 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 association
 Associated 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 www.nature.com

◦ 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
 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
www.uptodate.com
 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