There have been interesting studies about the immunopathogenesis of IBD and SpA, which have shown alterations in key molecules that regulate the immune response in the gut of patients with SpA, and some of them are almost the same as those found in CD[19]. For instance E-cadherin, a transmembrane glycoprotein that mediates the intercellular adhesion of epithelial cells is expressed highly in the gut of patients with IBD[20] and in patients with SpA[21], and subclinical acute and chronic gut inflammation, even in those without macroscopic lesions, which indicates that the alteration in the regulation of these proteins may be an early event in the development of gut inflammation. Besides, E-cadherin is a ligand of α4β7 integrin in intraepithelial T cells. Two studies have shown increased expression of this integrin in T cell cultures from the gut mucosa of patients with AS[22] and CD[23]. Increased expression of this integrin has been found in patients without histological signs of gut inflammation, which suggests that there are common abnormalities in patients with SpA and IBD that precede clinical inflammation.

Other alterations that are common in both groups of diseases are those described in CD4⁺ T cells. Currently, four types of CD4⁺ T cells have been described: Th1 cells are identified as interferon γ (IFN-γ) producers; Th2 cells produce primarily interleukin (IL)-4, IL-5, IL-10 and IL-13; Th17 cells produce mainly IL-17A and they also produce IL-17F, IL-21, IL-22, granulocyte-monocyte colony-stimulator factor (GM-CSF), CCL-20, and potentially tumor necrosis factor (TNF) and IL-6. These cytokines have pro-inflammatory properties and they act on a broad range of cell types to induce the expression of several cytokines (TNF, IL-1β, IL-6, GM-CSF, G-CSF), chemokines (CXCL1, CXCL8, CXCL10), and metalloproteinases. On the other hand, regulatory T cells (Tregs) have a suppressor function; they influence the immune system by cell-to-cell contact and also via regulatory mechanisms that are still not fully elucidated. It is known that they are able to produce IL-10 and transforming growth factor (TGF)-β, and it is interesting that Th17 and Treg developmental programs are reciprocally interconnected. Upon T-cell receptor stimulation, a naïve T cell can be driven to express Foxp3 and become a Treg cell in the presence of TGF-β, but in the presence of TGF-β plus IL-6 or IL-21, the Treg developmental pathway is abrogated, and instead, T cells develop into Th17 cells[24]. Initial studies have shown Th1 predominance in intestinal mucosa of patients with IBD and SpA, however, recent studies have suggested that, in both groups of patients, Th17 cells may have an important role in initiation and perpetuation of autoimmune inflammation. One study that involved 499 patients with CD and 216 with UC has shown increased IL-17F mRNA expression in intestinal biopsies of patients compared to controls[25]. A recent study has shown an increased proportion of Th17 cells in patients with SpA[26] and increased IL-17, IL-6, TGF-β and IFN-γ levels in synovial fluid of patients with SpA, when compared with patients with rheumatoid arthritis[27]. Also, some authors have suggested that dysfunction of Tregs participates in the immunopathogenesis of these diseases, and they have proposed their use as therapeutic agents in IBD[24,28].

TNF-α is a pro-inflammatory cytokine that is produced mainly by macrophages and activated T cells. It is a key molecule in chronic inflammation of SpA and IBD. In the latter, the interaction between antigen-presenting cells (APCs) and intestinal bacterial flora contributes to the development of uncontrolled CD4⁺ cell activation, which leads to the release of pro-inflammatory cytokines such as TNF-α, IL-6, IL-12, IL-23 and IL-17. In SpA, models of transgenic rats and clinical observations have suggested that pathogenic microorganisms and their interaction with APCs also have a crucial role in the initiation and perpetuation of the altered immune response that leads to joint and enthesis inflammation. Additionally, increased intestinal permeability has been found in patients with SpA and IBD. This fact could alter the innate immune response to bacterial antigens[29]. These discoveries have had important therapeutic implications for these groups of patients.

Other relevant molecules involved in the pathogenesis of both groups of diseases are the toll-like receptors (TLRs) that play an important role in the innate immune response against pathogenic microorganisms. Several studies have shown increased expression of TLR-4 and TLR-2 in APCs of patients with SpA[30,31] and in intestinal biopsies of patients with UC and CD[32-34]. The alterations in function and regulation of these molecules may have an important role in the initiation and perpetuation of chronic inflammation in these diseases[35]. There are studies that have correlated several mutations and genetic variations of these receptors with susceptibility for these diseases. The results are controversial, probably due to the heterogeneity of the patients and the ethnic groups that have been included in the studies[36-39].

Abnormal responses to certain microorganisms have been described in patients with IBD or SpA; for instance, increased levels of the same serotypes of Klebsiella pneumoniae have been found more frequently in patients with IBD and SpA, compared with healthy controls and controls with celiac disease[40]. Besides, several studies have shown increased levels of antibodies against Klebsiella antigens, and against collagens type I, III, IV and V in patients with CD or AS. There are molecular similarities between Klebsiella nitrogenase and HLA-B27 genetic markers and between Klebsiella pullulanase and collagen fibers types I, III and IV. Therefore, several authors have proposed that there may be molecular mimicry between Klebsiella and human molecules that could participate in the initiation and perpetuation of these diseases[41], i.e. anti-Klebsiella IgA cross-reacts with HLA-B27 antigen, and antibodies to enteric bacteria are able to lyse lymphocytes from HLA-B27 patients with AS.

The participation of the HLA-B27 molecule in the immunopathogenesis of SpA has been well known since 1973 when Brewerton and Schlosstein detected its high prevalence in patients with AS, psoriatic arthritis (PsA), reactive arthritis and anterior uveitis[42]. Its functional relevance was demonstrated elegantly in 1990 by Hammer et al[43]; their group developed a transgenic rat with the human HLA-B27 molecule. These rats developed a multisystemic inflammatory disease that had several clinical and histopathological similarities to SpA and IBD[43]. An important finding was that these rats did not develop joint or gut inflammation when they were in a bacteria-free environment, which supports the theory of the participation of microorganisms in the pathogenesis of these diseases[44]. Some studies involving patients with IBD have shown an association of HLA-B27 molecule with the presence of sacroiliitis, spondylitis, enthesitis, peripheral arthritis, erythema nodosum, uveitis and oral ulcers[14].

Other genes have been associated with the clinical presentation of several arthropathies associated with IBD[45]. The Oxford Group has found an association of type 1 arthropathy (pauci-articular, self limited, with relapses) with HLA-DRB1*0103, HLA-B35 and HLA-B24, while type 2 arthropathy (polyarticular, progressive) is associated with HLA-B44 in British patients[46]. One study that evaluated Spanish patients has found an association of the mini-haplotype TNF a6B5 with the presence of joint manifestations in patients with UC[47]. Another study has found that a polymorphism of the gene CARD15 is associated with the presence of gut inflammation in patients with SpA, and the same polymorphism is over-represented in patients with CD[48].

On the other hand, there is evidence to suggest that, for patients with IBD, tobacco use and history of appendectomy are risk factors for developing extraintestinal manifestations, particularly seronegative SpA and dermatological manifestations such as erythema nodosum and pyoderma gangrenosum[49].

In summary, the autoimmune pathogenic mechanisms shared by IBD and SpA include genetic susceptibility to abnormal antigen presentation, aberrant recognition of self, the presence of autoantibodies against specific antigens shared by the colon and other extra-colonic tissues, and increased intestinal permeability. The response against microorganisms may have an important role through molecular mimicry and other mechanisms.

The frequency of peripheral arthritis in IBD ranges from 17% to 20%, and it is more common in CD[51]. In a retrospective study that included 1459 patients with IBD, peripheral arthritis was present in 6% of patients with UC and in 10% of patients with CD[52]. Another study has shown arthritis in 10%, enthesitis in 7%, and a history of arthritis in 29% in a group of patients with IBD[53].

The Oxford Group[52] has classified the peripheral arthritis associated with IBD (also called peripheral enteropathic arthropathy) without axial involvement, as pauci-articular or polyarticular arthropathy (Table 1). In the pauci-articular form, joint symptoms are usually acute and self-limited; the joint involvement is asymmetric and migratory, with participation of both large and small joints, and lower limbs are more affected. Many episodes last from 6 to 10 wk but relapses are frequent and they tend to coexist with IBD relapses; these patients have high frequencies of other extraintestinal manifestations such as erythema nodosum and uveitis. It is interesting that in 31% of these patients the arthropathy may appear even 3 years before the diagnosis of IBD is made. On the other hand, the polyarticular form tends to have a chronic course and it may be destructive; its course is independent of IBD exacerbations and the coexistence of other extraintestinal manifestations is rare, except for uveitis[50,54]. Enthesopathy, particularly affecting the Achilles tendon or plantar fascia insertion are common manifestations.

In most of the cases, intestinal symptoms precede or coexist with joint manifestations, but in some patients, arthritis precedes the gut manifestations, even by several years. In a prospective study that included 123 patients with SpA, 6% of the patients developed CD from 2 to 9 years after the first joint symptom. For UC, some studies have described a temporal relationship between arthritis and gut inflammation relapses[50]; there have been case reports of patients that have developed arthritis at the same time as ileal pouchitis after total proctocolectomy for UC activity. However, other studies have shown that colectomy has almost no effect on joint inflammation[50,55]. The most consistent finding is that colon involvement increases the susceptibility to peripheral arthritis.

There have been isolated case reports about patients that have presented with progressive, destructive monoarthritis with granulomatous synovial inflammation, and CD has been diagnosed when extension studies have been carried out as part of the diagnostic workup[56].

Axial involvement is part of CD and UC, although it is more common in CD (5%-22%) than in UC (2%-6%), and in general, the prevalence is 10%-20% for sacroiliitis and 7%-12% for AS[51,57,58]. A study that included patients from a referral center has shown that 30% of the patients with IBD had inflammatory low back pain, 33% had abnormal Shober index, and 30% had unilateral or bilateral grade I or II sacroiliitis. In fact, 35% of the patients fulfilled the European Spondyloarthropathy Study Group criteria for SpA[53,59], and 10% fulfilled the criteria for AS. Other studies from referral centers have shown similar results and higher prevalence than for population studies, which probably reflects referral bias[13,17,53,58,60] (Table 2).

The clinical picture is virtually the same as the one for patients with AS without extra-articular manifestations. Axial symptoms usually precede gut symptoms; clinical course is totally independent of the intestinal manifestations and intestinal surgery does not alter the course of SpA. Ankylosing spondylitis associated with IBD can develop at any age, whereas idiopathic AS usually starts before 40 years of age. In idiopathic AS, males are more affected than females (ratio 2.5:1), while in AS associated with IBD, the male to female ratio is 1:1[61].