definition history gut-synovium axis enteropathic arthritis: ◦ inflammatory bowel disease ...
TRANSCRIPT
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
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