Medical Therapy of Fibrostenotic Crohn's Disease.

INTRODUCTION: The present review serves to provide a concise overview of the current knowledge on therapeutic strategies with regard to fibrostenotic lesions in Crohn's disease.
METHODS: A literature search was performed focusing on the last 5 years, and current concepts of pathophysiology, epidemiology, and treatment have been summarized.
RESULTS: Fibrostenotic lesions in Crohn's disease are currently considered to be a consequence of the chronic inflammatory nature of the disease. Hence, therapeutic strategies are limited to the concept that early treatment of the inflammatory lesions can prevent structural changes, and to various endoscopic and surgical approaches. Direct targeting of the fibrostenotic lesion itself has not been the focus until now. This review will provide an overview of the pathophysiology and epidemiology of fibrostenotic lesions including current therapeutic approaches. Since research with regard to other organ systems and fibrosis is far more advanced, current strategies from available studies in these areas will be discussed. The results and the potential impact for Crohn's disease will be considered.
CONCLUSION: The vision of these approaches is to reverse structural changes and restore normal function.

Pathophysiologic Thoughts and Background

A primary hit is required in order to induce an accumulation of extracellular matrix subsequently leading to fibrotic lesions [1]. The chronic inflammatory condition existing in Crohn's disease suffices to induce and perpetuate the progression of fibrosis [1]; however, disease chronicity is a prerequisite since acute and even ulcerating intestinal inflammation can heal with complete restitution of the intestinal structure. While several molecules and factors have been associated with fibrosis, the question arises which of these have been found to be of functional impact.

In the animal model of trinitrobenzene sulfonic acid (TNBS)-induced colitis, inhibition of interleukin (IL)-13 signaling was sufficient to attenuate intestinal fibrosis [2]. Work from the same group indicated that IL-13 production induced transforming growth factor (TGF)-β1 production of macrophages [3]. In line with this, increased expression of IL-13 was found in intestinal smooth muscle from Crohn's disease patients [4]. However, another study did not indicate any differences in tissue IL-13 expression in Crohn's disease patients [5].

In other organs, the IL-17 subtypes A and E have been shown to exert profibrotic activity including cardiac fibroblasts, hepatic stellate cells, skin fibroblasts, and lung epithelial cells [6,7,8,9]. Accordingly, IL-17 tissue concentrations were increased in models for intestinal inflammation [10]. In fibrosing Crohn's disease, tissue IL-17A but not IL-17E has been found to be up-regulated. Furthermore, myofibroblasts from Crohn's disease strictures express the IL-17A receptor and indicate more collagen production [11]. Strikingly, in a clinical trial in which IL-17A was blocked with secukinumab, this strategy failed to improve disease activity in Crohn's disease [12], indicating the complex nature of this network.

As introduced above, the central molecule mediating fibrosis is TGF-β1 [13]. Hence the TGF-β/Smad signaling pathway is pivotal for the development of fibrosis [13,14]. Additional recent evidence provides further insight into the underlying mechanistic pathways. Several cytokines including IL-6 are released by activated mesenchymal cells resulting in an activation of the STAT3 pathway. Remarkably, a unique pattern emerged in patients with Montreal B2 Crohn's disease, namely a phospho-STAT3(S727) response. In this study, neutralization of this pathway led to normalized expression of TGF-β1. The strategy of this approach was then functionally proven in the model of TNBS colitis where fibrosis development could be decreased in mice treated with a STAT3 inhibitor [15]. Besides cytokines, the balance of the extracellular matrix in between matrix metalloproteinases and tissue inhibitors of metalloproteinases (TIMP)-1 is critical for maintaining a healthy state [16,17].

Associated with recent advances in the understanding of the intestinal microbiota, evidence indicates that ligands to receptors of the innate immune system result in the activation of the NFκB pathway in intestinal mesenchymal cells [18]. Experimental models indicate that this ultimately leads to the development of inflammation and fibrosis [19]. Hence, the direct contact with microbiota is unique for intestinal fibrosis, in particular when compared to other organ systems where fibrosis plays a role. Nevertheless, the concept of intestinal fibrosis is still lacking significant information required to develop more specific therapeutic approaches. Hence, with regard to future strategies, we will focus on approaches developed for other organ systems.

Epidemiology

The incidence of Crohn's disease has continuously increased over the past 50 years [20,21,22]. For instance, in Northern France, it has increased from 5.3/100,000 in 1988 to 7/100,000 in 1999 [22]. The understanding of the natural history of Crohn's disease has improved mainly owing to the postoperative recurrence model [23,24]. This model depicts the inflammatory nature of the disease ultimately resulting in structural damage. According to this model, as early as 8 days after surgery for Crohn's disease, a first localized inflammatory infiltrate can be found in the ileum above the anastomosis [25]. This is followed by the development of aphthous lesions that are visible in as many as 66% of patients within 3 months post surgery. In a next step, inflammation precedes the development of ulcers and strictures [24] and hence structural changes. These strictures can be associated with fistulas [26]. This model equally applies to the progression of Crohn's disease without surgery. However, the time of progression can vary from weeks to years, and can be stopped or even reversed, spontaneously or through treatment. Population-based data from Denmark indicate that after 1 year of being diagnosed, 55% of Crohn's disease patients are in remission and 15% only have mild disease [27]. However, up to one third of patients will have highly active disease. Comparably, data from Olmstedt County revealed that 64.4% of the follow-up time of patients is characterized by medical or surgical remission [28].

While superficial lesions tend to heal without structural residues, a stricture associated with prestenotic dilatation can currently not be reversed. This stricturing phenotype reflects the development of fibrostenotic lesions and tends to recur even after surgery [29,30]. The development of strictures strongly depends on the disease distribution. Here, ileal disease location results more frequently in stricturing disease than colonic disease location [31]. Strictures may be subdivided into fibrotic and inflammatory as well as mixed forms [32].

In Crohn's disease, about 50% of patients develop complications such as strictures, fistulas, and abscesses that frequently require surgery within 10 years following the initial diagnosis [33,34]. Data from two cohorts (from Spain and Minnesota, respectively) covering two different time periods indicate that the number of surgeries has not decreased over time. One may conclude that applying clinical symptoms as treatment targets fails to ensure that the underlying condition is adequately controlled [35,36,37]. In line with the post-surgery model, patients with an early inflammatory course tend to develop more severe disease, hence there is a substantial need for strategies aimed at disrupting the natural disease course. This requires that high-risk groups can be identified early on. Variables associated with a complicated disease course include smoking, young age, steroids at diagnosis, perianal disease, and extraintestinal manifestations [38,39,40,41,42]. Considering these aspects surrounding the natural history and evolution of the disease, one could conclude that patients at highest risk require early aggressive therapy in order to prevent structural damage. However, prospective trials proving this concept are currently lacking.

Current Therapeutic Concepts

Considering the above stated, strictures including inflammatory alterations might benefit from anti-inflammatory therapy through decreasing the inflammation-driven edema [43]. However, recent epidemiological data indicate that although early immunosuppressive therapy has been introduced in Crohn's disease patients with an increased risk for a more aggressive disease course, the frequency of stricturing disease did not change [44]. However, as already emphasized above, controlled prospective trials on this matter are lacking. When considering current medical strategies applied in Crohn's disease, steroids have been shown to decrease collagen production in vivo and to inhibit collagen activity [45]. In humans, steroid treatment exerted some antifibrotic effects in retroperitoneal fibrosis [46], systemic sclerosis [47,] and idiopathic pulmonary fibrosis [48]. While local injections of steroids showed some efficacy in Crohn's disease [49], intestinal fibroblasts responded to steroids with enhanced collagen expression [50]. In addition, long-term steroid treatment is obsolete in patients with intestinal bowel disease. Azathioprine has shown some beneficial effects in retroperitoneal fibrosis [51] and fibrotic pulmonary disease [52,53]. In Crohn's disease, there is limited evidence indicating a delay in post-surgery fibrostenotic complications [54]. In line with this, anti-TNFα strategies exerted antifibrotic effects in liver [55] and pulmonary fibrosis [56] as well as systemic sclerosis [57]. This can be explained by TNFα-mediated myofibroblast activation, increased collagen production, TIMP-1 expression, and a decrease in MMP2 activity and collagen degradation [58]. Retrospective data indicate a partial amelioration of stricture formation with anti-TNFα therapy [59] and a delay in the time to surgery [60].

Nevertheless, specific antifibrotic strategies are urgently required for the treatment of stricturing Crohn's disease. At this point, treatment strategies do not differ between inflammatory, penetrating, and stricturing disease.

Based on these data, the current treatment options are rather simplistic. Primary therapy comprises anti-inflammatory approaches as well as endoscopic dilatation and surgery [61,62]. Isolated strictures with a length below 5 cm and a lack of ulceration qualify for endoscopic dilatation [61,62,63,64]. While endoscopic dilatation can widely improve symptoms, a substantial part of these patients still require surgery in the long term [61,62]. Alternatively, dependent on the length of the stenosis, various surgical techniques are suitable. This includes classic stricturoplasty for short segments as well as more advanced techniques for longer segment strictures [65]. Endoscopy as well as surgery are associated with complications including perforation, infection, anastomotic leakage, abscess, and fistula [61,66,67]. In addition, even after surgery, there is a substantial recurrence rate [24,68,69]. This insufficient concept clearly highlights the need for more specific therapeutic approaches.

Future Options

At this point, Crohn's disease patients with established strictures are considered to inevitably require surgery in the future. Nevertheless, experimental data suggest that intestinal fibrosis might disappear after elimination of the profibrotic stimulus [19]. In the following, mainly based on data from other organ systems, potential future strategies are discussed. A visual summary of the concept is provided in figure 1.

Fig. 1

Development of fibrostenotic lesions in Crohn's disease and potential therapeutic approaches.

Based on the pathophysiological considerations discussed above, targeting the TGF-β1 pathway appears promising. Indeed, there is evidence from clinical trials outside the intestine supporting this concept [70,71]. However, TGF-β1-deficient mice early on develop a multi-organ lethal inflammatory syndrome [72,73]. In line with this, clinical trials assessing a monoclonal antibody targeting TGF-β1 in systemic sclerosis revealed relevant side effects [74]. From this, one might conclude that this strategy is not suitable as a systemic approach. An alternative option might be agents that affect the underlying pathway; this includes HMG-CoA reductase inhibitors as well as renin-angiotensin system modulators [75,76,77,78]. Similarly, PPAR-γ agonists antagonize the Smad3 pathway [79].

Another angle are the inflammatory mediators. Here IL-6 activates IL-13 followed by the induction of the TGF-β pathway via IL-13Rα [2]. As discussed above, antagonism of IL-13 is effective in preventing fibrosis development in experimental colitis [3,80]. Anti-IL-13 strategies are currently being evaluated for liver and pulmonary fibrosis [1,81,82,83]. Hence, although anti-IL-13 strategies failed in ulcerative colitis, they might represent a novel strategy in fibrostenotic Crohn's disease [84].

Several growth factors have been shown to be involved in the development of fibrosis. For instance, vascular endothelial growth factor (VEGF)-A has been described to be upregulated in inflammatory bowel diseases [85]]. Platelet-derived growth factor (PDGF) is known to increase proliferation and migration of fibroblasts and myofibroblasts [14]. In this context, in human intestine, PDGF facilitates extracellular matrix deposition and is upregulated in inflamed colonic tissue of Crohn's disease patients [86]. Blocking strategies from other organs suggest an antifibrotic effect in vivo [87].

Extracellular matrix modulators have been implicated in the pathogenesis of fibrostenotic diseases; however, current clinical and experimental data fail to show efficacy [88,89].

Lastly, mTOR inhibitors have shown direct antifibrotic properties by inhibition of IL-4, IL-6, IL-13, TGF-β, IL-17 as well as type I and III collagen [90,91]. Efficacy has been proven for other organ systems including lung, skin, kidney, and liver [14]. With regard to Crohn's disease, one randomized trial indicated that everolimus is as effective as azathioprine in achieving steroid-fee remission [92]. However, data specifically evaluating an antifibrotic effect in Crohn's disease are lacking.

Conclusion

Medical therapy for fibrostenotic Crohn's disease is still highly restricted and lacking innovative approaches. Several points will have to be addressed in the future to improve current therapy. Ultimately, identifying the first stimulus sufficient to activate the fibrostenotic pathway appears to be an intriguing aim, albeit at this point not for the near future. In the meantime, we should take advantage of the knowledge gained in other organ systems to facilitate the introduction of novel strategies in Crohn's disease. The vision that fibrostenotic lesions can be reversed would represent a complete change in the disease concept.

Disclosure Statement

BS has received speaker's fees from Abbvie, Ferring, Falk, MSD, Merck, and Takeda, and consultation fees from Abbvie, Falk, Hospira, Merck, MSD, Mundipharma, and Takeda.