Inflammatory bowel disease (IBD) describes relapsing remitting chronic inflammation of the gastrointestinal tract. Clinically, ulcerative colitis (UC) and Crohn’s disease (CD) are commonly encountered and account for significant morbidity globally, particularly in the Western world.1–3 Recently, it has been shown that the incidence of IBD is increasing worldwide, with the highest prevalence in Europe and North America.4 The current paradigm for the pathogenesis of IBD revolves around the interplay between dysbiosis of the colonic microbiota, failure in epithelial barrier function, and disordered inflammatory response in the underlying mucosa, in genetically susceptible individuals, all potentially influenced by environmental lifestyle factors.5,6 Despite the use of immunosuppressive drugs and emergence of biologic therapy for the treatment of IBD, there remains a significant cohort of patients with refractory or relapsing disease and those who cannot tolerate currently available medical therapy. In addition, existing therapeutic options carry an increased risk of infective and malignant disease.7 Although biologic therapy, in particular, seems to influence disease natural history, at least in the short term with a negative impact on surgical intervention rate, a significant number of patients continue to require surgery as part of their management in the longer term. Anti–tumor necrosis factor (anti-TNF) therapy has revolutionalized the management of IBD and is the classical example of a treatment strategy targeting cytokine signaling in this disease context. The clinical trials reporting efficacy of anti-TNF strategies have been reviewed elsewhere.8–12 Two anti-TNF agents are currently in widespread use worldwide: infliximab and adalimumab, a mouse-human chimeric and fully humanized IgG1 anti-TNF monoclonal antibody, respectively. There is no doubt over their therapeutic benefit, for some but not all patients, with both primary and secondary nonresponse. These molecules are large and elicit immunogenicity with the formation of antibodies that can reduce efficacy over time. In addition, systemic distribution to all tissues confers risk of adverse events, such as infection, lupus-like autoimmunity reactions, skin eruptions, demyelinating central nervous system disease, and hypersensitivity reactions; these occur rarely in practice but long-term safety data are limited. The nature of delivery and associated monitoring comes with a significant financial burden. To overcome some of these issues, new delivery mechanisms for anti-TNF strategies have been developed, such as certolizumab pegol, a pegolated Fab′ fragment10,12 and golimumab,13 a fully humanized anti-TNF agent that can be delivered subcutaneously. The search for alternative treatment options that can achieve remission with mucosal healing, alongside an excellent safety profile at an affordable cost continues.
Within the gastrointestinal mucosa, aberrations in both innate and adaptive immunity have been implicated in the immunopathogenicity of IBD. Cytokines, the soluble mediators of the inflammatory response, are secreted by a myriad of immune cell types and act to control the nature, effectiveness, severity, progression, and persistence of the immune reaction. The interleukins (ILs) are key constituents of the cytokine profile found in gastrointestinal mucosa in IBD and thus have been identified as potential future therapeutic targets. Although there are numerous cytokines, this review aims to evaluate the role of several designated ILs that are implicated in the pathogenesis of IBD and discuss how their manipulation has been explored as a therapeutic strategy for this disease. The ILs chosen for discussion reflect those that currently show most promise as future therapeutic targets, as well as discussing some of the most recently identified ILs, exploring their potential role in IBD and whether they show promise as a druggable target—when considering anti-cytokine strategies in IBD, what lies beyond anti-TNF therapy?
THE “INFLAMMASOME” CYTOKINES—IL-1β, IL-18, AND IL-33
IL-1β is a potent pro-inflammatory cytokine secreted from innate immune cells. It exerts a profound chemotactic role for neutrophil recruitment, stimulates effector innate cells such as dendritic cells and macrophages, and is also involved in the recruitment and activation of the adaptive T-cell response.14–16 As such, it is tightly regulated with co-expression of a natural antagonist (IL1RA) and a complex activating mechanism via the inflammasome. IL-1β is initially translated as the inactive precursor pro-IL1β. The inflammasome, a multiprotein complex, is assembled following cellular and pathogen danger signals, such as ATP, hypoxia, or activation of innate receptors, particularly the NLR family of cytosolic receptors (such as NLRP3 & NLRP6). The inflammasome then activates caspase-1 to cleave pro-IL1β into the active form that is then secreted into the surrounding microenvironment.17 IL-1β has, for more than 2 decades, been known to be expressed at higher levels in colonic biopsies from patients with IBD, produced in increased quantities from mononuclear cells in areas of actively inflamed colonic mucosa,18–21 supporting the hypothesis that it is acting in a pro-inflammatory manner exacerbating disease activity.
In addition, this hypothesis is supported by evidence that animal models of colitis were ameliorated with IL-1 blocking strategies. Cominelli et al22 reported that modulating IL-1 activity via intravenous human recombinant ILRA interrupted the induction and progression of chemically induced colitis in rabbits. A similar efficacy was shown in a rat colitis model23 and knockout of caspase 1, the IL1β converting enzyme, conferred a protective role against murine dextran sodium sulfate (DSS) colitis.24 In addition, elevated IL1β levels that occurred in a transgenic mouse model were associated with hypersusceptibility to colitis induction.25
Most recently, genetic variation in the IL1β gene associated with higher serum levels was linked to a lowered response to biologic therapy in a small cohort of human patients26 and also to steroid dependence in UC,27 suggesting a potential influence on treatment outcome.
There are now 3 Food and Drug Administration–approved therapies clinically available for blocking the IL1 pathway: recombinant IL-1 receptor antagonist (anakinra), a soluble decoy receptor (rilonacept), or monoclonal antibody toward IL-1β (canakinumab). Anakinra was the first of these and has been a moderately successful treatment for rheumatoid arthritis for over 2 decades. The others were developed more recently and are used in a variety of autoimmune and autoinflammatory conditions.28 There are also 8 others in clinical trial, targeted toward systemic inflammatory conditions, such as diabetes, acute ischemia and heart remodeling following infarction, rheumatological conditions such as gout and osteoarthritis, and other lesser known systemic inflammatory conditions, such as Schnitzler syndrome and macrophage activation syndrome. To date, we are not aware of a human trial with any IL1β blocking/modulating agent for IBD.
IL-18, like IL-1β, is a central cytokine of the innate inflammatory response, released in the active form by inflammasome activation. IL-18 acts synergistically with IL-12 to promote interferon-γ production and drive Th1-mediated cell responses. It was previously shown that IL-18 is increased in the gastrointestinal mucosa from patients with CD.29,30 Neutralizing the bioactivity of IL-18 with a recombinant isoform of the naturally occurring antagonist, IL-18–binding protein (IL-18BP), has been tested in mouse IBD models. Treatment ameliorated 2,4,6-trinitrobenzene sulfonic acid (TNBS) murine colitis with reduction in colonic mucosal pro-inflammatory cytokine profile, including TNF and IL-6.31 IL-18BP was also effective in murine DSS colitis,32 and IL-18 antisense messenger RNA was effective in murine T-cell transfer colitis.33
However, the overall role for IL-18 in the pathogenesis of IBD is far from clear. Intriguingly, knockout of IL-18 and its receptor in mice showed enhanced colitis activity in response to DSS treatment.34 Mice genetically lacking NLPR3 inflammasome activity (Nlpr3−/−, caspase-1−/−, or ASC−/−) do not spontaneously develop colitis but have exacerbated disease activity in response to injury with DSS or TNBS. The underlying mechanisms may be multifactorial and involve reduced IL-18 leading to increased epithelial barrier injury and decreased repair, increased bacterial translocation and disordered mucosal inflammatory activity, such as lack of protective IL-10 and TGF-β expression. Treatment with recombinant IL-18 was beneficial in caspase-1−/− mice with DSS colitis. In addition, NLRP3−/− mice showed reduced epithelial expression of antimicrobial factors, such as defensins and reduced macrophage and neutrophil functions.35,36 The specific cellular population producing active IL-18 may have opposing effects in the pathogenesis of IBD. If colonic epithelial cells exhibit inflammasome activation and an increase in IL-18, this may act in a protective fashion through positively influencing restitution of the epithelial barrier, thereby blocking bacterial translocation. In contrast, if the cellular source is myeloid cells of the underlying mucosa, this may act in a pro-inflammatory manner worsening disease activity. Therefore, until IL-18 can be targeted in a specific cell compartment, blocking it therapeutically for intestinal inflammation would seem to be a double-edged sword with potentially deleterious outcomes.
IL-33 is a newer IL-1 family member. Several studies have now shown an increased expression of IL-33 and its receptor, ST2, in human IBD37–41 especially in active UC, at both the gene and protein level in gut mucosa, particularly the epithelial compartment, and serum. As such, it was postulated that this was linked to the classical “Th2” paradigm pathogenesis of UC and the recognized role of IL-33 in enhancing expression of the cardinal type-2 cytokines, IL-4, IL-5, and IL-13 as defense against intestinal helminth infection.42,43 IL-33 is produced by a large array of cell types, including intestinal epithelial cells and gut myofibroblasts in severe active UC.40 Given its nuclear localization and structural similarities to IL-1α and HMGB1, there is debate as to whether IL-33 is better termed a novel “alarmin” released from dead cells rather than acting as a “cytokine” that is actively secreted.44
In experimental IBD in mice, a recent study by Sedhom et al41 showed that IL-33 promoted colonic injury through disruption of epithelial barrier integrity, enhancing permeability, and negatively influencing mucosal wound healing. Indeed, expression of IL-33 was found in TNBS and DSS murine colitis, with receptor deficiency (St2−/−) or the administration of a receptor neutralizing antibody conferring protection. Bone marrow chimeric experiments showed that IL-33 was largely acting on nonhematopoietic cells, possibly enterocytes, promoting injury. As such, the IL-33/ST2 axis has emerged as a potential new therapeutic target in IBD.
IL-6 is a pleiotropic cytokine that has a role in augmenting the innate immune response and molding the adaptive immune response, via the enhancement of T-cell survival. IL-6 also influences epithelial cell growth and proliferation and, along with its anti-apoptotic action, is implicated in the pathogenesis of several malignancies, including colorectal cancer.45,46 IL-6 induces bone catabolism, neoangiogenesis, and is a pivotal activator of the acute phase response by hepatocytes to infection or injury. IL-6 primarily acts through binding to its membrane-bound receptor, IL-6R, with subsequent association to the more ubiquitously expressed gp130 chain that induces signal transduction via Janus kinase (JAK)-mediated STAT-3 phosphorylation. However, IL-6 can also activate downstream action via an alternative pathway that involves binding to a soluble form of the IL-6R; this soluble complex can then act on cell surface gp130, providing a mechanism for activating cells that lack the transmembrane IL-6R chain, termed IL-6 “trans-signaling”.47 It has been long known that IL-6 is increased in the colonic mucosa48–50 and serum51,52 of patients with IBD. It was previously shown that IL-6 serum levels were correlated with disease activity in CD and served as a predictive prognostic biomarker for disease relapse.53–55 Moreover, the circulating levels of IL-6 and other cytokines are decreased after successful treatment with anti-TNF therapy.56 More recently, enhanced IL-6 expression has been linked to early-onset disease in a pediatric population assessed at initial presentation.57
After emergence of these data suggesting that IL-6 expression is central to IBD pathogenesis, there has been successful amelioration of experimental colitis through blocking the activity of this cytokine in animal models. Administration of a monoclonal antibody toward the IL-6 receptor was shown to be efficacious in the treatment of murine TNBS-induced colitis, as well as in IL-10–deficient mice that develop spontaneous colitis and also in SCID mice with CD45RBhigh CD4+ T-cell reconstitution.50 The efficacy of IL-6 blockade with a monoclonal antibody targeted to both the trans-membrane and the soluble IL-6 receptor fractions was also corroborated by Yamamoto et al58 in the murine T-cell transfer model of colitis. In addition, Atreya et al50 also used a therapeutic strategy of a fusion protein comprised of a recombinant gp130 protein fused to the Fc region of human IgG1, specifically to block the IL-6 trans-signaling pathway involving the soluble IL-6 receptor, and this was also successful in treatment of murine colitis in the models outlined above. Indeed, it was found that the majority of the colonic lamina propria T cells in experimental colitis do not express the membranous IL-6R, highlighting the importance of the trans-signaling mechanism in the pathogenesis of IBD. These studies uncovered the underlying mechanism by which IL-6 promotes intestinal inflammation as mediated through its anti-apoptotic action via differential expression of the anti-apoptotic genes, Bcl-xL and Bcl-2, within mucosal T cells. There is also an emerging role for IL-6 in disordered intestinal epithelial barrier integrity. IL-6 expression in the colonic mucosa has been linked to increased expression of claudin-2, a tight junction protein, with pore forming properties.59
Blocking IL-6 has emerged as a promising novel therapeutic approach for IBD. The humanized anti-IL-6 monoclonal antibody, tocilizumab, is available in the clinical arena for the treatment of rheumatoid arthritis and other rheumatological conditions, such as systemic juvenile idiopathic arthritis and Castleman disease. To date, there has been one phase I/II trial of this anti-IL-6 monoclonal antibody therapy in human IBD.60 A small number of patients with active CD were treated with this biologic by 6 separate infusions, administered at 2 or 4 weekly intervals, and compared with placebo. Although 80% (8/10) of the anti-IL-6–treated group reported a clinical response, disappointingly, only 2 patients (20%) entered clinical remission, and there was no difference between groups in endoscopic or histological disease activity reported at the end of the trial period. However, different approaches to IL-6 inhibition have been developed; there is an ongoing phase I human trial assessing a novel approach of IL-6 inhibition in CD61 using an avimer protein (IL-6 avimer formation reviewed by Silverman et al62) and a phase 1 study on the use of gp130-Fc protein for blockade of the sIL-6R (Conaris). Anti-IL-6 therapy offers a potential additional benefit, given the tumor promoting properties of IL-6 and its pivotal role in the development of colonic malignancy, including colitis-associated cancer.46,63 Therapeutically blocking this cytokine is likely to reduce the risk of developing this complication of IBD. Indeed, this has been reported in animal models because IL-6 knockout mice develop fewer colonic tumors in response to DSS/azoxymethane, an established model for colitis-associated cancer.64 In addition, using a strategy of antibody blockade of IL-6 signaling interrupts the development and progression of colorectal malignancy.65,66
IL-27, a heterodimeric cytokine containing the subunits p28 and EBI3, belongs to the IL-12 cytokine family, and signals via interaction with a receptor that comprises the constitutively expressed gp130 along with the specific WSX-1/IL-27ra component. The biology of IL-27 has been reviewed previously67; in summary, IL-27 was originally thought to primarily evoke a pro-inflammatory action mediated by driving Th1 differentiation and expansion.68 Shortly after its discovery, expression of IL-27 was found to be increased in colonic biopsies of patients with IBD, particularly CD69,70 and as such was deemed to be part of the pro-inflammatory milieu driving disease activity. However, over the past decade it has become increasingly clear that IL-27 has a profound anti-inflammatory action, driving differentiation of anti-inflammatory Foxp3-Tr1 regulatory T cells that secrete the central anti-inflammatory cytokine, IL-10.71 In addition, studies on the response to parasitic infection have shown that IL-27 suppresses Th2 effector cell function, and IL27ra-null mice have revealed IL-27 signaling to be engaged in suppression of Th17-driven pathology.72,73
Given this more recent anti-inflammatory role for IL-27, preclinical studies have assessed IL-27 signaling in IBD pathogenesis, to determine whether it would be better to block IL-27, or alternatively to administer IL-27 itself for the treatment of IBD. The first of these studies by Honda et al74 suggested that IL-27 was pro-inflammatory in IBD; although WSX-1/IL27ra-null mice did not develop spontaneous colitis, they had suppressed colitis disease activity in the DSS-induced murine model. Consistent with a pro-inflammatory role, IL27ra-null mice subsequently succumbed to overwhelming Th17-driven intestinal inflammation in DSS-induced colitis and absence of IL-27 signaling influenced the cytokine profile of activated innate cells.75 However, an anti-inflammatory effect was seen when IL-27 itself was assessed as a potential treatment strategy when subcutaneous administration ameliorated TNBS colitis.76 Therefore, the roles for IL-27 for IBD are not clear-cut and there continues to be contradictory evidence emerging in the literature. A recent study reported an exacerbation of colitis driven by IL-27 via suppression of regulatory T-cell subsets.77 Mice with STAT-3 deletion in myeloid cells exhibit a phenotype of spontaneous colitis. Additional deletion of IL-27-p28 led to no difference in disease emergence compared with wild-type both in severity and time to disease onset.78 Our laboratory has shown that oral administration of IL-27 directly to inflamed intestinal mucosa can suppress colitis disease activity in the T-cell transfer murine model79 and acute TNBS-induced disease.80
Many of the studies on IL-27 biology have centered on adaptive immunity but there is emerging evidence that IL-27 can regulate the innate immune response, priming monocyte lipopolysaccharide response with increased pro-inflammatory cytokine expression via upregulation of TLR-481 and also attenuated neutrophil adhesion and reactive oxygen species production.82 In addition, IL-27 has been shown to enhance epithelial proliferation and restitution and promote a differential gene expression profile in a human intestinal epithelial cell line.83 Given that the in vivo inflamed colonic environment contains all of these cellular components, the complexities of IL-27 expression and function is apparent and unraveling the nature of these and how they can be manipulated is continuing.
As the debate regarding the therapeutic potential of IL-27 for IBD continues, a link for IL-27 to the pathogenesis of human IBD has emerged from genome wide association studies on a pediatric population. A study showing a polymorphism in the regulatory region of the p28 gene that renders individuals low producers, increases risk of developing early-onset IBD.84 This supports an anti-inflammatory role for IL-27 in human IBD.
IL-35 was first identified and named in 2007 by Collison et al85 and consists of the EBI3 subunit along with IL12-p35. IL-35 exerts predominantly anti-inflammatory activity, through several mechanisms, namely, suppression of T effector cell proliferation,85 suppression of Th17 cell differentiation,86 and the promotion of an inducible regulatory cell phenotype from naive T cells.85 These regulatory T cells in turn secrete IL-35 that are potently immunosuppressive in vitro and in vivo and named iTr35 cells.87 This mechanism of action, first described in murine models, has now been reported in human studies.88
The complete biological repertoire of this relatively new cytokine is not fully understood, such as how much of this 2-chain cytokine is produced and assembled, by which cells, what cells respond, and what are the signaling pathways? The literature to date on the biology of IL-35 has been reviewed elsewhere.89,90
Clearly, manipulation of IL-35 to take advantage of the anti-inflammatory properties is appealing for therapeutic benefit for a range of inflammatory disorders. Therefore, what is known of this cytokine in IBD? In a murine model of T-cell colitis subsequently rescued with regulatory T-cell (Treg) transfer once disease emerged, the pivotal role of IL-35 to maximize this suppressive function was revealed. Ebi3−/− and p35−/− Treg cells did not fully rescue clinically apparent IBD in this model in contrast to Treg cells expressing both subunits and secreting IL-35.85 However, knock out of p35 resulted in attenuated colitis mediated by intrarectal installation of a haptenating agent, such as TNBS91; however, p35 is also a component of pro-inflammatory IL-12. Mice that spontaneously develop colitis (IL10−/−) exhibit accelerated disease with concomitant knock out of p35.92 This may reflect the lack of IL-35 secretion from regulatory T cells and inhibition of this suppressive mechanism to reach maximal capacity. In another study, mice with depletion of both the EBI3 subunit (depleting both IL-27 and IL-35) developed profound severe colitis compared with p28 alone (sole depletion of IL-27) and wild type, suggesting a central and superior suppressive influence of IL-35 in a number of mouse models of chronic colitis.
Systemic delivery of an IL-35 adenoviral vector inhibited disease activity in both DSS and TNBS colitis models, through a reduction in colonic gene expression of pro-inflammatory cytokines and Th1/Th17-associated transcription factors.78 Therefore, bolstering IL-35 induced anti-inflammatory action for therapeutic gain in IBD may be a promising future therapeutic strategy, either through promoting its production in vivo or via delivery of IL-35 itself.
IL-22, a member of the IL-10 cytokine family, signals via its transmembrane receptor with subsequent JAK/STAT activation.93 IL-22 is secreted from a wide variety of both innate and adaptive inflammatory cells, including natural killer cells, Th17 cells, Th22 cells, and the newly described Type 3 innate lymphoid cell population resident in the intestinal mucosa.93 Based on receptor expression pattern, the primary target cells of this cytokine are nonhematopoietic, mainly epithelial cells at the interface between host and environment, that is, gut, lung, and skin. In IBD, expression of IL-22 is increased in inflamed mucosa, both in UC and in CD.94–99 In addition, patients with CD have increased serum IL-22, the magnitude is related to disease activity and correlate with variants in the IL-23R gene, an IBD susceptibility gene.100
Mouse models of colitis have revealed a potential role of IL-22 in suppressing disease activity. In both T-cell transfer and DSS models of IBD, natural killer cell produced IL-22 was implicated in protection, whereas T-cell IL-22 had no benefit.101 In a TNBS-induced colitis, augmenting colonic IL-22 suppressed disease activity, and this protective effect was removed with IL-22 neutralizing antibody.102 IL-23 receptor/RAG2 double-deficient mice do not express IL-22 and when challenged with DSS, severe colitis ensued with poor prognosis. This phenotype can be rescued by delivery of recombinant IL-22.103 IL-22 also acts to directly influence epithelial barrier integrity104 and epithelial cell proliferation95 and to enhance the mucus barrier through an increased goblet cell population and increased muc1 that in turn provides the protein scaffold for the mucus layer. As such, IL22-depleted mice demonstrate impaired wound healing in response to DSS105 and neutralizing IL22 with antibody delayed wound healing responses in DSS-treated wild-type mice.106 IL-22 also induced expression of anti-bacterial proteins, such as RegIIIβ and Reg IIIγ, in a protective response toward gastrointestinal infection.104,107
However, despite evidence for a protective role of IL-22 in the gastrointestinal tract leading to initial expectation that augmenting IL-22 may be a novel therapeutic strategy for IBD, the picture is not clear. For every manuscript that reports a protective role of IL-22 expression, there seems to be another refuting this with data demonstrating a deleterious outcome. It is clear that the outcome of IL-22 expression depends on the context, the cytokine milieu in the surrounding microenvironment, is tissue dependent, is dependent on the timing of IL-22 expression, the cell source, perhaps accounting for both protective and pathological outcomes reported.93 The regulation pathways controlling IL-22 expression and action are complex and are linked to several other cytokines, such as IL-17A, and this has been reviewed elsewhere.108 The endogenous regulation includes a soluble inhibitory receptor, IL-22BP.109,110
The fact that evolution has created a rigorous control system for IL-22 perhaps provides a clue that overexpression of this cytokine may have deleterious consequences. Indeed, there is now another consideration when considering the role of IL-22 as a therapy for IBD—what of the long-term effects? Emerging evidence shows that IL-22 can promote colonic tumorigenesis. Compelling evidence from Huber and et al111 demonstrates that depletion of IL-22BP results in an unchecked increase in IL-22 that ultimately accelerates colonic tumorigenesis in both colitis-associated and spontaneous murine models of colorectal cancer. Through assessing the IL-22/IL-22BP balance in a timewise manner after mucosal damage with DSS, it seems that IL-22 is increased, with a reduction in IL-22BP during acute inflammatory activity and is an important component to counteract mucosal inflammation and restore epithelial barrier integrity. However, during the recovery phase, this balance was reversed. Otherwise, prolonged continuous IL-22 expression promoted malignant transformation likely due to unchecked influence on epithelial cell proliferation. Similarly, Jiang et al99 have shown that IL-22–expressing colonic mucosal leukocytes from a colitic mouse, subcutaneously co-transplanted with Hct-116 cells, resulted in enhanced cell proliferation and tumor growth as well as metastases, through IL-22–driven anti-apoptotic and pro-proliferative mechanisms.100
MULTIPLE CYTOKINE INHIBITION FOR IBD
Each of the cytokines above has been discussed as a single entity, with consideration of individual cytokine targeted therapy as potential treatment strategies for IBD. An emerging concept in the therapeutic arena is a single drug targeting multiple cytokines simultaneously to control disease activity. This reflects the complexities of the inflammatory activity in inflamed mucosa that includes a network of potent cytokines that interact together.
One example of this strategy is tofacitinib, the small molecule pan JAK inhibitor. JAK are a family of cytoplasmic enzymes critical to downstream signaling of many cytokines after engagement with the common gamma chain transmembrane receptor. This drug has been shown to be efficacious in the treatment of psoriasis112 and is now Food and Drug Administration approved for methotrexate refractory rheumatoid arthritis.113,114 In the context of IBD, Sandborn et al115 reported the results of a phase 2 trial of this drug for moderate-to-severe UC. Eight weeks of treatment resulted in significant response and remission both endoscopically and clinically at the highest dose of 15 mg twice per day compared with placebo. Despite oral administration and a more targeted immunosuppressive effect, infection remains a risk as well as dyslipidemia, the mechanism of which is not fully understood as yet. Initial reports indicate that tofacitinib does not confer clinical benefit for CD although an improvement in systemic inflammatory parameters was achieved.116 This article generated discussion within the literature117–120 and the results from ongoing phase 3 trials are anticipated to truly assess the usefulness of this agent for multi-cytokine inhibition in IBD.
Another example of multi-cytokine targeted therapy for IBD is ustekinumab. Cytokines are heterodimeric molecules, composed of 2 subunits, many of which are shared among cytokine family members, for example, IL-12 is composed of the p35 and p40 subunits, IL-35 is composed of the EBI3 and p35 subunits, IL-27 is composed of the EBI3 and p28 subunits, and IL-23 is composed of the p19 and p40 subunits. Ustekinumab takes advantage of this phenomenon as an IgG1-κ monoclonal antibody against the p40 subunit, inhibiting both IL-23 and IL-12 simultaneously. These cytokines have both been implicated in the pathogenicity of IBD, bolstering the Th1 and Th17 cell response, respectively, and this has been reviewed elsewhere.121–124 Preclinical models have shown that blocking IL-12 in vivo ameliorated TNBS colitis.125 Genome wide association studies identified polymorphisms in the IL-23 receptor gene as an important genetic determinant of IBD risk126,127 and genetic variation in the p40 molecule itself also has been associated with IBD susceptibility.128 In the clinical arena, an initial phase II trial several years ago enrolling around 100 patients did not show a persistent benefit with 3 mg of ustekinumab for moderate-to-severe CD, despite an initial improved clinical response at 6 weeks.129 However, on subgroup analysis, this trial did highlight potential efficacy in a specific patient cohort, namely patients with anti-TNF refractory CD. A subsequent randomized phase IIb trial enrolling more than 500 patients confirmed this with clinical response at 6 weeks reported in almost 40% of patients taking 6 mg dose compared with 23% with placebo. Furthermore, this agent was found to be of benefit for maintenance therapy up to 22 weeks in those that showed initial response.130 This is an important discovery and sparks hope of a treatment option in patients where all else has failed to control their disease.
WHAT DOES THE FUTURE HOLD?
It is clear that the understanding of the pathophysiology of IBD is increasing, but the complexities of this process continue to be daunting. For each novel soluble mediator of inflammatory activity that is discovered in the colonic mucosa, there seems to be a “yin and yang” function, and it is clear that each of these potential therapeutic targets can give rise to paradoxical outcomes, dependant on the context, timing within disease evolution, and underlying host/environmental factors. IBD itself also displays heterogeneous intrapatient and interpatient behavior and the reasons for this remain unclear, for example, what governs severity or extent of disease, what determines the timing of an acute flare and responsiveness of that flare to currently available treatments? IBD for now is a moving target. In the future, some of these cytokine-targeted therapies may be successful for a specific patient cohort or at a certain time within disease activity, for example, bolstering IL-22 during an acute flare of colitis may be beneficial but only for a short period until remission is achieved, to avoid the long-term pro-tumorigenic potential. In this age of individualized medicine, this is likely to require a targeted therapeutic strategy based on specific patient denominators, such as host genetics, biomarkers of the inflammatory spectrum, and cytokine milieu in the gastrointestinal mucosa along with features of the luminal environment, such as colonic microbial diversity. As new lessons are learnt from genetic studies, preclinical models of intestinal inflammation, the diversity of the microbiome in health and disease and how this interacts with the host, there is the potential to greatly widen understanding of this disease, from factors governing initiation, perpetuation of intestinal inflammation, and long-term complications, such as stricturing disease or development of malignancy. Coupled with this is the development of novel delivery systems that may allow more targeted drug delivery, for example, biopharmaceuticals that use bacterial vectors to deliver therapeutic proteins, such as anti-inflammatory cytokines directly to the inflamed mucosa131 and also the development of small molecules such as tofacitinib, the small molecule pan JAK inhibitor discussed above. Therefore, the future seems bright. An improved and beneficial balance between successful control of mucosal inflammation and avoidance of systemic adverse events should be achievable for the treatment of this debilitating disease.
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