use in the United States by the FDA for the treatment of MS and CD, with a black box warning about the risk of PML with a mandatory prescribing program and recommended JC virus antibody testing (product monograph). A similar approach for MS has occurred in Canada but not for CD. A second-generation lymphocyte-trafficking inhibitor, vedolizumab, appears to be highly gut selective. Vedolizumab is a α4β7 integrin antagonist that has recently been shown to be efficacious for the induction and maintenance of steroid-free clinical remission in both CD and UC. Vedolizumab specifically blocks α4β7 integrin/MAdCAM-1 interactions. In CD, 14.5% of patients randomized to vedolizumab at week 6 attained a CDAI-defined clinical remission (CDAI <150) in comparison with 6.8% of those randomized to placebo. Responders were then re-randomized to receive vedolizumab every 4 weeks or 8 weeks and followed until week 52. Thirty-nine percent and 36.4% of patients receiving vedolizumab every 8 weeks and 4 weeks, respectively, were in clinical remission at week 52, as compared with 21.6% of those assigned to placebo. Similarly, in UC, week 6 clinical response rates were 47.1% and 25.5% in patients receiving vedolizumab induction versus placebo, respectively. At week 52, 41.8% and 44.8% of patients receiving vedolizumab every 8 weeks and 4 weeks, respectively, were in clinical remission (Mayo score ≤2 with no endoscopic subscore >1), as compared with 15.9% of those receiving placebo. Although more biologics have been developed, and are being developed, we still grapple with the fairly underwhelming clinical response and remission rates observed in anti–TNF-α induction and maintenance trials and real-world clinical practice. Several factors may contribute to limitations in efficacy observed in clinical trials. It is possible that subject selection was unfavorable in earlier randomized controlled trials (RCTs) of anti–TNF-α therapy from the perspective of disease duration and disease activity. Certainly, mean and median duration of disease was substantially longer than that of clinical trials, such as SONIC, in which the highest rates of steroid-free clinical response and remission for infliximab-treated subjects have been observed to date. Clinical trials of IBD have historically been plagued by high placebo-response rates, partly as a result of the enrollment of patients who lack true inflammatory disease. Instead, alternate disease processes, such as superimposed irritable bowel syndrome, may have resulted in higher clinical disease activity scores. Over the past several years, a movement toward incorporation of objective measures of disease activity, such as colonoscopy or serum/fecal inflammatory biomarkers, has taken place to minimize enrollment of patients who lack active intestinal inflammation.
Consequently, it is hypothesized that the initiation of therapies earlier in disease course, the use of immunosuppressive (IS) and biologic therapies only in individuals with active inflammatory disease, and the optimization of therapies based on the use of objective measures of inflammatory disease activity may enhance the effectiveness of IBD biologic therapy for our patients.
Evolution of disease monitoring and goals of therapy
Evidence has accumulated suggesting that patients should be treated with the goal of achieving mucosal healing (MH) rather than simply improvement in clinical symptoms or clinical response with a view to reducing disability and bowel damage. This concept of “deep remission” (combined clinical, endoscopic, and biomarker-based remission) is based on the presumption that mucosal healing and inflammatory biomarkers are adequate surrogate markers of end-organ disease. Although there is ample indirect evidence that treating to mucosal healing is associated with reductions in disease relapse as well as improvements in long-term disease-related outcomes, such as the need for hospitalizations and surgeries, no direct randomized controlled evidence exists to support this practice. Additionally, no definition of mucosal healing has been validated, and definitions of MH may vary from study to study. To date, only the EXTEND (extend the safety and efficacy of adalimumab through endoscopic healing) trial has attempted to address the concept of “deep remission” as a goal of therapy for IBD. The EXTEND trial showed that subjects achieving deep remission were more likely to have improved disease-specific quality of life, have fewer disease flares, fewer CD-related hospitalizations, greater work productivity, and less activity impairment compared with subjects with mucosal healing alone. Frøslie and colleagues from Norway demonstrated in a population-based inception cohort study that, in UC, MH was associated with a reduced future risk of colectomy, and that, in CD, MH was associated with reduced disease activity after 5 years, as well as reduced future need for corticosteroids. Despite these findings, definitions of disease remission need to be validated in disease modification trials. Not only have treatment definitions evolved to include more rigorous, objective end points of disease control, but therapeutic goals also have evolved to include the evaluation of structural bowel damage and avoidance of IBD-related disability.
The approach to the medical therapy of IBD has evolved rapidly over the past decade as a result of changing treatment goals, as well as new breakthroughs related to the understanding of disease pathogenesis, disease course, and the introduction of more than one class of biologic therapy. Traditional therapeutic paradigms have focused on stepwise, sequential introduction of therapies of differing mechanisms beginning with the least expensive, least systemically active medications and gradually intensifying therapy. This approach has historically been applied across the board to all patients regardless of their clinical and phenotypic features. Improvements in our ability to predict which individuals with IBD are likely to experience an aggressive disease course, along with the development of a larger number of therapeutic options, has led to a paradigm shift in our approach to IBD. Rather than applying a one-size-fits-all approach, we are moving toward a model of personalized medicine based on risk stratification in an effort to modify disease course. A new term has been coined to convey the role of medication therapy for the attainment of this new treatment goal; a term that reflects the philosophy of our rheumatology colleagues. IS and biologic therapies in IBD are now referred to as disease-modifying anti-IBD drugs (DMAIDS). The concept of pursuing a more accelerated step approach to the treatment of individuals at greatest risk for a disabling disease course and intervening with DMAIDs at an earlier time point for these individuals has been embraced by many.
The case for earlier medication intervention in IBD
The case for earlier intervention with biologic therapy in IBD is supported from observational, subgroup analyses and RCT data in both the adult and pediatric patient populations ( Table 1 ). RCTs in both adult and pediatric populations, including patients with shorter IBD disease duration (mean 2 years), have demonstrated clinical response and remission rates that are higher than historically observed rates among clinical trial populations with longer disease duration and previous exposure to IS or biologic agents. In the REACH study, pediatric patients with moderate to severely active CD were treated with an open-label 3-dose induction regimen of infliximab, and week 10 responders were re-randomized to infliximab infusion every 8 weeks or 12 weeks. A larger proportion of patients assigned to infliximab every 8 weeks, versus every 12 weeks, were in clinical response or remission. The clinical response rates were 73.1% and 63.5% at 30 and 54 weeks, respectively. The SONIC trial was a randomized controlled double-blind trial in which the efficacy of infliximab monotherapy, azathioprine monotherapy, and the 2 drugs in combination were compared in a population of adult subjects with moderate to severely active CD who were naive to both IS and biologic therapies. The primary end point of corticosteroid-free clinical remission at week 26 was significantly higher in the combination group in comparison with either the infliximab or azathioprine monotherapy group (56.8%, 44.4%, and 30%, respectively). Similar results were observed at week 50. In addition to clinical remission, mucosal healing at week 26 was significantly better in the group receiving combination therapy in comparison with either monotherapy group alone (43.9%, 30.1%, and 16.5%, respectively). Significant differences in the rate of development of serious infections were not observed among the 3 treatment groups.
| Author, Year | Agent | Study Design | Disease Duration Before Medication | Efficacy Estimate |
|---|---|---|---|---|
| Löfberg et al, 2012 | Adalimumab | Open-label phase IIIb | 7.8 a y | Odds of clinical remission decreases by a factor of 0.96 (0.94–0.98) per unit increase in disease duration (y) |
| Schreiber et al, 2010 | Certolizumab | Post hoc analysis of a randomized, double-blind (Schreiber et al, 2007) | <1 y | Clinical remission (68.4%) and response (89.5%) among those with <1 y vs 57.3% and 44.3% among ≥5 y |
| Colombel et al, 2010 | Infliximab ± azathioprine vs azathioprine | Randomized, double-blind | 2.3 a y | Steroid-free clinical remission Combination: 56.8% Azathioprine: 30% Infliximab: 44.4% |
| D’Haens et al, 2008 | Infliximab/azathioprine | Open-label randomized early combined immunosuppression vs conventional treatment | 2 a y | Clinical remission Absolute difference 19.4% ( P = .03) |
| Hyams et al, 2007 | Infliximab | Randomized, open-label Pediatric subjects | 1.6 a y | Clinical response 88.4% and clinical remission 58.9% b |
| Hanauer et al, 2002 | Infliximab | Randomized, double-blind | 7.9 a y | Clinical remission and response Median disease duration 7.5 vs nonresponders 9.3 |
Related posts:
Anti–Tumor Necrosis Factor-α Monotherapy Versus Combination Therapy with an Immunomodulator in IBD
Update on Anti-Tumor Necrosis Factor Agents in Crohn Disease
Pharmacokinetics of Biologics and the Role of Therapeutic Monitoring
Biologics of IBD
The Use of Biologic Agents in Pregnancy and Breastfeeding
Update on Janus Kinase Antagonists in Inflammatory Bowel Disease
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