Rheumatologic Manifestations of Gastrointestinal Diseases

Enteropathic Arthritis

• 1.

  How often does an inflammatory peripheral or spinal arthritis occur in patients with idiopathic inflammatory bowel disease (IBD)?

  Arthritis is the most common extraintestinal manifestation (EIM) of either type of IBD (Crohn’s disease [CD] and ulcerative colitis [UC]) affecting up to 20% of patients ( Table 63-1 ).

  Table 63-1

  Frequency of Peripheral or Spinal Arthritis in Inflammatory Bowel Disease

  	Ulcerative Colitis	Crohn’s Disease
  Peripheral arthritis	5%-10%	10%-15%
  Sacroiliitis/spondylitis *	5%-15%	10%-20%

  * Overall, 5% of ulcerative colitis patients and 10% of Crohn’s disease patients develop ankylosing spondylitis, whereas 15%-20% of all inflammatory bowel disease patients have asymptomatic radiographic sacroiliitis.

• 2.

  What are the most common joints involved in UC and CD patients with an inflammatory peripheral arthritis?

  Upper extremity and small joint involvement is more common in UC than in CD. Both UC- and CD-related arthritis affect the knee and ankle predominantly ( Figure 63-1 ).

  

• 3.

  Describe the clinical characteristics of the inflammatory peripheral arthritis associated with idiopathic IBD.

  Type I (arthritis often parallels IBD activity) occurs in 4% to 6% of patients with IBD. It affects both males and females equally. Children are affected as often as adults. The arthritis is typically acute (80%) in onset and asymmetric (80%). It usually involves fewer than five joints (i.e., oligoarticular), especially the knees or ankles. It occurs prior to (30% of cases) or early in the course of the bowel disease and is strongly associated (80%) with flares of IBD and other extraarticular manifestations (erythema nodosum, uveitis). Synovial fluid analysis reveals an inflammatory fluid with up to 50,000 white blood cells (WBC)/mm ³ (predominantly neutrophils) and negative findings on crystal examination and cultures. There is an increased prevalence of human leukocyte antigen (HLA)-B27, HLA-B35, and HLA-DRB1*0103 in this type of arthritis. Most arthritic episodes are self-limited (80% within 3 months) and do not result in radiographic changes or deformities.

  Type 2 (arthritis independent of IBD activity) is less common, occurring in 3% to 4% of IBD cases. The arthritis tends to be symmetric (80%), polyarticular (metacarpophalangeal joints, knees, and ankles more than other joints), runs a course independent of the activity of IBD, and does not coincide with extraarticular manifestations (except uveitis). Active synovitis persists for months (90% of cases) and episodes of exacerbations and remissions may continue for years. Because of its chronicity, this type of arthritis can cause erosions and deformities. There is an association of this arthritis with HLA-B44 but not with HLA-B27 .

• 4.

  What other EIMs commonly occur in patients with idiopathic IBD and inflammatory peripheral arthritis?

  Approximately 25% of patients with IBD have a combination of EIMs. The development of one manifestation increases the risk of developing others. In IBD patients with arthritis, the following EIMs may be seen:

  • P =Pyoderma gangrenosum (less than 5%)

  • A = Aphthous stomatitis (less than 10%)

  • I =Inflammatory eye disease (acute anterior uveitis) (5%-15%)

  • N = Nodosum (erythema) (less than 15%)

• 5.

  Does the extent and activity of IBD correlate with the activity of the peripheral inflammatory arthritis?

  Patients with UC and CD are more likely to develop a peripheral arthritis if the colon is extensively involved. In patients with type 1 arthritis, most arthritic attacks occur during the first few years following onset of the bowel disease, but late occurrences also occur. The episodes coincide with flares of bowel disease in 60% to 80% of patients. The arthritis may precede symptoms of IBD in up to 30% of cases, especially in children with CD. Consequently, lack of gastrointestinal (GI) symptoms and even a negative stool guaiac test do not exclude the possibility of occult CD in a patient who presents with a characteristic arthritis.

• 6.

  Which points in the history and physical examination are helpful in separating inflammatory spinal arthritis from mechanical low back pain in an IBD patient?

  On the basis of history and physical examination, 90% of patients with inflammatory spinal arthritis can be differentiated from patients with mechanical low back pain ( Table 63-2 ).

  Table 63-2

  Clinical Differentiation of Inflammatory Spinal Arthritis and Mechanical Low Back Pain

  	Inflammatory SA	Mechanical LBP
  Onset of pain	Insidious	Acute
  Duration of morning stiffness	> 60 min	< 30 min
  Nighttime pain	Yes	Infrequent
  Exercise effect on pain	Improvement	Worsen
  Sacroiliac joint tenderness	Usually	No
  Range of back motion	Global loss of motion	Abnormal flexion
  Reduced chest expansion	Sometimes	No
  Neurologic deficits	No	Possible
  Duration of symptoms	> 3 mo	< 4 wk

  LBP, Low back pain; SA, spinal arthritis.

• 7.

  Does the activity of inflammatory spinal arthritis correlate with the activity of the IBD?

  No. The onset of sacroiliitis or spondylitis can precede onset of IBD by years, occur concurrently, or follow onset by years. Furthermore, the course of the spinal arthritis is completely independent of the course of IBD.

• 8.

  What HLA occurs more commonly than expected in patients with inflammatory spinal arthritis associated with IBD?

  HLA-B27 is found in 55% of CD patients and 70% of UC patients with inflammatory sacroiliitis or spondylitis. This contrasts with an 8% frequency of HLA-B27 in a normal, healthy, white population. Thus a patient with IBD who possesses the HLA-B27 gene has 7 to 10 times increased risk of developing inflammatory sacroiliitis or spondylitis compared with IBD patients who are HLA-B27 negative.

• 9.

  What serologic abnormalities are seen in patients with IBD?

  • Erythrocyte sedimentation rate (ESR) and C-reactive protein are elevated, whereas rheumatoid factor and antinuclear antibody are negative.

  • Perinuclear antineutrophil cytoplasmic antibody is seen in more than 55% to 70% of UC patients and fewer than 20% of colon-predominant CD patients. It is usually directed against lactoferrin and less commonly bactericidal permeability increasing protein, cathepsin G, lysozyme, or elastase. It is never directed against myeloperoxidase.

  • Anti- Saccharomyces cerevisiae is present in 40% to 70% of CD patients and rarely (< 15%) in UC patients.

• 10.

  Describe the typical radiographic features of inflammatory sacroiliitis and spondylitis in IBD patients.

  The radiographic abnormalities in IBD patients with inflammatory spinal arthritis are similar to those seen in ankylosing spondylitis. Patients with early inflammatory sacroiliitis frequently have normal plain radiographs. In these patients, magnetic resonance imaging of the sacroiliac joints demonstrates inflammation and edema ( Figure 63-2 A ). Over several months to years, patients develop sclerosis and erosions in the lower two thirds of the sacroiliac joint (see Figure 63-2 B ). In some patients, these joints may completely fuse.

  

  Patients with early spondylitis may also have normal radiographs. Later, radiographs may show shiny corners at the insertion of the annulus fibrosis, anterior squaring of the vertebrae, and syndesmophyte formation ( Figure 63-3 A ). Syndesmophytes (calcification of annulus fibrosis) are thin, marginal, and bilateral. A “bamboo spine” (bilateral syndesmophytes traversing the entire spine from lumbar to cervical) (see Figure 63-3 B ) occurs in 10% of patients. Patients who develop inflammatory hip disease are at increased risk for subsequently developing a bamboo spine.

  

• 11.

  What other rheumatic problems occur with increased frequency in IBD patients?

  • Achilles tendon and plantar fascia enthesitis

  • Clubbing of fingernails (5%, mostly CD)

  • Hypertrophic osteoarthropathy (periostitis)

  • Psoas abscess or septic hip from fistula formation (CD)

  • Osteoporosis secondary to medications (i.e., prednisone)

  • Granulomatous lesions of bone and joints (CD)

  • Vasculitis (< 5%)

  • Amyloidosis

• 12.

  Can treatment alleviate the symptoms of inflammatory peripheral arthritis or spinal arthritis in IBD patients?

  See Table 63-3 .

  Table 63-3

  Alleviation of Arthritic Symptoms in Inflammatory Bowel Disease

  	Peripheral Arthritis	Sacroiliitis/Spondylitis
  NSAIDs *	Yes	Yes
  Intra-articular corticosteroids	Yes	Yes (sacroiliitis)
  Sulfasalazine	Yes	No
  Immunosuppressives (MTX, 6-MP)	Yes	No
  Anti-TNFα	Yes	Yes
  Bowel resection
  UC	Yes	No
  CD	No	No

  CD, Crohn’s disease; FDA, Food and Drug Administration; IBD, inflammatory bowel disease; 6-MP, 6-mercaptopurine; MTX, methotrexate; NSAID, nonsteroidal antiinflammatory drug; TNF, tumor necrosis factor; UC, ulcerative colitis.

  * NSAIDs may exacerbate IBD. Sulfasalazine helps the peripheral arthritis in UC patients more than CD patients. Anti-TNFα agents that are FDA-approved and effective include infliximab, adalimumab, golimumab, and certolizumab pegol.

• 13.

  What rheumatic disorders are associated with pouchitis, lymphocytic colitis (LC), and collagenous colitis (CC)?

  Pouchitis is inflammation of the ileal pouch created following colectomy for UC. It occurs in up to 40% to 60% of patients having this surgery. Patients present with watery or bloody diarrhea. Some develop arthritic manifestations ( Table 63-4 ). Treatment includes metronidazole and ciprofloxacin. Surgical revision may be necessary in treatment-resistant cases.

  Table 63-4

  Rheumatic Disorders Associated with Pouchitis, Lymphocytic Colitis, and Collagenous Colitis

  	Pouchitis	LC	CC
  IBD-like peripheral inflammatory arthritis	Yes	Yes	Yes
  Rheumatoid arthritis	No	Yes	Yes
  Ankylosing spondylitis *	No	No	No
  Thyroiditis or other autoimmune disease	No	Yes	Yes

  CC, Collagenous colitis; IBD, inflammatory bowel disease; LC, lymphocytic colitis.

  * Up to 60% of patients with ankylosing spondylitis have asymptomatic Crohn-like lesions on right-sided colon biopsies. However, only 4% to 5% will evolve into overt inflammatory bowel disease.

  Microscopic colitis includes both LC and CC. Patients present with watery diarrhea and may develop arthritic manifestations (10%-20%) or autoimmune thyroiditis (see Table 63-4 ). Patients older than 65 years (80%) and females (60%) are most commonly affected. The diagnosis can only be made by tissue histologic examination obtained by colonoscopy. Budesonide is effective for inducing and maintaining clinical and histologic remission for CC and LC, and loperamide may ameliorate diarrhea . Evidence for benefit of bismuth subsalicylate and mesalamine with or without cholestyramine for treatment of CC or LC is weak.

• 14.

  Why are patients with IBD more prone to develop an inflammatory arthritis?

  The pathogenesis of gut-joint iteropathy is unknown. However, inflammation of the gut and joints appear to be tightly linked. When ileocolonoscopies are done on spondyloarthropathy (ankylosing spondylitis, reactive arthritis) patients without GI symptoms, up to 25% have macroscopic lesions and up to 60% have microscopic evidence of asymptomatic CD. Over time, 6% to 10% of these patients develop overt symptomatic CD. Alternatively, up to 10% of IBD patients without evidence of a spondyloarthropathy at onset of their GI symptoms will develop overt arthritis on followup.

  Environmental antigens capable of inciting rheumatic disorders enter the body’s circulation by traversing the respiratory mucosa, skin, or GI mucosa. The human GI tract has an estimated surface area of 400 m ² (200 times the body’s skin surface area) and functions not only to absorb nutrients but also to exclude potentially harmful antigens. The gut-associated lymphoid tissue, which includes Peyer patches, the lamina propria, and intraepithelial T cells, constitutes 25% of the GI mucosa and helps to exclude entry of bacteria and other foreign antigens. Whereas the upper GI tract is normally exposed to 10 ³ mucosa-adhering bacteria, the lower GI tract is constantly in contact with millions of bacteria (up to 10 ¹² /g of feces). The total number of bacterial cells called the human microbiota that we are exposed to is 10 times that of the number of cells of the body.

  Inflammation, whether from idiopathic IBD or from infection with pathogenic microorganisms, can disrupt the normal integrity and function of the bowel, leading to increased gut permeability. This increased permeability may allow nonviable bacterial antigens in the gut lumen to enter the circulation more easily. These microbial antigens could either deposit directly in the joint synovia, leading to a local inflammatory reaction, or cause a systemic immune response, resulting in immune complexes that then deposit in joints and other tissues. Genetic susceptibility is required to develop the immunologic response in the gut and joint, which results in persistent inflammation and tissue injury.