Definition History Gut-synovium axis Enteropathic arthritis:

◦ Inflammatory Bowel Disease Mechanism

◦ Infectious enteritis (reactive arthritis)◦ Whipple’s disease◦ Intestinal bypass surgery◦ Celiac disease

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

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

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% ?

Peng S. WRAMC. Feb 2009

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

Holden w, et al. Rheumatic Disease Clinics of North America 2003;29:513-530.

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

De Vos, et al. Gastroenterology 1996;110(6):1696-703.

Reactive Arthritis◦ Acute lesions

Undifferentiated arthritis◦ Chronic > acute lesions

AS◦ Chronic >>acute lesions

Arthritis remission = normal gut histology Joint flares = gut inflammation

De Vos et al. Gastroenterol. 1996;110:1696.Mielants et al. J Rheumatol. 1995;22:2279.

Rudwaleit M and Baeten D. Best Pract Res Clin Rheumatol. 2006;20:451-471.

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

Rudwaleit M and Baeten D. Best Pract Res Clin Rheumatol. 2006;20:451-471

Chronic inflammation at greatest risk Peristently high C-reactive protein Radiographic sacroiliitis in the absence of

HLA-B27

Crohn’s:◦ Entire GI tract from

mouth to anus: Ileitis 30% Ileocolitis 40% Colitis 30%

Bimodal age distribution

20-100 per 100,000 Skip Lesions and

transmural inflammation

Limited to the colon, most have rectal involvement◦ Proctosigmoiditis 50%◦ Left sided colitis 30%◦ Extensive colitis 20%

Age 20-25 yrs 70-150 per 100,000 Contiguous lesions Micro-ulcerations Crypt abscesses

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

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

Peripheral arthritis:◦Type I Pauciarticular (5 or fewer joints)

◦Type II Polyarticular

Axial Arthritis (Type III):◦Sacroiliitis/Spondylitis

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

Orchard TR,et al. Gut 1998;42:387-391.

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

Holden w, et al. Rheumatic Disease Clinics of North America 2003;29:513-530.

Incidence:◦2.5% in UC and 4% in Crohn’s

Polyarticular arthritis:◦ 5 or more joints◦Most common: MCP’s

No HLA-B27 associationAssociated with HLA-B*44

Exacerbations/remissions

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 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

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

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

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

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

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

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

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

Kethu S. J Clin Gastroenterol 2006; 40(6):467-475.

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

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

www.hopkins-arthritis.org

Spine:◦ 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

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

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

www.uptodate.com

Erythema Nodosum: 10-15%◦ 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

www.nature.com

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

Kethu S. J Clin Gastroenterol 2006; 40(6):467-475.

NSAIDS:◦ 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)

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 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

Rudwaleit M and Baeten D. Best Pract Res Clin Rheumatol. 2006;20:451-471

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

Lab abnormalities: ◦ 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

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Peripheral 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

Fatal if not treated Initial antibiotic therapy:

◦ Ceftriaxone 2 grams IV q 12+ streptomycin 1 g IV q 24 hrs for 10-14 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

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

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

Therapy◦ NSAIDs◦ Antibiotics◦ Corticosteroids

Effective for both the arthritis and dermatitis Surgical revision

◦ Total revision is curative

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

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

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

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

www.nature.com

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

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

De Vos, et al. Long term evolution of gut inflammation in patients with spondyloarthropathy. Gastroenterology 1996;110(6):1696-703.

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;29:513-530. Orchard TR, et al. Peripheral arthropathies in inflammatory bowel disease: their articular distribution and

natural history. Gut 1998;42:387-391. Kethu S. Extraintestinal Manifestations of Inflammatory Bowel Disease. J Clin Gastroenterology

2006;40(6):467-475. Gioncjetti P, et al. Extraintestinal menifestations and complications in inflammatory bowel diseases. World J

Gastroenterol 2006; 12(30):4819-4831. Khan M. Update on spondyloarthropathies. Ann Intern Med 2002;136:896-907. Colombo E, et al. Enteropathic spondyloarthropathy: A common background with inflammatory bowel

disease? World J Gastroenterology 2009;15(20):2456-2462. Orchard TR, et al. Peripheral arthropathies in inflammatory bowel disease: their articular distribution and

natural history. Gut 1998;42:387-391. Reveille J, et al. Spondyloarthritis: update on pathogenesis and management. The American Journal of

Medicine 2005; 118: 592-603. Wollheim F, et al. Enteropathic arthritis: how do the joints talk with the gut? Curr Opin Rheumaatol 2001;

13:305-309. Mielants H, et al. Gut Inflammation in the Spondyloarthropathies. Current Rheumatology Reports 2005;

7:188-194. Minerva P, et al. Enteropathic Arthopathies 2008. Emedicine. www.uptodate.com www.nature.com www.mdconsult.com