41.

Chapter 34 Enteropathic Arthritis

Manual of Rheumatology and Outpatient Orthopedic Disorders

---

Chapter 34 Enteropathic Arthritis

---

Kyriakos A. Kirou and Allan Gibofsky

Inflammatory bowel disease
Enteropathic reactive arthritis
Other spondyloarthritides
Whipple's disease
Intestinal bypass arthritis (arthritis-dermatitis syndrome)
Celiac disease
Pancreatic disease
Syndromes associated with vasculitis

Enteritis has been pathogenetically linked to arthritis in certain human (and experimental animal model) systemic inflammatory disorders, collectively comprising the enteropathic arthritides. Bacteria have been thought to play a significant role in these diseases, either when exposure to normal intestinal flora is increased (as in ulcerative colitis, in which intestinal permeability is increased), or when enteric infection with certain arthritogenic bacteria, such as Shigella, occurs (reactive arthritis). However, synovial fluid cultures are characteristically negative, and by definition, septic arthritides are excluded from the classification of enteropathic arthritides. Genetic factors are also implicated. In particular, inflammatory bowel disease- related arthritis and reactive arthritis belong to the clinically distinct group of spondyloarthritides, which are characterized by familial aggregation and a strong association with the class I major histocompatibility complex (MHC) allele HLA-B27 (see Chapter 6). Other common features of the spondyloarthritides, of which ankylosing spondylitis is the prototype, include sacroiliitis (with or without spondylitis), enthesitis, asymmetric oligoarthritis, uveitis, mucocutaneous inflammation, and seronegativity for rheumatoid factor. Notably, subclinical gut inflammation has been documented in all forms of spondyloarthritis.

Enteropathic arthritides that are not associated with HLA-B27 include those occurring in the context of Whipple's disease and celiac disease and after intestinal bypass surgery. If the inclusion criteria for enteropathic arthritides were loosened to accept disorders that simply combine joint and abdominal symptoms, the list could be extended to include vasculitic syndromes, pancreatic disease, Beh §et's disease, and familial Mediterranean fever .

I. Inflammatory bowel disease. Ulcerative colitis and Crohn's disease share similar extra-intestinal and rheumatic manifestations . Both peripheral and axial arthritis can occur.

1. Epidemiologic and genetic considerations
   1. In whites, the prevalence of either ulcerative colitis or Crohn's disease is between 50 and 100 in 100,000.
   2. Peripheral arthritis occurs in 10% to 25% of patients and is slightly more common in Crohn's disease. Men and women are equally affected, and the peak age of onset is between 25 and 44 years . There is no association with HLA-B27.
   3. Axial involvement is more frequent in Crohn's disease (5% to 22%) than in ulcerative colitis (2% to 6%). There is no male predominance, as there is in ankylosing spondylitis, and only 50% to 70% of patients are positive for HLA-B27. In fact, the presence of ankylosing spondylitis in patients negative for HLA-B27 should predict inflammatory bowel disease or psoriatic arthritis.
2. Clinical manifestations and diagnosis
   1. Peripheral arthritis
      1. Usually acute, migratory, and transient. Recurrences are common.
      2. Asymmetric and oligoarticular pattern, typically involving the large and small joints of the lower extremities. Dactylitis can occur.
      3. Usually follows bowel symptoms. It tends to correlate with extent and activity of gut inflammation and often coincides with other bowel activity-related extra-intestinal manifestations (erythema nodosum, enthesitis, aphthous oral ulcerations, finger clubbing, and possibly also uveitis).
      4. Laboratory studies
         1. Anemia and a high erythrocyte sedimentation rate are common with flares of arthritis.
         2. Results of synovial fluid analysis are consistent with inflammatory arthritis: 4,000 to 40,000 leukocytes per milliliter (70% to 90% polymorphonuclear leukocytes). Cultures are sterile.
         3. Joint radiographic findings are nonspecific, with soft- tissue swelling and juxtaarticular osteoporosis. Asymmetric metatarsophalangeal erosions and reactive bone formation can rarely be seen.
      5. Differential diagnosis of inflammatory bowel disease peripheral arthritis
         1. Migratory arthritis should be distinguished from rheumatic fever.
         2. Acute monarthritis can closely resemble septic arthritis, gout, or pseudogout.
   2. Axial involvement (sacroiliitis and spondylitis)
      1. Clinically and radiographically indistinguishable from idiopathic ankylosing spondylitis.
      2. Occurs independently of bowel disease activity and extent, and frequently precedes it by several years. In as many as 6% of patients with ankylosing spondylitis, Crohn's disease may evolve .
      3. Differential diagnosis in cases in which intestinal symptoms are not present at presentation can be difficult. Other causes of low back pain should be considered (see Chapter 18).
3. Treatment
   1. Therapy should be directed primarily at the intestinal inflammation, as it will usually control the acute peripheral arthritis also.
   2. Sulfasalazine (1 g twice daily) is effective in ulcerative colitis (both treatment of active disease and prevention of relapses ) but less so in Crohn's disease. Importantly, it has been recently shown to be useful and well tolerated in the management of peripheral arthritis in many forms of spondyloarthritis. However, it may be less effective in axial inflammation than a nonsteroidal inflammatory drug (NSAID), such as indomethacin.
   3. NSAIDs in standard doses are effective in the treatment of peripheral arthritis and axial inflammatory symptoms. However, because they may induce flares of ulcerative colitis, they should be used with caution.
   4. Intraarticular corticosteroid injections can be very helpful, especially in monarticular disease. Systemic corticosteroids should not be used for arthritis alone.
   5. Colectomy cures peripheral arthritis in ulcerative colitis but does not alter the course of spondylitis.
4. Prognosis
   1. Prognosis for peripheral disease is generally good. Chronic disease will develop in only 10% of patients.
   2. Prognosis for axial disease is similar to that of ankylosing spondylitis.

II. Enteropathic reactive arthritis is a form of spondyloarthritis that typically occurs 1 to 3 weeks after an acute intestinal infection with certain arthritogenic bacteria (e.g., Shigella flexneri, Campylobacter jejuni, and some Salmonella and Yersinia species). It is usually seen in a patient positive for HLA-B27. Occasionally, diarrhea can be subclinical, making the diagnosis less obvious. The large joints of the lower extremities are usually affected, and full Reiter's syndrome can occur (see Chapter 36). Antibiotics have not been shown to alter the disease course.

III. Other spondyloarthritides. Less prominent intestinal symptoms may occur in other forms of spondyloarthritis. In fact, endoscopic studies of the colon and ileum have shown macroscopic inflammatory lesions in 18% to 50% of patients with spondyloarthritis. The prevalence of such lesions is even higher by histologic criteria. Acute inflammatory changes resemble those of bacterial enteritis, and chronic inflammatory lesions are similar to those seen in Crohn's disease. Chronic gut inflammation is associated with more severe and persistent arthritis or spondylitis, and the condition occasionally evolves into clinically apparent Crohn's disease.

IV. Whipple's disease. This rare multisystem disease has been recently shown to be caused by a gram-positive actinomycete ( Tropheryma whippelii ).

1. Clinical presentation. Whipple's disease affects men ages 35 to 60. It is characterized by the insidious onset of fever, arthritis, malabsorption, generalized lymphadenopathy, skin hyperpigmentation, uveitis, or progressive encephalopathy. The typically symmetric, transient, and nondeforming polyarthritis occurs in 80% of the patients and may precede enteritis by several years.
2. Diagnosis. Until recently, the diagnosis depended on duodenal biopsy and the demonstration of deposits in lamina propria macrophages that stained with periodic acid “Schiff (PAS). In other tissues, electron microscopic demonstration of characteristic rod-shaped bacilli was necessary. However, a specific diagnosis can now be made from tissue and even from peripheral blood, with use of the polymerase chain reaction to verify the presence of the causative microorganism.
3. Treatment. Antibiotic therapy is effective, but relapses can occur. Parenteral antibiotic therapy with penicillin G (1.2 million U/d) and streptomycin (1 g/d) is recommended for the first 2 weeks, followed by oral trimethoprim/sulfamethoxazole (160/800 mg twice daily) for 1 to 2 years. Agents that do not cross the blood “brain barrier should probably be avoided.

V. Intestinal bypass arthritis (arthritis-dermatitis syndrome). Jejunoileostomy or jejunocolostomy, performed for morbid obesity, often results (after 2 to 30 months) in the arthritis-dermatitis syndrome. A symmetric and migratory nondeforming polyarthritis of the large joints is observed in 20% to 80% of patients and may become chronic in 25%. Other features include erythema nodosum, macular and vesiculopustular skin lesions, Raynaud's phenomenon , serositis, glomerulonephritis, retinal vasculitis, and superficial thrombophlebitis. The syndrome has been attributed to bacterial overgrowth in the blind loop with alteration of bowel permeability and formation of bacterial antigen-containing immune complexes.

1. Laboratory studies, including evaluation of peripheral blood, synovial fluid, stool, and joint radiography are not diagnostically helpful.
2. Treatment. NSAIDs are effective against arthritis, but courses of oral antibiotics (e.g., with tetracycline, clindamycin, or metronidazole) may offer additional help. Nevertheless, only surgical re-anastomosis of the bypassed intestinal segment provides a cure. By 1985, bypass surgery for obesity was largely abandoned , so the clinician is unlikely to see further cases.

VI. Celiac disease, or gluten-induced enteropathy, is a rare disease characterized by mucosal abnormalities of the small intestine and malabsorption. Association with many autoimmune disorders has been noted, and arthritis occurs in fewer than 50% of patients.

1. Clinical presentation and diagnosis. Arthritis is usually polyarticular and often involves hand and wrist joints. Half of patients have no intestinal symptoms. In that clinical scenario, the presence of malaise, weight loss, and low serum folate levels can be very helpful in diagnosis. Bone pain resulting from osteomalacia may also occur.
2. Treatment. Arthritis usually responds well to a gluten-free diet.

VII. Pancreatic disease. Chronic pancreatitis or pancreatic cancer can sometimes be associated with nodular subcutaneous fat necrosis and arthritis. A history of alcoholism is common.

1. Laboratory studies. Serum pancreatic enzymes are usually elevated. Synovial fluid may contain calcified necrotic fat particles, which can be confused with negatively birefringent crystals on polarized microscopy.
2. Treatment. Prompt diagnosis is essential, and therapy should be focused on the underlying pancreatic disease.

VIII. Syndromes associated with vasculitis, such as Henoch-Sch nlein purpura and systemic lupus erythematosus, can give rise to both abdominal pain (caused by involvement of mesenteric arteries) and arthritis. Diagnostic and treatment efforts are directed at the primary disease.

Bibliography

Calin A, Taurog JD. The spondyloarthritides. Oxford, UK: Oxford University Press, 1998.

Lowsky R, et al. Brief report: diagnosis of Whipple's disease by molecular analysis of peripheral blood. N Engl J Med 1994;331:1343.

Mielants H, Veys EM. Enteropathic arthritis. In: Koopman WJ, ed. Arthritis and allied conditions. Baltimore: Williams & Wilkins, 1997.

Singer R. Diagnosis and treatment of Whipple's disease. Drugs 1998;55:699.

Books@Ovid
Copyright 2000 by Lippincott Williams & Wilkins
Stephen A. Paget, M.D., Allan Gibofsky, M.D., J.D. and John F. Beary, III, M.D.
Manual of Rheumatology and Outpatient Orthopedic Disorders