Inflammatory bowel disease (IBD) is a well-known extra-articular manifestation in spondyloarthritis (SpA); about 6.5% of patients with ankylosing spondylitis develop IBD during the course of the disease. The pathogenesis of both SpA and IBD is considered to be the result of a complex interplay between the host (genetic predisposition), the immune system and environmental factors, notably microorganisms, leading to a disturbed immune system and chronic inflammation. Over the past decade, the role of tumor necrosis factor inhibition (infliximab, etanercept, adalimumab, golimumab) in improving signs and symptoms and overall quality of life has been well documented in various forms of SpA. Future research will clarify the role of other potential targets.
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Inflammatory bowel disease (IBD) is a well-known extra-articular manifestation in spondyloarthritis (SpA); about 6.5% of patients with ankylosing spondylitis develop IBD during the course of the disease.
- •
The pathogenesis of both SpA and IBD is considered to be the result of a complex interplay between the host (genetic predisposition), the immune system and environmental factors, notably microorganisms, leading to a disturbed immune system and chronic inflammation.
- •
Over the past decade, the role of tumor necrosis factor inhibition (infliximab, etanercept, adalimumab, golimumab) in improving signs and symptoms and overall quality of life has been well documented in various forms of SpA. Future research will clarify the role of other potential targets.
Introduction
In spondyloarthritis (SpA), there is a prominent and intriguing link between joint and gut, which has been broadly studied over the past 30 years. Inflammatory bowel disease (IBD) is a well-known extra-articular manifestation in SpA; about 6.5% of patients with ankylosing spondylitis (AS) develop IBD during the course of the disease. Furthermore, up to 60% of patients with AS show microscopic gut inflammation without obvious gastrointestinal discomfort.
On the other hand, articular involvement (axial and peripheral) often hits patients primarily diagnosed with IBD. The reported incidence of asymptomatic sacroiliitis varies from 11% to 52% according to the detection technique, with up to 10% developing AS. Arthritis is typically pauciarticular, transient, migratory, asymmetrical, and mostly nondeforming.
Extensive research has been performed to clarify the role of gut inflammation in the pathogenesis of SpA. Despite substantial progress, the exact mechanisms by which gut inflammation triggers joint inflammation remain unclear.
This article focuses on the overlap between SpA and IBD and discusses future strategies in the treatment of SpA.
Microscopic gut inflammation
One of the first forms of evidence for a relationship between bowel inflammation and peripheral arthritis stems from the clinical observation that peripheral joint inflammation may appear in genetically predisposed patients after a bacterial gut infection, such as Salmonella typhimurium , Yersinia enterocolitica , Shigella , and Campylobacter jejuni . The risk of the development of a reactive arthritis is genetically influenced, for example, by human leukocyte antigen (HLA)-B27, although clearly additional genes significantly modulate this risk.
Mielants and colleagues observed a very high frequency of microscopic gut inflammation in patients with different forms of SpA. Up to two-thirds of patients with SpA showed microscopic signs of gut inflammation without obvious signs of gastrointestinal discomfort. Two histologic types of microscopic gut inflammation can be distinguished: acute and chronic inflammation. This classification refers to the observed morphologic characteristics and not to the disease duration. In the acute type of inflammation, the normal mucosal structure is preserved and changes are limited to an infiltration of the epithelium with neutrophils and eosinophils, crypt abscess formation, and an infiltration of the lamina propria with polymorphonuclear cells. Chronic inflammation is characterized by a disturbed mucosal architecture, with crypt distortion, villous blunting and fusion, increased mixed lamina propria cellularity, and the presence of basal lymphoid aggregates.
Equally high frequencies of acute and chronic microscopic gut inflammation were recently observed in the Gent Inflammatory Arthritis and spoNdylitis cohorT (GIANT), a prospective observational cohort of patients diagnosed with SpA and classified according to the Assessment of SpondyloArthritis International Society (ASAS) criteria. In this cohort, about 50% of the patients showed microscopic gut inflammation, with the acute type of inflammation being present in up to 20% and the chronic type in up to 30% of patients ( Fig. 1 ).
Importantly, the chronic type of inflammation may be considered as an early stage of Crohn disease (CD) and, additionally, as a risk factor for developing CD over time. About 20% of the patients with chronic gut inflammation on baseline ileocolonoscopy evolved into overt IBD in a 5-year period.
The impact of nonsteroidal antiinflammatory drugs (NSAIDs) on bowel inflammation in SpA has always been a topic of discussion. Often, patients with IBD are advised to avoid the use of NSAIDs to prevent disease exacerbation. Nevertheless, the association between NSAIDs and IBD flares cannot be considered as proven because the data are inconsistent. Several retrospective studies have been performed to elucidate the role of NSAIDs in causing flares of IBD; some found no association, whereas others reported a flare-up of symptoms.
However, 2 randomized, controlled, double-blind trials in patients with inactive IBD receiving a cyclooxygenase 2–selective inhibitor (celecoxib/etoricoxib) or placebo showed no significant difference in the frequency of disease exacerbation.
Regarding microscopic gut inflammation, comparable prevalence rates were observed among patients with SpA receiving antiinflammatory drugs compared with patients not treated with NSAIDs. Furthermore, in arthritic controls treated with NSAIDs, no signs of microscopic gut inflammation were detected. Similarly, in the authors’ own GIANT cohort, they found normal, acute, and chronic gut involvement in 60%, 20%, and 20%, respectively, in patients with axial SpA not receiving NSAIDs versus 47.7%, 18.2%, and 34.1% in patients undergoing NSAID treatment (van praet and colleagues, 2012, unpublished data).
Microscopic gut inflammation
One of the first forms of evidence for a relationship between bowel inflammation and peripheral arthritis stems from the clinical observation that peripheral joint inflammation may appear in genetically predisposed patients after a bacterial gut infection, such as Salmonella typhimurium , Yersinia enterocolitica , Shigella , and Campylobacter jejuni . The risk of the development of a reactive arthritis is genetically influenced, for example, by human leukocyte antigen (HLA)-B27, although clearly additional genes significantly modulate this risk.
Mielants and colleagues observed a very high frequency of microscopic gut inflammation in patients with different forms of SpA. Up to two-thirds of patients with SpA showed microscopic signs of gut inflammation without obvious signs of gastrointestinal discomfort. Two histologic types of microscopic gut inflammation can be distinguished: acute and chronic inflammation. This classification refers to the observed morphologic characteristics and not to the disease duration. In the acute type of inflammation, the normal mucosal structure is preserved and changes are limited to an infiltration of the epithelium with neutrophils and eosinophils, crypt abscess formation, and an infiltration of the lamina propria with polymorphonuclear cells. Chronic inflammation is characterized by a disturbed mucosal architecture, with crypt distortion, villous blunting and fusion, increased mixed lamina propria cellularity, and the presence of basal lymphoid aggregates.
Equally high frequencies of acute and chronic microscopic gut inflammation were recently observed in the Gent Inflammatory Arthritis and spoNdylitis cohorT (GIANT), a prospective observational cohort of patients diagnosed with SpA and classified according to the Assessment of SpondyloArthritis International Society (ASAS) criteria. In this cohort, about 50% of the patients showed microscopic gut inflammation, with the acute type of inflammation being present in up to 20% and the chronic type in up to 30% of patients ( Fig. 1 ).
Importantly, the chronic type of inflammation may be considered as an early stage of Crohn disease (CD) and, additionally, as a risk factor for developing CD over time. About 20% of the patients with chronic gut inflammation on baseline ileocolonoscopy evolved into overt IBD in a 5-year period.
The impact of nonsteroidal antiinflammatory drugs (NSAIDs) on bowel inflammation in SpA has always been a topic of discussion. Often, patients with IBD are advised to avoid the use of NSAIDs to prevent disease exacerbation. Nevertheless, the association between NSAIDs and IBD flares cannot be considered as proven because the data are inconsistent. Several retrospective studies have been performed to elucidate the role of NSAIDs in causing flares of IBD; some found no association, whereas others reported a flare-up of symptoms.
However, 2 randomized, controlled, double-blind trials in patients with inactive IBD receiving a cyclooxygenase 2–selective inhibitor (celecoxib/etoricoxib) or placebo showed no significant difference in the frequency of disease exacerbation.
Regarding microscopic gut inflammation, comparable prevalence rates were observed among patients with SpA receiving antiinflammatory drugs compared with patients not treated with NSAIDs. Furthermore, in arthritic controls treated with NSAIDs, no signs of microscopic gut inflammation were detected. Similarly, in the authors’ own GIANT cohort, they found normal, acute, and chronic gut involvement in 60%, 20%, and 20%, respectively, in patients with axial SpA not receiving NSAIDs versus 47.7%, 18.2%, and 34.1% in patients undergoing NSAID treatment (van praet and colleagues, 2012, unpublished data).
Genetics and environment
The pathogenesis of both SpA and IBD is considered to be the result of a complex interplay between the host (genetic predisposition) and environmental factors, notably microorganisms, leading to a disturbed immune system and chronic inflammation.
Over the last couple of years, our understanding of the genetic basis of SpA has tremendously advanced, and several genes have been linked to SpA. Apart from the strong link with HLA-B27, association with genes involved in intracellular antigen processing (endoplasmic reticulum amino peptidase-1 [ERAP1] interacting with HLA-B27) and genes involved in cytokine production (especially those important in the regulation of the interleukin (IL)-17–IL-23 pathway) play a role in the susceptibility for AS. Likewise, for IBD, multiple genetic markers are known.
In an Iceland genealogy database, a remarkable overlap in the genetic background between AS and IBD was revealed because there was an elevated cross-risk ratio between either of these diseases. A 3-fold increased risk to develop IBD was identified in first-degree relatives of patients with AS; conversely, equal risk was found in relatives from patients with IBD being much more susceptible to develop AS. Hence, IBD and AS share a common genetic susceptibility, particularly in the IL-17–IL-23 pathway. This topic is discussed more thoroughly elsewhere in this issue.
Besides this shared genetic susceptibility, an inappropriate inflammatory response to intestinal microbes is assumed to play an important role. This role is supported by the detection of IBD-associated circulating antibodies to various microbial antigens, including anti-Saccharomyces cerevisiae antibodies, anti–Escherichiae coli outer membrane porin C, and perinuclear antineutrophil cytoplasmic antibodies. In a study by De Vries and colleagues, 55% of patients with AS without overt IBD showed at least one antibody associated with IBD.
Future research will have to address the role of these and other IBD-associated antimicrobial reactivities in SpA.
The Intestinal Microbiome and SpA-Associated Inflammation
Several hypotheses have been proposed to explain the close relationship between joint and gut inflammation in SpA. A first theory points at the potential role for intestinal bacteria in the origin of articular inflammation. Alterations in gut flora itself may be an important contributing factor, for example, caused by an abnormal number of microorganisms or by fluctuations in the composition of the microbial flora, which is generally referred to as the microbiome. In healthy individuals, immunologic tolerance to the gut microbiome is obtained, whereas this homeostatic balance is disrupted in patients with IBD, overall resulting in dysbiosis. The composition of the intestinal flora in patients with IBD is altered compared with healthy individuals, resulting in a general loss in diversity, a reduction in protective Firmicutes and Bacteroidetes, and a relative increase in Enterobacteriaceae , such as E coli, although their absolute numbers remained unaltered. Whether these alterations are at the origin of inflammation or a result of defective immune balances remains incompletely resolved. Up until now, the causative species remain unidentified.
On the other hand, the gut mucosal immune system is the first defense against invasion of pathogens, and the intestinal flora also directly influences the immune response. A dysfunctional interaction between gut bacteria and the mucosal immune system could result in immunologic intolerance. The intestinal epithelium plays a pivotal role in the primary defense against pathogens. One important cell type within the epithelium is Paneth cells. These intestinal secretory cells located at the bottom of the bowel crypts have the ability to secrete antimicrobial products, including lysozyme and defensins. Besides Paneth cells, goblet cells also secrete defensins. Defensins are reduced in ileal Crohn disease in contrast with colonic Crohn or ulcerative colitis. In ileal biopsy samples from patients with AS and chronic inflammation or recent-onset Crohn disease, a marked upregulation in Paneth cell antimicrobial peptides was observed. Dysfunction of Paneth cells occurring during the early stages of intestinal inflammation may be a signature for development of bowel inflammation.
The most compelling evidence for the pathogenic role of bacteria in the pathogenesis of gut and joint inflammation in SpA is derived from animal models. Germfree raised mice fail to develop a normal immune system and display reduced intestinal lymphoid tissue. Furthermore, HLA-B27 transgenic rats reared in a germfree environment do not develop arthritis or colitis, whereas the restoration of intestinal flora leads to the development of colitis within weeks.
The contribution of HLA B27 to the interrelationship of gut and joint inflammation remains unclear. Rosenbaum and colleagues hypothesized that HLA-B27 positivity predisposes the individual to develop AS by modifying the composition of the endogenous flora and alter the immune response to infectious agents. Hence, there are various ways how HLA-B27 may be implicated. It encodes for a protein that presents antigens to induce immune responses but could also present arthritogenic peptides. Furthermore, it regulates positive and negative selection of T cells in the thymus and can form dimers that are recognized by natural killer (NK) cells, which might also promote inflammation and contribute to AS pathogenesis.
The most persuasive connection between the microbiome and SpA is the appreciation that certain bacterial species, such as Chlamydia , Salmonella , Shigella , Yersinia , and Campylobacter , can trigger reactive arthritis.
Cellular Targets in Gut and Joint Inflammation
The main cellular targets for these intracellular pathogens that are associated with SpA are macrophages. Therefore, one of the most attractive hypotheses remains that trafficking of mononuclear cells from the intestine to the joints could be a critical factor in the development of gut and joint inflammation. As such, macrophages could contribute to disease pathogenesis by the uptake of bacterial components in the intestine, followed by the presentation to T cells and migration to the joint. In support of this hypothesis, a particular subset of macrophages, expressing the scavenger receptor CD163, was enriched in the colon of patients with SpA and Crohn disease, even in noninflamed regions, while this specific subset was also selectively increased in SpA synovium. Global disease activity correlated well with the number of CD163 + macrophages and polymorphonuclear cells in the synovium. These cells are also an important source of proinflammatory cytokines, such as TNF.
However, the target cell responding to proinflammatory cytokine production may well be another cell type. This idea is supported by strong experimental evidence for the role of the stromal cells in gut and joint inflammation revealed in the TNF ΔARE mouse model. Chronic and dysregulated TNF production, caused by the deletion of the adenylate/uridylate (AU)-rich elements in the regulatory sequences of the murine TNF genome, provokes simultaneous development of a Crohnlike inflammatory bowel disease and articular inflammation. The articular inflammation shows substantial resemblance to the SpA concept because it involves peripheral synovitis, enthesitis, and sacroiliitis. Signaling through TNF receptor I (TNFRI) seemed to be a prerequisite for the development of both gut inflammation and arthritis. Yet, only recently is was demonstrated that selective TNFR1 expression within the stromal compartment, synovial fibroblasts and intestinal myofibroblasts, provided a sufficient target for TNF in the development of both gut and joint inflammation. In addition, TNF production in intestinal epithelial cells was sufficient to cause murine Crohnlike ileitis; however, when TNFRI expression was limited to intestinal epithelial cells, deregulated TNF production was not sufficient to cause chronic inflammation. In conclusion, epithelial-derived TNF can trigger the activation of the stroma, namely, the intestinal myofibroblasts residing in the deeper bowel wall layers. Further research is required to unravel the precise effector pathways by which stromal cells can induce bowel inflammation and arthritic disease.
However, whether SpA is a disease driven by innate versus adaptive immunity is still unclear. In patients with SpA, the synovium is also infiltrated by T and B lymphocytes ; these T cells have an altered functional behavior with a decreased T H 1/T H 2 ratio.
Therefore, aberrant trafficking of lymphocytes between the gut and the joint may be another mechanism for the combined intestinal and articular inflammation in SpA. Naive lymphocytes continuously recirculate in between different lymphoid organs until they encounter a specific antigen. Following an antigen encounter, homing of matured lymphocyte is mediated by a distinct set of adhesion molecules, such as integrins and selectins, and by chemokine receptors. Homing to the intestine is mediated by 2 members of the β7 integrin subfamily: α4β7 and αEβ7. 46 The expression of the α4β7 integrin on memory T cells allows their binding to mucosal addressin cell adhesion molecule-1 (MadCAM-1), which is selectively expressed by mucosal endothelial cells, whereas the αEβ7 integrin, constitutively expressed by mucosal intraepithelial T cells, binds to E-cadherin, which is expressed on gut epithelial cells. The interaction of the α4β7 integrin and MAdCAM-1 is thought to contribute to the chronic bowel inflammation. A hallmark of Crohn disease (and other inflammatory conditions) is the recruitment and inappropriate retention of leukocytes, particularly T cells at the site of inflammation. Patients suffering from Crohn disease showed a reduced expression of αEβ7 on intraepithelial lymphocytes in the ileum even in noninflamed mucosa. Also, mucosal lymphocytes isolated from inflamed bowel from patients with IBD were able to bind in vitro to inflamed synovial vessels. In addition, it was shown that activated T cells carrying the α4β7 and αEβ7 integrins were enriched in inflamed synovial tissue in patients with early SpA. However, the expression of the αEβ7 integrin could be modulated by the chronic inflammatory environment itself and local TGF-β production.
As mentioned earlier, targeting of molecules involved in leukocyte trafficking or retention may provide promising new treatment options in IBD. Natalizumab, a recombinant humanized monoclonal antibody directed at the integrin subunit a4, systemically blocks the integrins α4β7 and α4β1 and was the first approved treatment in the class of selective adhesion molecule inhibitors for Crohn disease. However, serious safety concerns (eg, increased incidence of the fatal infectious disease progressive multifocal leukoencephalopathy by decreasing immunosurveillance in the central nervous system) resulted in the temporarily withdrawal of the product. A more selective antibody, vedolizumab, directed against the α4β7 integrin also showed good clinical efficacy in Crohn disease and ulcerative colitis.
More recently, the contribution of the IL-23/IL-17 axis to SpA became widely appreciated. This finding is strongly supported by the fact that IL-23 receptor polymorphisms could confer protection against AS and associated conditions, such as psoriasis and IBD. The IL-23/IL-17 axis is also strongly activated in the colon of HLA-B27 transgenic rats, concurrent with intestinal inflammation. HLA-B27 misfolding and the subsequent unfolded protein response strongly increases the production of IL-23.
Serum concentrations of IL-23 are elevated in patients with AS. It remains, however, unclear how IL-23 is responsible for inflammation at different sites in SpA. IL-23 upregulation was also reported in microscopic gut inflammation (in the terminal ileum) in patients with AS in comparison with healthy controls. However, this was not associated with a clear T H 17 polarization.
Recently, it was shown that a resident double-negative T-cell population within the entheseal region in collagen-antibody–induced arthritis mice is also highly responsive to IL-23, and these cells are able to produce proinflammatory cytokines, such as IL-6, IL-17, and IL-22, in response to IL-23 receptor engagement.
Interestingly, innate immune cells are also capable of IL-17 production. It was recently reported by histologic analysis of zygapophyseal joints of patients with AS that CD15 + neutrophils and myeloperoxidase-positive myeloid cells, but not classical T cells, are the major cellular sources of IL-17 in the inflamed bone marrow. A specific subset of NK cells (NK-22 cells) that are located in the mucosa-associated lymphoid tissue secrete IL-22 in response to acute exposure to IL-23. Expression of the IL-22 receptor is restricted to mesenchymal cells. Therefore, IL-22 production by immune cells is thought to regulate inflammation and provide protection particularly at mucosal sites by controlling stromal responses. Whether this pathway is also operational in the inflamed SpA joint remains elusive.
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