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==Historical Perspective==
The pathophysiology of Enteropathic arthropathy:<ref name="pmid3649644">{{cite journal |vauthors=Navis ES |title=Controlling violent patients before they control you. Advice on keeping your cool when your patient is losing his |journal=Nursing |volume=17 |issue=9 |pages=52–4 |date=September 1987 |pmid=3649644 |doi= |url=}}</ref><ref name="pmid3495471">{{cite journal |vauthors=Cuvelier C, Barbatis C, Mielants H, De Vos M, Roels H, Veys E |title=Histopathology of intestinal inflammation related to reactive arthritis |journal=Gut |volume=28 |issue=4 |pages=394–401 |date=April 1987 |pmid=3495471 |pmc=1432823 |doi= |url=}}</ref><ref name="pmid20485176">{{cite journal |vauthors=Jacques P, Elewaut D, Mielants H |title=Interactions between gut inflammation and arthritis/spondylitis |journal=Curr Opin Rheumatol |volume=22 |issue=4 |pages=368–74 |date=July 2010 |pmid=20485176 |doi=10.1097/BOR.0b013e3283393807 |url=}}</ref><ref name="pmid1001980">{{cite journal |vauthors=Mallas EG, Mackintosh P, Asquith P, Cooke WT |title=Histocompatibility antigens in inflammatory bowel disease. Their clinical significance and their association with arthropathy with special reference to HLA-B27 (W27) |journal=Gut |volume=17 |issue=11 |pages=906–10 |date=November 1976 |pmid=1001980 |pmc=1411211 |doi= |url=}}</ref><ref name="pmid8733445">{{cite journal |vauthors=Brown MA, Pile KD, Kennedy LG, Calin A, Darke C, Bell J, Wordsworth BP, Cornélis F |title=HLA class I associations of ankylosing spondylitis in the white population in the United Kingdom |journal=Ann. Rheum. Dis. |volume=55 |issue=4 |pages=268–70 |date=April 1996 |pmid=8733445 |pmc=1010149 |doi= |url=}}</ref><ref name="pmid10640771">{{cite journal |vauthors=Mertz AK, Wu P, Sturniolo T, Stoll D, Rudwaleit M, Lauster R, Braun J, Sieper J |title=Multispecific CD4+ T cell response to a single 12-mer epitope of the immunodominant heat-shock protein 60 of Yersinia enterocolitica in Yersinia-triggered reactive arthritis: overlap with the B27-restricted CD8 epitope, functional properties, and epitope presentation by multiple DR alleles |journal=J. Immunol. |volume=164 |issue=3 |pages=1529–37 |date=February 2000 |pmid=10640771 |doi= |url=}}</ref><ref name="pmid19468997">{{cite journal |vauthors=Fantini MC, Pallone F, Monteleone G |title=Common immunologic mechanisms in inflammatory bowel disease and spondylarthropathies |journal=World J. Gastroenterol. |volume=15 |issue=20 |pages=2472–8 |date=May 2009 |pmid=19468997 |pmc=2686905 |doi= |url=}}</ref><ref name="pmid7964509">{{cite journal |vauthors=Taurog JD, Richardson JA, Croft JT, Simmons WA, Zhou M, Fernández-Sueiro JL, Balish E, Hammer RE |title=The germfree state prevents development of gut and joint inflammatory disease in HLA-B27 transgenic rats |journal=J. Exp. Med. |volume=180 |issue=6 |pages=2359–64 |date=December 1994 |pmid=7964509 |pmc=2191772 |doi= |url=}}</ref><ref name="pmid15539413">{{cite journal |vauthors=Laukens D, Peeters H, Marichal D, Vander Cruyssen B, Mielants H, Elewaut D, Demetter P, Cuvelier C, Van Den Berghe M, Rottiers P, Veys EM, Remaut E, Steidler L, De Keyser F, De Vos M |title=CARD15 gene polymorphisms in patients with spondyloarthropathies identify a specific phenotype previously related to Crohn's disease |journal=Ann. Rheum. Dis. |volume=64 |issue=6 |pages=930–5 |date=June 2005 |pmid=15539413 |pmc=1755516 |doi=10.1136/ard.2004.028837 |url=}}</ref><ref name="pmid16937463">{{cite journal |vauthors=Rothfuss KS, Stange EF, Herrlinger KR |title=Extraintestinal manifestations and complications in inflammatory bowel diseases |journal=World J. Gastroenterol. |volume=12 |issue=30 |pages=4819–31 |date=August 2006 |pmid=16937463 |pmc=4087615 |doi= |url=}}</ref>
*In 1989, Attwood et al published an abstract in Gut, describing “Oesophageal Asthma – an episodic dysphagia with eosinophilic infiltrates”.
*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.  
*These investigators compared a group of 15 adults who presented with dysphagia without esophageal obstruction and normal pH monitoring to a group of 100 adults with GERD as defined by increased acid exposure in the distal esophagus.  
*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.  
*Differences between the two groups were that the group without increased acid exposure was found to have significantly greater number of eosinophils than the group with GERD.
*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.  
*The key finding of this case series was that it identified patients with dysphagia, with a range of severity up to complete bolus obstruction, presented with dense esophageal eosinophilia.  
*A significant evidence for the pathogenic role of gut bacteria in the pathogenesis of SpA is derived from animals models.
*In 1993, they published these key findings that described adults with dysphagia, normal pH monitoring and dense esophageal eosinophilia (>20 eos/HPF) and termed this Esophageal Eosinophilia with dysphagia.  
*Genetic factors play a predisposing role while environmental factors, such as infectious agents, may play a causative role.
*A distinct clinicopathological syndrome 10. Importantly, control patients with proven GERD had a mean of 3.3 eos/HPF in the esophageal epithelium. Endoscopic appearances using fiber optic technology likely limited descriptions of the full details now observed in this disease and may partially explain the fact that no endoscopic abnormalities were visualized in their series.  
*Among the genetic factors, HLA-B27 has the strongest genetic association with SpA and in particular with ankylosing spondylitis (AS).  
*Seven patients had food hypersensitivity, and all required advanced intervention (dilatation and / or steroids in one case) for resolution of symptoms.
*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%).  
*In 1994, Straumann et al described a series of 10 patients with acute recurrent dysphagia seen over a 4-year period, who showed discrete endoscopic changes, and high concentrations of epithelial esophageal eosinophils, who improved following systemic steroid and antihistamine treatment11.  
*Pure asymptomatic sacroiliitis in CD is not strongly associated with HLA-B27 and a very recent study indicates a prevalence of 7%.  
*From this series it was clear that the endoscopic findings including rings, white exudates and furrows were variably expressed since some patient’s esophageal mucosae appeared relatively normal.
*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.
*He termed this Idiopathic Eosinophilic Esophagitis.
*In order to describe the role of HLA-B27 in the pathogenesis of EA, different theories have been proposed.
*Taken together, these 2 reports from 2 different continents, described key clinical findings observed in adults with dysphagia who had dense mucosal eosinophilia that was limited to the esophagus who did not have GERD.  
*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.  
*Importantly, endoscopic findings were variable, leading to the necessity of procuring endoscopic pinch biopsy to make the diagnosis.  
*Another theory proposes that homology between HLA-B27 sequences and bacterial antigens may activate T-cell and inflammation by antigen mimicry mechanism.  
*Since this practice was not widespread, because of the lack of diagnostic utility, larger recognition of this newfound disease remained somewhat limited.
*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.  
*These two series, published by a gastroenterologist in private practice, Dr. Straumann and a surgeon, Dr. Attwood formed the beginnings their quest to define key clinical features and therapeutic approaches over the next 20 years.
*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.  
* Eosinophilic esophagitis is an immunoallergic disorder resulting from the interaction between genetics and environmental triggers such as repeated exposure to food and aeroallergens.
*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.
* Patients presenting with EOE have a history of:
*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.  
* Elevated serum IgE levels
*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.  
* Response to interventions such as diet restriction
*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.  
* History of food hypersensitivity
*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.
* Eosinophils originate from CD34+ myeloid precursor cells in the bone marrow, mature to a granulated state and migrate to vascular spaces.
*A CARD15-mediated NFκB-dependent inflammatory reaction might be an important pathogenic process within the joints.  
* The eosinophils are absent in an otherwise normal esophagus, the presence of the eosinophils in the esophagus suggests GERD or EoE.
*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.  
*They tend to be present in all layers of the esophagus in EoE, but predominate in the lamina propria and submucosal regions.  
*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).  
* The documented cytokine expression profile in the esophageal tissue of EoE patients is that of a TH2 inflammatory response.
*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.
* IL-5 and 13 are produced by the type-2 helper T cells (Th2) in response to the antigenic proteins from the food or inhalation.  
*In addition to genetic susceptibility, an important role was also been given to the environmental factors in triggering the onset of disease.  
* IL-13 further stimulates the epithelial cells of the esophagus to produce large proteins to induce a gene called eotaxin-3, which in turn recruits eosinophils from the peripheral blood into the tissue.  
*In fact, bacterial gut infections such as Yersinia enterocolitica, Salmonella typhimurium, Campylobacter jejuni, and Shigella spp may cause joint inflammation in genetically predisposed patients.  
* IL-5 prolongs the survival of the eosinophils.
*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.  
*The activated TH2 response leads to the recruitment and activation of
*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.
** '''Eosinophils'''
*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.  
** '''Mast cells'''
*This expression can activate innate immune cells (NK) to produce IL-22 that may help control inflammation at mucosal sites.  
* Mast cells degranulate and cause tissue damage and repair.  
*Otherwise, damage and pathogen-associated molecular pattern molecules (DAMPs and PAMPs) and cellular stretch might promote initiation of joint inflammation.  
* Cytokines produced by TH-1 cells are
*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.
** '''Tumor necrosis factor (TNF)-α'''
*In this stage, stromal cells become more important, as targets for proinflammatory cytokines
** '''Interferon (IFN)-γ'''
*
* TNF-α is expressed by the epithelial cells of the esophagus whereas the INF-γ is upregulated by the Peripheral T cells.
*
* Delayed or type- IV hypersensitivity is the mechanism is involved in the EoE rather than the non-IgE.
*
*It is postulated that the EoE-defining endoscopic and histologic manifestations are a culmination of the disease process which, may have debilitating long-term effects including strictures and food impactions in untreated or poorly managed cases of EoE.
*
 
* CD34+ myeloid precursor cells in the bone marrow produce eosinophils and then the eosinophils develop granulation and migrate to vascular spaces.
* Eosinophils although present in all the layers of the esophagus in patients with EoE, they are predominant in the lamina propria and submucosa of the esophagus.
* The preformed granule proteins of the eosinophils are
**ECP- Eosinophil Cationic Protein
**MBP- Major Basic Protein
**EPO- Eosinophil Peroxidase
**EDN- Eosinophil Derived Neurotoxin
* Upon the stimulation and the degranulation, the eosinophils release the granule proteins into the tissues.
* Eosinophils synthesize and release cytokines such as
**IL-5
**IL-13
**Transforming growth factor (TGF)-α and -β
**Chemokines (eotaxins and RANTES)
**lipid mediators such as platelet activating factor (PAF) and leukotriene C4.
* IL-5, IL-13, and granulocyte-macrophage colony stimulating factor (GM-CSF) can cause the maturation and migration of the eosinophils.
 
* Eosinophils cause inflammation in the EoE patients by the following mechanisms
** Angiogenic molecules from the eosinophils recruits the inflammatory cells and the increase the vascularity.  
** Fibrogenic mediators such as TGF-β1 and matrix metalloproteinase 9 (MMP)-9 causes the airway remodeling.
** MBP and MMP-9 disrupt the integrity of the epithelial cells of the esophageal through their involvement in smooth muscles, fibroblasts, and cell-adhesion molecules.  
** The above-mentioned processes lead to tissue remodeling eventually causing an overall esophageal dysfunction.
**TGF-β and eosinophilic granule proteins MBP and EPO are the key eosinophil effector proteins. The importance of eosinophils in mediating tissue fibrosis is supported by evidence in both murine and human models.  
**These findings not only highlight the importance of targeting fibrosis reversal in treatment of EoE, but also underline the importance of eosinophils in tissue remodeling.  
 
==Pathogenesis==
* The eosinophils are absent in an otherwise normal esophagus, the presence of the eosinophils in the esophagus suggests GERD or EoE.
* IL-5 and 13 are produced by the type-2 helper T cells (Th2) in response to the antigenic proteins from the food or inhalation.  
* IL-13 further stimulates the epithelial cells of the esophagus to produce large proteins to induce a gene called eotaxin-3, which in turn recruits eosinophils from the peripheral blood into the tissue.  
* IL-5 prolongs the survival of the eosinophils.
 
 
==Endoscopy==
*Mucosal biopsies of the esophagus should be obtained in all patients in whom EoE is a clinical possibility regardless of the endoscopic appearance.
*Endoscopic abnormalities in patients with EoE are as follows:<ref name="urlTable 3: Proposed classification and grading system for the endoscopic assessment of the esophageal features of eosinophilic esophagitis (<a id=ref-link-section-1 title= href=/articles/#ref44">44</a>)">{{cite web |url=https://www.nature.com/articles/ajg201371/tables/3 |title=Table 3: Proposed classification and grading system for the endoscopic assessment of the esophageal features of eosinophilic esophagitis (<a id=ref-link-section-1 title="" href=/articles/#ref44>44</a>) |format= |work= |accessdate=}}</ref><ref name="urlVertical lines in distal esophageal mucosa (VLEM): a true endoscopic manifestation of esophagitis in children? - PubMed - NCBI">{{cite web |url=https://www.ncbi.nlm.nih.gov/pubmed/9199905?dopt=Abstract&holding=npg |title=Vertical lines in distal esophageal mucosa (VLEM): a true endoscopic manifestation of esophagitis in children? - PubMed - NCBI |format= |work= |accessdate=}}</ref><ref name="urlFragility of the esophageal mucosa: a pathognomonic endoscopic sign of primary eosinophilic esophagitis? - PubMed - NCBI">{{cite web |url=https://www.ncbi.nlm.nih.gov/pubmed/12612531?dopt=Abstract&holding=npg |title=Fragility of the esophageal mucosa: a pathognomonic endoscopic sign of primary eosinophilic esophagitis? - PubMed - NCBI |format= |work= |accessdate=}}</ref><ref name="urlEosinophilic esophagitis: red on microscopy, white on endoscopy. - PubMed - NCBI">{{cite web |url=https://www.ncbi.nlm.nih.gov/pubmed/15383737?dopt=Abstract&holding=npg |title=Eosinophilic esophagitis: red on microscopy, white on endoscopy. - PubMed - NCBI |format= |work= |accessdate=}}</ref><ref name="urlThe prevalence and diagnostic utility of endoscopic features of eosinophilic esophagitis: a meta-analysis. - PubMed - NCBI">{{cite web |url=https://www.ncbi.nlm.nih.gov/pubmed/22610003?dopt=Abstract&holding=npg |title=The prevalence and diagnostic utility of endoscopic features of eosinophilic esophagitis: a meta-analysis. - PubMed - NCBI |format= |work= |accessdate=}}</ref>
**Fixed esophageal ring which is corrugated
**White exudates or plaques
**Longitudinal furrows
**Mucosal pallor
**Diffuse esophageal narrowing
**Mucosal fragility leading to esophageal lacerations during the endoscopy
However, because these endoscopic features have been described in other esophageal disorders, none can be considered pathognomonic for EoE.
<references />
<references />

Latest revision as of 19:12, 11 April 2018

The pathophysiology of Enteropathic arthropathy:[1][2][3][4][5][6][7][8][9][10]

  • 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
  1. ↑ Navis ES (September 1987). "Controlling violent patients before they control you. Advice on keeping your cool when your patient is losing his". Nursing. 17 (9): 52–4. PMID 3649644.
  2. ↑ Cuvelier C, Barbatis C, Mielants H, De Vos M, Roels H, Veys E (April 1987). "Histopathology of intestinal inflammation related to reactive arthritis". Gut. 28 (4): 394–401. PMC 1432823. PMID 3495471.
  3. ↑ Jacques P, Elewaut D, Mielants H (July 2010). "Interactions between gut inflammation and arthritis/spondylitis". Curr Opin Rheumatol. 22 (4): 368–74. doi:10.1097/BOR.0b013e3283393807. PMID 20485176.
  4. ↑ Mallas EG, Mackintosh P, Asquith P, Cooke WT (November 1976). "Histocompatibility antigens in inflammatory bowel disease. Their clinical significance and their association with arthropathy with special reference to HLA-B27 (W27)". Gut. 17 (11): 906–10. PMC 1411211. PMID 1001980.
  5. ↑ Brown MA, Pile KD, Kennedy LG, Calin A, Darke C, Bell J, Wordsworth BP, Cornélis F (April 1996). "HLA class I associations of ankylosing spondylitis in the white population in the United Kingdom". Ann. Rheum. Dis. 55 (4): 268–70. PMC 1010149. PMID 8733445.
  6. ↑ Mertz AK, Wu P, Sturniolo T, Stoll D, Rudwaleit M, Lauster R, Braun J, Sieper J (February 2000). "Multispecific CD4+ T cell response to a single 12-mer epitope of the immunodominant heat-shock protein 60 of Yersinia enterocolitica in Yersinia-triggered reactive arthritis: overlap with the B27-restricted CD8 epitope, functional properties, and epitope presentation by multiple DR alleles". J. Immunol. 164 (3): 1529–37. PMID 10640771.
  7. ↑ Fantini MC, Pallone F, Monteleone G (May 2009). "Common immunologic mechanisms in inflammatory bowel disease and spondylarthropathies". World J. Gastroenterol. 15 (20): 2472–8. PMC 2686905. PMID 19468997.
  8. ↑ Taurog JD, Richardson JA, Croft JT, Simmons WA, Zhou M, Fernández-Sueiro JL, Balish E, Hammer RE (December 1994). "The germfree state prevents development of gut and joint inflammatory disease in HLA-B27 transgenic rats". J. Exp. Med. 180 (6): 2359–64. PMC 2191772. PMID 7964509.
  9. ↑ Laukens D, Peeters H, Marichal D, Vander Cruyssen B, Mielants H, Elewaut D, Demetter P, Cuvelier C, Van Den Berghe M, Rottiers P, Veys EM, Remaut E, Steidler L, De Keyser F, De Vos M (June 2005). "CARD15 gene polymorphisms in patients with spondyloarthropathies identify a specific phenotype previously related to Crohn's disease". Ann. Rheum. Dis. 64 (6): 930–5. doi:10.1136/ard.2004.028837. PMC 1755516. PMID 15539413.
  10. ↑ Rothfuss KS, Stange EF, Herrlinger KR (August 2006). "Extraintestinal manifestations and complications in inflammatory bowel diseases". World J. Gastroenterol. 12 (30): 4819–31. PMC 4087615. PMID 16937463.
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