Enteropathic Arthritis

Enteropathic Arthritis

Outline Definition History Gut-synovium axis Enteropathic arthritis:
Inflammatory Bowel Disease Mechanism Infectious enteritis (reactive arthritis) Whipple’s disease Intestinal bypass surgery Celiac disease

Definition Arthropathies associated with disease of large and small intestines: Inflammatory bowel disease Crohn’s disease Ulcerative colitis Infectious enteritis (reactive arthritis) Whipple’s disease Intestinal bypass surgery Celiac disease

History 1922: Smith performed segmental bowel surgery to treat patients with RA 1935: Hench describes arthritis flares during colitis exacerbation subsiding with remission 1964: American Rheumatism Association considers enteropathic arthritis its own entity 1976: Moll and Wright propose inclusion of the enteropathic groups into the seronegative sponyloarthropathies The distinction between RA and IBD arthropathies was that IBD had pauci-articular, asymmetric pattern of peripheral joint involvement, the occurrence of sacroiliitis and spondylitis and peripheral enthesopathy and the absence of RF and nodules.

Patterns of Intestinal Inflammation in SpA
Type of SpA Macroscopic Microscopic Enterogenic ReA 30-46% 64-89% Urogenital ReA Uncommon 19% Undiff SpA 24-38% 24-72% AS 29-49% 25-62% Psoriatic (axial) 26% ? Subclinical gut inflammation has been described in AS as well as other SpA Peng S. WRAMC. Feb 2009

Inflammation Most with spondyloarthropathies do not have signs or symptoms of intestinal inflammation Many have subclinical intestinal inflammation 67% have macroscopic and microscopic gut inflammation on colonoscopy Acute changes similar to infectious enterocolitis Chronic changes suggestive of early CD Chronic lesions more common with a family history of AS or CD Retrospective studies of patients who have spondyloarthropathy (excluding those with psoriatic arthritis or spondyloarthropathy associated with IBD, show that up to 67% have features of macro and microscopic gut inflammation on ileocolonoscopy and some will go on to develop overt IBD. 2 types: acute inflammation resembling infectious enterocolitis and chronic inflammatory changes more suggestive of CD. Holden w, et al. Rheumatic Disease Clinics of North America 2003;29:

Inflammation Acute inflammatory lesions
Normal mucosal structure with infiltration of epithelium with: Neutrophils and eosinophils Crypt abscess formation Infiltration of lamina propria with PMN cells Chronic inflammatory lesions Disturbed mucosal architecture Irregular, blunted fused villi Distorted crypts and basal lymphoid aggregates Two histological types of gut inflammation can be distinguished in SpA: acute and chronic inflammation De Vos, et al. Gastroenterology 1996;110(6):

Inflammation Reactive Arthritis Undifferentiated arthritis AS
Acute lesions Undifferentiated arthritis Chronic > acute lesions AS Chronic >>acute lesions Arthritis remission = normal gut histology Joint flares = gut inflammation Reactive arthritis  acute changes, 20% of patients with ReA develop AS within 10-20yrs Undifferentiated SpA  chronic > acute AS chronic>>acute; clinically overt IBD (crohn’s or UC) has been present in 5-10% of patients with AS ***11 pts developed IBD 10 had chronic lesions Subset of patient underwent 1-3 repeat ileocolonoscopies Subset of 49 patients Normal histology remained normal 16 pts in remission for arthritis  NO intestinal inflammation 33 pts with persistent arthritis 14 pts had persistent chronic lesions 6 pts had developed IBD 7 of 19 pts with Undiff SpA  AS All had persistent intestinal lesions 11 pts with >2 ileocolonscopies Arthritis remission = nl gut histology Joint flares = reappearance of gut inflammation We’ll talk about this more with mechanisms of IBD arthropathy; however, there seems to be a “gut-synovium axis” We’ll looking at pre-inflammatory changes with this study. We’ll also talk about a study looking at patients with overt inflammation. We’ll talk about significance of genetics later De Vos et al. Gastroenterol. 1996;110:1696. Mielants et al. J Rheumatol. 1995;22:2279.

Inflammation Acute type inflammation in the gut in an AS patient – features like bacterial infection Chronic type inflammation of gut in AS patient – features like IBD Rudwaleit M and Baeten D. Best Pract Res Clin Rheumatol. 2006;20:

Spondyloarthopathic Ileitis and Crohn’s Disease
Subclinical vs. preclinical Crohn’s disease Study of 123 patients with SpA who underwent ileocolonoscopy Baseline and repeat at 2-9 years Normal 32% Acute lesions 23 % Chronic lesions 45%  6% developed CD 18% were HLA-B27 Rudwaleit M and Baeten D. Best Pract Res Clin Rheumatol. 2006;20:

Risk Factors for Arthritis and GI Disease
Chronic inflammation at greatest risk Peristently high C-reactive protein Radiographic sacroiliitis in the absence of HLA-B27

Inflammatory Bowel Disease
Crohn’s: Entire GI tract from mouth to anus: Ileitis 30% Ileocolitis 40% Colitis 30% Bimodal age distribution per 100,000 Skip Lesions and transmural inflammation Important histopathologic features of Crohn’s disease is the impairment of the integrity of the epithelial barrier. The adhesion molecule E-cadherin plays and important role in the barrier integrity by mediating homotypic, homophillic intracellular adhesion in epithelial cells. Up-regulation of E-cadherin and its associated catenins was demonstrated in clinically overt IBD. -- It is not only involved in epithelial cell-cell adhesion, it is also a ligand for the alphaEB7 integrin on intra-epithelial T cells. So, e-cadherin may not only alter the epithelial barrier function but may also play a role in the homing of specific T-lymphocyte populations in SpA gut mucosa.

Ulcerative Colitis Limited to the colon, most have rectal involvement
Proctosigmoiditis 50% Left sided colitis 30% Extensive colitis 20% Age yrs per 100,000 Contiguous lesions Micro-ulcerations Crypt abscesses

IBD and Peripheral Arthritis
9-53% of patients with IBD Arthritis is the most common extra-intestinal manifestation of IBD More likely with large bowel disease Can occur before bowel symptoms and at any time in the disease course Most frequent with extensive UC and CD: Abscesses Perianal disease Erythema Nodosum Pyoderma Gangrenosum

IBD and Peripheral Arthritis
Male=Female Occurs with children and adults Relationship between flares and severity of bowel disease (UC) In UC, surgical resection of diseased segment usually stops the arthritis In CD, surgical resection does not help arthritis

Classification of Arthritis
Peripheral arthritis: Type I Pauciarticular (5 or fewer joints) Type II Polyarticular Axial Arthritis (Type III): Sacroiliitis/Spondylitis

Type 1 (Pauciarticular) Peripheral Arthritis
Equal incidence between males and females Peak age of onset 25-44 Incidence is 3.6% in UC and 6% in Crohn’s Often parallels the intestinal activity Associated with HLA-DRB1*0103, HLA-B27 and HLA-B*35 Precedes the diagnosis of IBD and predominately involves the lower extremities In a recent large retrospective series from Oxford of 976 patients who had UC and 483 patients with CD the peripheral arthritis was subdivided into 2 groups. In this series, type 1 arthropathy was seen in 3.6% of patients with UC and in 6% with CD, type 2 2.5% in UC and 4% in crohn’s disease. In one cohort of patients peripheral arthritis was identified in 20% of patients with CD and 12% in patients with UC. Orchard TR,et al. Gut 1998;42:

Type 1 (Pauciarticular) Peripheral Arthritis
Pauciarticular arthritis: Less than 5 joints Most common joint: knee Acute (< 10 weeks) Self-limiting  90% less than 6 months Associated with IBD flares Strongly associated with extra-intestinal manifestations of IBD such as uveitis and EN Type 1 : parallels disease activity. Associated with bowel disease Early in the course of bowel disease Sometimes may precede bowel disease Incidence % overall in pt’s with Crohn’s and UC Does not result in joint deformities Holden w, et al. Rheumatic Disease Clinics of North America 2003;29:

Type II (Polyarticular) Peripheral Arthritis
Incidence: 2.5% in UC and 4% in Crohn’s Polyarticular arthritis: 5 or more joints Most common: MCP’s No HLA-B27 association Associated with HLA-B*44 Exacerbations/remissions Rarely precedes bowel disease Other joints involved – knees, ankles, elbows, shoulders, wrists, PIPs, MTPs Synovial biopsy is indistinguishable from RA

Type II (Polyarticular) Peripheral Arthritis
Chronic course independent of activity of the IBD Arthritis activity does not parallel bowel activity Duration: persists for months to years Associated with uveitis but not with other extraintestinal manifestations

Peripheral Arthritis Peripheral arthritis associated with IBD is seronegative Typically non-deforming and nonerosive Erosive disease affecting the hips, elbows, MCP joints, MTP joint and erosive polyarthritis has been described In MCP and MTP’s, arthropathy differs from RA as it is predominately asymmetric

Axial (Type 3) Arthritis
Ulcerative colitis 2-6%, Crohn’s 5-22% Presents as either: Spondylitis: 1-26% of IBD pts May occur with type I arthritis Sacroiliitis: Asymptomatic 4-18% of IBD pts Ankylosing spondylitis-like 3-10% of IBD pts Two types of sacroilitis in IBD: AS – indistinguishable from idiopathic AS and asymptomatic sacroilitis

Axial (Type 3) Arthritis
Male: female ratio 2:1 Occurs at any age Axial involvement and IBD course are usually independent Usually precede onset of IBD by many years Genetic associations CARD15 and ? HLA-B27 Inflammatory back pain Lumbar straightening, dorsal kyphosis, limited chest expansion Prospective study of 217 patients with SpA and no IBD at baseline ileocolonscopy found that 7.7% developed IBD within 2- 9years All these patient had non-specific inflammatory biopsy features on first exam and AS upon review ?association with HLA-B27 vs. CARD15 <5cm difference between full inspiration and full expiration when measured at the 4th intercostal space

Genetics and IBD Concordance in extra-intestinal manifestations of IBD
70% in parent-child pairs 84% in sibling pairs HLA-B27 CARD 15 Others: NOD2, HLA-B35, HLA-DRB1*0103, HLA-B44

HLA-B27 Pathologic role unknown
Impaired ability to process/present bacterial antigen to immune cells Constant source of immune stimulation Strongest association with idiopathic AS Less crucial in patients with IBD 50-70% + for HLA-B27 Idiopathic associated with HLA-B27 in more than 90% (75%-95%) of the cases; No association between isolated sacroiliitis and HLA-B27 Having established IBD and being HLA-B27 seems to put the patient at risk for development of AS; Radiographic sacroilitis in IBD patients if often unilateral and without clinical symptoms and is only weakly associated with HLA-B27 (0-20%). HLA b27 in the presence of intestinal inflammation such as IBD, HLA b27 seems to be relevant but less crucial compared with idiopathic AS ***It is these HLA-B27 positive individuals who develop persistent arthritis and spondylitis in presence of inflammatory bowel disease and in response to an infection of the bowel or urethrogenital tract Transgenic rats carrying human HLA-B27 and B-2-microglobulin develop many of the clinical features found in home reactive arthritis with IBD being the initial disease manifestation in the majority of animals. Susceptibility to this is related to gene copy number and expression of HLA-B27. However, HLA-b27 is not expressed on gut epithelium, even in chronic inflammatory bowel disease. Also, if the transgenic rat are raised in a germ-free environment, they do not develop GI and joint inflammation but the skin and male genital lesions are unaffected Animal models  findings demonstrate the need for a specific host predisposing factor and an environmental factor (exposure to bacterial pathogens) to produce disease Found in 75-95% of pts with idiopathic AS In 406 pts in Norway with IBD, HLA-B27 was positive in 13% of pts – similar to general population Higher association in pts with AS Radiographic AS in pts with IBD is only weakly associated with HLA-B27 Strong association of AS (with or without symptoms) **Type 1 peripheral arthritis is associated with HLA-B27 (26%), a rare DR1 antigen DRB1*103 is more common in type 1 than in type 2. HLA-B35 is also increased in type 1 and HLA-B44 is seen in type 2.

CARD 15 Gene coding for a protein involved in innate immunity
Increased risk of Crohn’s disease 78% of Crohn’s patients with sacroiliitis 48% of Crohn’s patients without sacroiliitis Association is independent of HLA-B27 Carrying the CARD15 mutations puts AS patients at risk for subclinical intestinal inflammation. CARD15 may form part of the genetic link between the intestinal inflammation and sacroiliac changes. CARD 15 (3 independent single nucleotide polymorphisms SNP’s in CARD15 are associated with crohn’s disease in 30-45% of patients. It is also involved in nuclear factor-kB (NF-kappa beta) activation and in apoptosis, although the precise pathologic role in crohn’s disease remains to be determined. -- Presence of CARD 15 polymorphisms in patients with SpA is associated with higher risk of chronic gut inflammation. Since only 6% with chronic gut inflammation will develop clinical IBD. CARD15 is not a useful predictor for the development of crohn’s disease in these patients but is associated with pathophysiologically associated with subclinical gut inflammation in spA. -- Also associated with the anti-saccharomyces cerevisiae antibodies

Rudwaleit M, et al. Best Pract Res Clin Rheumatol. 2006;20:451-471.

Mechanism Breach in GI wall integrity
Increased permeability to macromolecules Increased exposure to microbial and dietary antigens Loss of tolerance to own bacterial flora Host susceptibility to the increased antigenic load Recirculation of antigen-specific memory T- cells from gut to joints Exact mechanisms are unknown: HLA-B27 transgenic rats bred in pathogen free environment, gut and joint inflammation do not develop until normal bacterial flora is introduced. Unifying theory has been proposed  enhanced mucosal permeability and abnormally high levels of anaerobic bacteria colonizing inflammatory lesions in active IBD might lead to absorption of proinflammatory bacterial components, stimulating a pathologic immune response. This model does not explain axial involvement in IBD which is independent of gut pathology. Based on animal models, the role of bacterial antigens and the MHC class I linkage, it has been proposed that HLA-B27 is involved in priming and the re-activation of cytotoxic CD8+ T lymphocytes by presenting either specific bacterial peptides or arthritogenic self peptides that cross react with bacterial antigens -- Following hypothesis: specific T cells (not restricted to CD8+ T cells) are primed by bacterial antigens at the place of primary encounter with the bacterial antigens, the gut and subsequently recirculate between the gut and the peripheral joint where they could be re-activated by bacterial antigens or by cross reacting self peptides. -- In addition to antigen uptake and presentation by APC to t lymphocytes leading to T cell mediated inflammation, bacterial persistence could also lead to tissue inflammation by direct stimulation of inflammatory cells such as monocytes, macrophages and neutrophils but also intestinal epithelial cells (the so called innate immune system). --A group of molecules that play a central role in the innate immune recognition of bacterial products are the macrophage scavenger receptors. An important scavenger receptor is CD Macrophages expressing CD 163 are increased in the gut of crohn’s disease and SpA. They are also seen in the synovium. ** Taken together with NOD2/Card 15 role in SpA the data supports the concept of the combination of microbial triggering and an abnormal inflammatory response of the innate immune system in genetically susceptible hosts which can lead to a breakdown of the normal immunologic tolerance and to a pathogenic cellular immune response to specific bacterial species and/or cross reacting self molecules. As indicated this may lead to a disturbed balance between pro-inflammatory cytokines such as TNF alpha and anti-inflammatory cytokines such as IL-10 which may ultimately result in inflammation in the gut and joint

Kethu S. J Clin Gastroenterol 2006; 40(6):467-475.
Dysregulated immune responses to colonic bacteria might trigger T-cell mediated responses (T cells that are cross reactive to autoantigens), cytoekine production, and development of autoantibodies leading to colonic inflammation and possible extracolonic injury Cross-reactivity detected between a CEP and epitopes found in the eyes, biliary epithelium, and chondrocytes – all organs involved in EIMs Support theory of common antigen model based on “shared autoantigen” in 4 extracolonic organs – eye, skin, biliary epithelium, joints Human tropomysine (hTM) isoform 5 and colon epithelial specific protein (CEP) or complex are found in UC (not CD) and may act as autoantigen in pathogenesis of UC Autoantibodies belong to IgG1 subclass and can activate the complement system causing deposition of C3 and products of terminal complement complex (TCC) on coloncytes in UC CEP interacts with hTM5 and both are expressed on colon epithelial cell surface and released outside the cells Autoimmunity – 1st step is presentation of the autoantigenic pepitde (s) by non-specific antigen presenting cells – eg macrophages and dendriditc cells that trigger activation of the T(TH) cells that, in turn, help to prime a subset of B cells 2nd step – autoantigen-specific B cell subset expands in response to priming by autoreactive T cells Autoreactive T cells can induce cytotoxic lymphocytes (CTL) capable of recognizing specific cellular autoantigens Autoantigen specific B cells can also act as APC, maintaining perpetuation of inflammatory process Microbial peptide (s) crossreactive to the cellular autoantigenic epitope (molecular mimicry) or release of cryptic peptide by local factors such as truam may initiate the autoimmune response CEP/hTM5 associated epitope are expressed at selective extracolonic sites such as nonpigmented ciliary epithelium in the eye, keratinocytes, biliary epithelium, and chondrocytes Cytokines may also play a role ****In summary, in a genetically predisposed patient with IBD, complex interactions of bacterial or other local factors in the colon with APC may trigger activation of T cells leading to a cascade of events culminating in the production of cytokines and autoantibodies to a shared antigen in involved organs**** Kethu S. J Clin Gastroenterol 2006; 40(6):

Laboratory Lab findings as determined by activity of IBD
IDA, leukocytosis, thrombocytosis common RF negative Acute phase reactants increased HLA-B27and other HLA typing Synovial fluid: WBC 1500 – 50,000 PMN predominate Synovial membrane biopsy: Mild chronic inflammation indistinguishable from RA Proliferation of synovial lining cells, increased vascularity, infiltration of mononuclear cells

Radiology SI joints Indistinguishable from AS
Bilateral sacroiliac erosions “Pseudowidening” of the SI joint Fusion with complete obliteration of SI joint MRI is most sensitive/specific for sacroiliitis

Radiology Spine: Peripheral joints: Enthesitis:
Shiny corners or Romanus lesions Syndesmophytes Symmetric, delicate appearing, marginal Peripheral joints: Soft tissue swelling, juxta-articular osteoporosis, mild periositis, effusion Usually without erosions/destructions Enthesitis: Faint periosteal reaction at bony prominence

Postage stamp erosions

Kethu SR. J Clin Gastroenterol. 2006;40:467-475.

Ocular Manifestations
Anterior Uveitis: 0.5-3% of pts with IBD Unilateral vs. bilateral Associated with HLA-B27 and axial involvement Painful red eye, blurred vision and photophobia Optho consult and therapy with topical/systemic CS Episcleritis: 2-5% Hyperemia of sclera and conjunctiva No vision loss, painless TX: Treat underlying IBD NSAIDs and topical steroids Anterior uveitis: 0.5-3% of patients with IBD, anterior and can be unilateral most common vs bilateral -- painful red eye, blurred vision, photophobia, HA, iridospasm, not associated with IBD activity -- Need a rapid dx: optho consult --Tx: topical and systemic CS

Skin Manifestations Erythema Nodosum: 10-15% Pyoderma Gangrenosum:
Raised, warm tender nodules Coincides with exacerbations of IBD and thus with peripheral arthritis Therapy: NSAIDs, colchicine, TNF-inhibitors Pyoderma Gangrenosum: More common in UC 5% Associated with severe IBD Therapy: Systemic CS Infliximab, cyclosporine, cellcept EN: most common skin manifestation, unrelated to severity or extent of IBD. Tx the underlying IBD also dapsone can be used Pyoderma gangrenosum: pustules fluctuant; nodulesulcers

Osteoporosis Prevalence of 15% RR for fracture in IBD is 40-60%
Inflammatory bone-resportive cytokines IL-1,IL-6 and activated T cells Higher levels of RANKL expressed in CD Therapy: Bisphosphonates Calcium/vitamin D Minimize steroid use Weight bearing exercises Risk equal with males and females Screening DEXA scan: CS > 3 months, postmenopausal women or males > 50years and patients with low stress fractures Kethu S. J Clin Gastroenterol 2006; 40(6):

Therapy NSAIDS: Sulfasalazine Azathioprine 6-mercaptopurine
Adverse effects on bowel symptoms Concern about NSAID’s and development of IBD Limited evaluation with COX-2 inhibitors Sulfasalazine Azathioprine 6-mercaptopurine Aminosalicylates (mesalamine) New onset of IBD symtpoms or worsening of previously diagnosed bowel dz in pt whose arthritis is being tx’ed with NSAIDs presents challenging management problem Best way to eval?? Stop NSAIDs and eval for improvement in symptoms and mucosal appearance Sulfasalazine - absorbed in colon - antiarthritic Azathioprine & 6-MP – beneficial for IBD & arthritis Mesalamine – although good for gut, no direct anti-inflammatory effect on synovium Anticytokine therapy for Crohn’s and for RA or reactive arthritis Only anecdotal reports & small uncontrolled series that address usefulness of anti-TNF alpha tx

Therapy Biologics: Infliximab Beneficial for Crohn’s disease
Fistula formation Perianal disease Less efficacy in UC Etanercept No benefit for GI disease Adalimumab Approved for AS and IBD Similar benefits to infliximab Type I: Follows response of bowel disease, in UC colectomy often results in remission of peripheral arthritis Type II and III (axial arthritis): no improvement with medical or surgical treatment of IBD Difference is not entirely clear but may relate to defective apoptosis of mucosal T-cells in IBD – which is readily reverted by infliximab but not by etanercept Thus, infliximab is preferred

Therapy Type 1 peripheral arthritis: Treat the IBD
Sulfasalazine, MTX, AZA, TNF inhibitors and CS Type II and III (axial) arthritis No improvement with medical or surgical treatment of IBD NSAIDs effective but may exacerbate gut symptoms Sulfasalazine, MTX and Azathioprine TNF inhibitor therapy: use after no response with NSAIDs at 3 months Periperhal is nondestructive – therefore, symptomatic relief Treatment for axial disease is also symptomatic However, spine disease can progress to bony ankylosis Sulfasalazine favorable effect on peripheral arthritis but not much effect on axial MTX is frequently recommend  no evidence that it is beneficial in axial arthropathy Nonpharmacologic therapy such as PT for back exercises to prevent back deformities Role for TNF-alpha in spinal disease cannot be formally recommended?? TNF alpha agents is recommended when pts do not respond adequately to NSAIDs given for at least 3 mos

Given available evidence, AS patients in daily practice should be assessed thoroughly by taking a detailed history for symptoms suggestive of IBD If IBD is suspected on clinical grounds, endoscopic exam should be performed Currently, strategy of ileocolonoscopy is NOT recommended on every pt with AS. First, although chronic inflammation of gut histology is associated with later development of Crohn’s, the overall risk is small. Second, no evidence that AS pts with asymptomatic pre-existing histological gut inflammation are more prone to NSAID-induced colitis or IBD than pts with nl histology of gut Rudwaleit M and Baeten D. Best Pract Res Clin Rheumatol. 2006;20:

Enteropathic Enteropathy
Reactive Arthritis (Infectious enteritis) Whipple’s Intestinal Bypass surgery Celiac Disease

Whipple’s Disease Rare multisystem systemic disease
Infection caused by Tropheryma Whippelii Predominance in the small bowl Male to female ratio of 9:1 Mean age 55 (range 20-82) Symptoms: Diarrhea, weight loss, fever and arthritis LAD, hyperpigmentation, serositis, CNS In 1907, G.H Whipple described a 36 year old physician with: “gradual loss of weight and strength, stools consisting chiefly of neutral fat and fatty acids, indefinite abdominal signs and a peculiar arthritis”. The patient died. Bacteria is related to Actinomycetes -- Infected sites show very little inflammatory response to the organism -- It exerts no visible cytotoxic effects upon the host cells -- Host immunodeficiency? And Found in the saliva of 35% of healthy hosts Si/Sx: Axillary & cervical LAD, Synovial fluid – ,000/mm3, PMN predominant, X-ray – no erosive lesions

Whipple’s disease Lab abnormalities: Biopsy: PCR of tissue or blood
Anemia, hypoalbuminemia, low serum carotene and iron Increased stool fat Biopsy: Villi become distended with foamy and PAS + macrophages Rod-shaped free bacilli in the lamina propria PCR of tissue or blood

Whipple’s disease PAS-positive macrophages in the small intestine of an untreated patient with Whipple's disease

Whipple’s disease Peripheral arthritis Axial arthritis
Polyarticular and symmetric 67% as their only symptoms Migratory and episodic Precedes GI symptoms by 5 years Arthritis flares not related to GI symptoms Erosions rare Axial arthritis Incidence controversial 8-20% Relation to HLA-B27 unclear Weiner SR, Utsinger P. Whipple disease. Semin Arthritis Rheum 1986;15(3):157-67: Series of 25 patients with arthropathy (symmetric migratory polyarthritis was most common pattern seen Affects mainly knees, ankles and wrists; 40% hd axial involvment with SI and lumbar tenderness Radiographic signs similar to AS with sacroilitis, syndesmophytes and apophyseal anklyosis

Treatment Fatal if not treated Initial antibiotic therapy:
Ceftriaxone 2 grams IV q 12+ streptomycin 1 g IV q 24 hrs for days Then one year of Trimethoprim-sulfamethoxazole : 1 DS po bid Doxycycline: 100 mg po bid Can see Jarisch-Herxheimer reaction Fevers, chills, headache, hypotension, severe abdominal pain or pleuritic chest pain tetracycline is mainstay of therapy for many years Standard of care is bactrim Alternative is doxy Some recommend 2 weeks of IV therapy upfront

Intestinal bypass arthritis
Jejunocolic and jejunoileal bypass surgeries Inflammatory joints in 6-52% Usually within 3 years of surgery Females > males No HLA association Arthritis: Peripheral symmetric, polyarticular, Knees, wrists, MCP’s and MTP’s Vesiculopustular skin rash Occurs in over ½ of patients with arthritis developed for weight loss in 1952 for weight loss Metabolic complications in 25% of pts so no longer performed Similar symptoms in pts who have any derangement causing bacterial overgrowth from post-op, inflammatory, or diverticular conditions 11 yrs later arthritis was recognized as post-op complication May develop within weeks to years Joint pain & tenderness exceed objective findings in most cases of intestinal bypass associated arthropathy

Pathogenesis: Bacterial overgrowth in blind loop Mucosal changes allow increased absorption of bacterial antigens Formulation and circulation of immune complexes Immune complexes demonstrated in synovium, synovial fluid and skin lesions Over ½ with bypass arthritis develop skin lesions Vesiculopustular, macular or nodular; --Disseminated papulopustular hemorrhagic dermatosis – scattered papulopustular lesions due to neutrophilc infiltration of skin is seen in bowel-associated deramtosis arthritis syndreom in pts with IBD Immune complex contains bacterial antigens, their Ab, IgA componenet, and various complement components

Therapy NSAIDs Antibiotics Corticosteroids Effective for both the arthritis and dermatitis Surgical revision Total revision is curative

Celiac disease Gluten-sensitive enteropathy
First described by Samuel Gee in1888 Dutch pediatrician Willem Dicke in the 1940’snoted affected children improved during WW2 food shortages Effects one in every 300 people in Europe and North America If unrecognized and untreated 12% mortality.

Celiac Sprue Manifestations
Small bowel develops villous flattening and atrophy leading to malabsorption Symptoms: Diarrhea and weight loss 50% of adult patients do not have diarrhea Malaise, weight loss and low serum folate Steatorrhea, distension, flatulence, greasy stools Associated disorders: Dermatitis herpetiformis, hyposplenism, arthritis and autoimmune disorders

Celiac disease Usually occurs in 2nd-4th decades Prevalence:
0.4% of whites of Northern European ancestry Pathogenesis unclear: Characteristic by diffuse damage to proximal small bowel mucosa Strongly associated with HLA-DR3 and DQw2 Gluten (with/without viral infection  humoral and cell mediated inflammatory response

Farrell R and Kelly C. N Engl J Med 2002;346:180-188

Celiac disease Arthropathy:
Peripheral 37% Axial 29% Combined 25% Most common pattern is a polyarticular, symmetrical arthritis affecting large joints Non-erosive and non-deforming Knees, hips and shoulders High frequency of HLA-B8 and DR3 May precede GI symptoms A study of 200 consectutive adults with sprue found that 26% had arthritis: 41% on a regualr diet and 22% with gluten free diet -- 37% peripheral, 29% axial and 35% both -- Most common pattern is a polyarticular symmetrical arthritis affecting large joints (knees hips and shoulders). Usually non-erosive and non-deforming. Sacroilitis found in 64% in one study.

Celiac disease Schematic representation of the five main lesions associated with gluten sensitivity. The lesions range in histologic severity from a mild alteration characterized by increased intraepithelial lymphocytes (type 0 lesion) to a flat mucosa with total mucosal atrophy, complete loss of villi, enhanced epithelial apoptosis and crypt hyperplasia (type 3 lesion). The type 4 lesion is seen in T cell lymphoma. Low power view of a small bowel biopsy from a patient with celiac disease. The mucosa is flat with complete loss of the normal villous architecture

Celiac disease Labs: All three tests > 99% positive and negative predictive values IgA endomysial ab 90% sensitivity and specificity IgG and IgA antigliadin Ab (both) >95% sensitive and specific IgA tissues transglutaminase Ab 90-98% sensitivity and 85-95% specificity Treatment Gluten free diet Gluten free diet: difficult, expensive and socially a pain 70% of patients have improvement within 2 weeks of starting diet, MVI (iron,folate,calcium and vitamin D)

Conclusion Arthritis is very common with IBD
Autoimmunity and genetic predisposition are important in pathogenesis HLA-B27 and CARD15 Role of gut inflammation in spondyloarthropathies Pathogenesis still not completely clear Therapy is symptomatic

Questions ???

Bibliography De Vos, et al. Long term evolution of gut inflammation in patients with spondyloarthropathy. Gastroenterology 1996;110(6): Rudwaleit M, Baeten D. Ankylosing spondylitis and bowel disease. Best Pract Res Clin Rheumatol. 2006;20:451– 471. Holden w, et al. Enteropathic arthritis. Rheumatic Disease Clinics of North America 2003;29: Orchard TR, et al. Peripheral arthropathies in inflammatory bowel disease: their articular distribution and natural history. Gut 1998;42: Kethu S. Extraintestinal Manifestations of Inflammatory Bowel Disease. J Clin Gastroenterology 2006;40(6): Gioncjetti P, et al. Extraintestinal menifestations and complications in inflammatory bowel diseases. World J Gastroenterol 2006; 12(30): Khan M. Update on spondyloarthropathies. Ann Intern Med 2002;136: Colombo E, et al. Enteropathic spondyloarthropathy: A common background with inflammatory bowel disease? World J Gastroenterology 2009;15(20): Reveille J, et al. Spondyloarthritis: update on pathogenesis and management. The American Journal of Medicine 2005; 118: Wollheim F, et al. Enteropathic arthritis: how do the joints talk with the gut? Curr Opin Rheumaatol 2001; 13: Mielants H, et al. Gut Inflammation in the Spondyloarthropathies. Current Rheumatology Reports 2005; 7: Minerva P, et al. Enteropathic Arthopathies Emedicine.

Enteropathic Arthritis

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