Extraintestinal manifestations occur in 21% to 36% of patients with inflammatory bowel disease (IBD).1-5 The extraintestinal manifestations of IBD can be divided broadly into 3 groups.² The first group includes disorders involving the skin, eye, joints, and mouth. For the most part, these disorders occur in patients with colonic disease, and activity of these colitis - related manifestations parallels the activity of the underlying intestinal disease. The second group includes manifestations that are secondary to complications of or a direct extension of bowel disease. These usually occur in patients with Crohn’s disease (CD), include kidney stones, obstructive uropathy, malabsorption and gallstones. The third group includes manifestations that cannot be categorized clearly into one of the first two groups. These nonspecific extraintestinal manifestations include osteoporosis, hepatic diseases, and amyloidosis. Complications involving vascular, haematologic, pulmonary, cardiac and neurologic system probably belong to this third group.

Pathogenesis of Extraintestinal Manifestations
The pathogenesis of extaintestinal manifestations of IBD is not well understood. The concept of an autoimmune based process is supported by the primarily immunologic derangements underlying the development of IBD and the increased risk of autoimmune disease among patients with IBD.⁶ The importance of intestinal bacteria to the development of extraintestinal response is supported by animal studies in which the expression of extraintestinal (and intestinal) diseases requires the presence of commensal bacteria in HLA-B27 transgenic mice and T-cell receptor-mutant colitis models.^7,8 In a germ free environment, these models do not manifest either intestinal or extraintestinal pathologies. The current concept of autoimmunity in IBD centers on shared epitopes between bacterial proteins and host self antigens. Autoantibodies against human tropomyosin isoform 5, a cytoskeletal protein, and colon epithelial specific protein have been shown in patients with UC.^9-11 Epitopes associate with the colonic epithelial protein and human tropomyosin isoform 5 are expressed at extracolonic site, such as non pigmented biliary epithelium in the eye, keratinocytes, biliary epithelium and chondrocytes.^12,13 This pattern of selective reactivity corresponds to the clinical manifestations of extracolonic diseases in UC.¹⁴ The above described immunologic process is influenced by genetic factors. Extraintestinal manifestations in patients with CD are seen more commonly in patients with HLA-A2, HLA-DR1 and HLA-DQw5, whereas extraintestinal manifestations in patients with UC are more likely to have HLA-DR 103 phenotype.¹⁵

Musculoskeletal manifestation
Most common extraintestinal manifestations of IBD, can be grouped broadly into rheumatologic disorders and metabolic bone diseases. Rheumatologic disorders: Peripheral arthropathy occurs in 5% to 20% of patients with IBD.^1-5,16 The risk of developing peripheral arthropathy increases with the extent of colonic disease and with the presence of complications such as abscesses, perianal disease, erythema nodosum, stomatitis, Uveitis and pyoderma gangrenosum. The characteristics of peripheral arthropathy in IBD are summarized in Table 1.

The peripheral arthropathy associated with IBD was subclassified into 2 distinct types.17 Generally neither type leads to permanent joint deformity. Both types of peripheral arthropathy are seronegative (i.e. rheumatoid factor negative). Axial arthropathy is less frequent than peripheral arthropathy, occurring in 3% to 5% of patients. In contrast to the peripheral type, axial arthropathy does not parallel IBD activity. The axial arthropathy associated with IBD may be categorized spondylitis and isolated sacroiliitis. Most patients with spondylitis are HLA-B27 positive.¹⁸

Isolated sacroiliitis may be asymptomatic. Most patients with sacroliitis are HLA-B27 negative and do not progress to ankylosing spondylitis. Patients with the radiographic finding of bilateral sacroiliitis are more likely to progress to ankylosing spondylitis.¹⁹ Ankylosing spondylitis occurs in 5% to 10% of patients with IBD, and most of these patients are HLA-B27 positive.¹⁸ The course typically is progressive, resulting in permanent skeletal damage. Advance cases may show squaring of vertebral bodies, marginal syndesmophytes, and bony proliferation and ankylosis classically known as the bamboo spine.

Metabolic bone disorders
Osteoporosis and osteopenia are common in patients with IBD, occurring in 23% to 59% of patients.^20-23 Factors contributing to the low bone mineral density and mass in IBD patients include corticosteroid therapy, low physical activity, inflammatory cytokines, small bowel disease or resection, and vitamin D deficiency.^20,23 Osteomalacia is characterized by accumulation of bone matrix that fails to mineralize properly, with resultant fragile bone that predisposes to deformities and pseudofractures. Osteomalacia occurs in 1% to 5% of patients with CD and usually is caused by vitamin D deficiency.^24,25

Dermatologic manifestations
Cutaneous disorder associated with IBD occur in 15% patients.² Erythema nodosum and pyoderma gangrenosum are the 2 most commonly encountered dermatologic manifestations of IBD. The prevalence of erythema nodosum is reported to be 10% to 20% in patients with IBD.^2,26 The lesions appear as tender, red nodules, usually on the extensor surface of the lower extremities. Erythema nodosum correlates well with bowel disease activity and often occurs in conjunction with peripheral arthritis. These lesions usually respond to treatment of the underlying IBD.

Pyoderma gangrenosum occurs in 1% to 10% of patients with IBD and seems to be more common in patients with UC than CD. Usually begin as an erythematous pustule or nodule that spreads rapidly to adjacent skin and develops into a burrowing ulcer with irregular, violaceous edges.²⁷ The lesions typically occur on the extensor surface of the lower extremities but may occur elsewhere, including sites of trauma.28 Sweet’s syndrome or acute febrile neutrophilic dermatosis, is a rare dermatologic manifestation associated with CD and UC.^29,30 Patients with IBD may develop a variety of oral lesions. Aphthous and angular stomatitis are non-specific but the most common oral lesions in patients with IBD. Pyostomatitis vegetans is a pustular eruption of the oral mucosa resulting in a cobblestone appearance and is associated with CD or UC in most cases.³¹

Ophthalmologic manifestations
Ophthalmologic manifestations of IBD are reported to occur in 1.6% to 4.6% of patients with UC and 3.5% to 6.3% of patients with CD.^1,2,5,16

The two most common ocular manifestations associated with IBD are episcleritis and uveitis. Episcleritis is characterized by painless hyperaemia of the sclera and conjunctiva without loss of vision. In patients with uveitis, prompt, systemic or topical therapy is necessary to present progression to blindness.³² The incidence of posterior subcapsular cataracts increases with steroid dose and duration of usage and is reported to occur in 25% patients receiving 15 mg of prednisone for 1 year.³³

Haematologic manifestations
The most common haematologic complication of IBD is anaemia. The anaemia in patients with IBD may be a result of iron, vitamin B, or folate deficiency, chronic disease, or autoimmune haemolysis. Leucocytosis and thrombocytosis usually are associated with active disease. Leucopenia and thrombocytopenia usually occur as complications of medications, especially immunosuppressants and sulphasalazine.^34-36 The incidence of thromboembolic events in patients with IBD ranges from 1.3% to 39% in various retrospective studies.37,38 Hypercoagulable states manifests predominantly as deep vein thombosis or pulmonary emboli but renal artery thrombosis, cerebro vascular accident; Coronary artery thrombosis; and venous thrombosis of mesenteric, portal and hepatic vessels all have been reported.^37,38

Genitourinary and renal manifestations
The three most common genitourinary and renal manifestations of IBD occurring as direct result of bowel disease are nephrolithiasis, obstructive uropathy and fistulization to the urinary tract. These complications occur in 4% to 23% of patients with IBD.³⁹ The prevalence of nephrolithiasis is reported to be 7% to 10% in patients with IBD.^40,41 Common stones types are uric acid and calcium oxalate. Calcium oxalate stones occur with hypercalcaemia associated with either distal illegal CD or illegal resection.⁴² Obstructive uropathy in patients with IBD, particularly CD may occur secondary to extrinsic compression of the ureter by the intestinal inflammatory process.⁴³

Metastatic Crohn’s disease
Metastatic CD refers to the direct involvement by the primary inflammatory process at sites outside of the gastrointestinal tract. Metastatic CD is a rare diagnosis with the skin being the most commonly involved site. The cutaneous lesions appear as ulcerating nodules usually in skin folds classically located in the anterior abdominal wall and submammary areas, but they also may occur in upper and lower extremities.^44-48

Summary
Numerous extraintestinal diseases have been associated with IBD. Dysregulation of the enteric immune response results in pathology in various organs outside of the gut. Better understanding of the pathogenesis of IBD and the complex interactions between the gut immune system and the extraintestinal systems would provide insights into the development of many of these extraintestinal manifestations. Much is unknown about the presence of cardiac, pulmonary, and haematologic diseases in patients with IBD. An important consideration in all patients with IBD presenting with extraintestinal manifestations should be a careful search for medication related complications.

Associate Professor, Gastroenterology Division, Department of Medicine, Gandhi Medical College, Bhopal, MP.