Enteropathic arthropathy
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Kalsang Dolma, M.B.B.S.[2]
Overview
Enteropathic arthropathy or Enteropathic arthritis refers to acute or subacute arthritis in association with or as a reaction to an enteric (usually colonic) inflammatory condition.
Pathophysiology
The pathophysiology of Enteropathic arthropathy:
- Although the pathogenesis of EA has not been plainly clarified, the observation that joint inflammation occurs in genetically predisposed subjects with bacterial gut infections provided an important evidence for a possible relationship between inflammation of the gut mucosa and arthritis.
- Current theories provide, in genetically predisposed subjects, an aberrant migration of intestinal lymphocytes or macrophages from inflamed gut mucosa to joints, in which an important role was played by gut bacteria.
- In fact, a dysfunctional interaction between the mucosal immune system and gut bacteria could result in an abnormal state of immunological tolerance toward flora by alterations in mucosal effector cells or by affecting regulatory cells.
- A significant evidence for the pathogenic role of gut bacteria in the pathogenesis of SpA is derived from animals models.
- Genetic factors play a predisposing role while environmental factors, such as infectious agents, may play a causative role.
- Among the genetic factors, HLA-B27 has the strongest genetic association with SpA and in particular with ankylosing spondylitis (AS).
- This association is reported in more than 90% of cases, also spondylitis in IBD is associated with the presence of HLA-B27, however, in lower frequencies than in AS (30%–80%).
- Pure asymptomatic sacroiliitis in CD is not strongly associated with HLA-B27 and a very recent study indicates a prevalence of 7%.
- In 2000, Orchard et al. described an association with HLA-DR0103, B35, and B27 in type 1 peripheral arthritis and neither B27 nor DR4 associations were observed in type 2 arthritis.
- In order to describe the role of HLA-B27 in the pathogenesis of EA, different theories have been proposed.
- One theory suggests that HLA-B27-expressing macrophages expose specific bacterial antigens that may activate CD4+ T-cells with their migration from gut to joint with the development of arthritis.
- Another theory proposes that homology between HLA-B27 sequences and bacterial antigens may activate T-cell and inflammation by antigen mimicry mechanism.
- Finally, the most recent theory is based on the endoplasmic reticulum stress: under normal conditions, the peptide-loaded HLA class I heavy chain binds the β2-microglobulin (β2m) in the endoplasmic reticulum. The folding process of the HLA-B27 heavy chain is slower than that of other HLA alleles thus leading to the generation of misfolded chains.
- Misfolded chains are usually removed in the endoplasmic reticulum, but in certain conditions, such as viral infection, they accumulate thus activating the protein BiP, the endoplasmic reticulum-unfolded-protein-response (UPR) and the nuclear factor κB (NFκB), which play a critical role in the induction of inflammation.
- Data suggest that deposition of β2m, caused by the high dissociation rate between the HLA-B27 heavy chain and β2m, occurring within synovial tissue, may lead to the initiation of chronic inflammation.
- Other HLA genes have been associated with SpA in IBD: HLA-DrB10103, HLA-B35, HLA-B24 in type 1 peripheral arthritis, and HLA-B44 in type 2 peripheral arthritis.
- Moreover, Mielants et al. showed an association between HLA-Bw62 and chronic gut lesions associated with a family history of AS and CD, with markers of inflammation, reduced axial mobility, the presence of sacroiliitis, destructive joint lesions, and a diagnosis of AS.
- Further confirming the relevance of HLA-B27 in the pathogenesis of enteroarthritis, Hammer et al. studied transgenic rats overexpressing HLA-B27 molecule. These rats developed a multisystemic inflammatory disease that had several clinical and histopathological similarities to SpA and IBD [54]. An important finding was that these rats did not develop joint or gut inflammation when they were in a germ-free environment [55]. This result supports the theory of the participation of microorganisms in the pathogenesis of these diseases.
- In humans with reactive arthritis, following Yersinia enterocolitica, Shigella spp. or Salmonella enteritidis and Typhimurium infection, bacterial antigens have been detected in joints [56–59]. Later studies further confirmed this evidence.
- Other molecular studies found similarities between Klebsiella nitrogenase and HLA-B27 and between Klebsiella pullulanase and collagen fibers types I, III, and IV.
- Interestingly, elevated levels of antibodies against Klebsiella and collagen fibers types I, III, IV, and V were detected in patients with CD and AS.
- In addition to HLA-B27, other genes have been identified as being related to SpA and IBD. In fact, several common genetic predispositions between SpA and IBD were identified, of which the association with IL-23R polymorphisms is most prominent.
- The functional role of IL-23 receptor polymorphisms remains unclear, the fact that IL-23 signaling plays a critical role in the Th17-mediated inflammation indicates that Th17 cells may represent a common pathogenetic mechanism in both IBD and SpA.
- The first susceptibility gene that has been identified for CD is CARD15 (or NOD2). Variants within this gene increase the risk for CD by threefold for heterozygous and fortyfold for homozygous individuals.
- An association was also found in SpA patients between the carriage of CARD15 variants and the development of chronic subclinical gut inflammation.
- Although CARD15 mutations do not seem to predispose to arthritis, it might confer a risk towards the development of (sub) clinical gut inflammation in SpA patients, rendering these patients more disposed to develop IBD.
- A CARD15-mediated NFκB-dependent inflammatory reaction might be an important pathogenic process within the joints.
- The protein is expressed in the joint tissue, and bacterial cell wall components have been demonstrated in the synovium of SpA patients, supporting the idea that CARD15 can locally trigger inflammation.
- Recently, additionally shared associations between SpA and IBD were found at chromosome 1q32 near KIF21B (genome-wide significant), STAT3, IL-12B, CDKAL1, LRRK2/MUC19, and chromosome 13q14 (experiment-wise association).
- As the genes IL-23R, STAT3, and IL-12B all influence Th17 lymphocyte differentiation/activation, this provides further evidence implicating the Th17 lymphocyte subset in the pathogenesis of SpA.
- In addition to genetic susceptibility, an important role was also been given to the environmental factors in triggering the onset of disease.
- In fact, bacterial gut infections such as Yersinia enterocolitica, Salmonella typhimurium, Campylobacter jejuni, and Shigella spp may cause joint inflammation in genetically predisposed patients.
- Given the prototypical link between certain bacterial infections and the onset of reactive arthritis, several studies have aimed to assess the role of intestinal flora in disease progression, as well as the resulting changes in mucosal response.
- On the basis of these observations, the possible pathways involved in joint and gut inflammation in EA may be the following: in the acute phase of inflammation, bacterial infections can cause acute intestinal inflammation.
- Certain bacteria may survive intracellularly in macrophages that can traffic to the joint and cause arthritis in a genetically predisposed host. *Proinflammatory cytokines such as TNF and IL-23 are produced locally, with Paneth cells being the most important producers of IL-23 in the intestine.
- This expression can activate innate immune cells (NK) to produce IL-22 that may help control inflammation at mucosal sites.
- Otherwise, damage and pathogen-associated molecular pattern molecules (DAMPs and PAMPs) and cellular stretch might promote initiation of joint inflammation.
- In the transition phase, acute intestinal and articular inflammation can be sustained due to defective immune regulation by TREG cells, or by ER stress, whereas iNKT cells act as regulators to control inflammation. Proangiogenic factors such as PlGF can lead to aberrant neovascularisation. *These events may lead to chronicity, further enhanced or maintained by repetitive cellular stress.
- In this stage, stromal cells become more important, as targets for proinflammatory cytokines (Figure 1).
Causes
- Reactive arthritis (Reactive to enteric infection)
- Spondyloarthropathies associated with inflammatory bowel disease (Crohn disease and ulcerative colitis)
- Malabsorption related: Intestinal bypass (jejunoileal), Celiac disease, Whipple disease
- Collagenous colitis