Extraintestinal Manifestations of Inflammatory Bowel Disease: Focus on the Musculoskeletal, Dermatologic, and Ocular Manifestations

Introduction

Crohn's disease and ulcerative colitis, the 2 main subtypes of inflammatory bowel disease (IBD), are autoimmune disorders of unknown etiology that primarily involve the bowel. Additionally, multiple other organ systems can be affected in IBD, including the bones and joints, skin, eyes, hepatobiliary system, lungs, and kidneys (Table). Collectively, these are called extraintestinal manifestations of IBD, and they can occur prior to, in conjunction with, or subsequent to active bowel disease. The overall prevalence of any extraintestinal manifestation in IBD patients ranges from 21%–40%.[1–3] In most large studies of IBD, the prevalence of extraintestinal manifestations is higher in Crohn's disease compared with ulcerative colitis.[2–4] There may also be racial differences in prevalence, with blacks having a higher risk for eye and joint manifestations, and Hispanics having a higher risk for skin manifestations, compared with whites.[5]

Table 1.

Common Extraintestinal Manifestations of IBD

Musculoskeletal
Peripheral arthritis Sacroiliitis Ankylosing spondylitis Osteoporosis
Dermatologic
Erythema nodosum Pyoderma gangrenosum Aphthous stomatitis
Ocular
Uveitis Scleritis Episcleritis
Hepatobiliary Disease
Primary sclerosing cholangitis
Vascular
Thromboembolic events
Renal
Nephrolithiasis

This article focuses on the clinical implications of extraintestinal manifestations involving the musculoskeletal system, eyes, and skin, including issues in diagnosis and treatment.

Musculoskeletal Manifestations

The peripheral and axial musculoskeletal syndromes associated with IBD are considered part of the seronegative spondyloarthropathies, and are seen in approximately 30% of patients with IBD.[6] Peripheral arthritis associated with IBD is typically classified into types 1 and 2.[7] Type 1 disease affects fewer than 5 large joints, is acute and is self-limited, and is usually associated with active disease in the bowel. Type 2 disease typically chronic, affects 5 or more small joints, is symmetrical, and is not associated with the activity of the bowel disease. Axial arthropathies, including sacroiliitis and ankylosing spondylitis, are also associated with IBD but are usually independent of disease activity. Ankylosing spondylitis and sacroiliitis involve inflammation of the spine and sacroiliac joints, respectively. They present as pain and stiffness in the low back that is worse in the morning and relieved with exercise.

Prevalence and Risk

In a large, retrospective review of IBD patients, joint complications were found in 16% and 33% of those with ulcerative colitis and Crohn's disease, respectively.[8] Type 1 peripheral arthritis was found in 4% of ulcerative colitis and 6% of Crohn's disease patients. Type 2 disease was found in 3% of patients with ulcerative colitis and 4% of patients with Crohn's disease. Ankylosing spondylitis was found in 1% of both ulcerative colitis and Crohn's disease patients. The remainder of the patients were categorized as nonspecific arthralgias.[8] Many other studies have also found a higher risk of joint manifestations in Crohn's disease compared with ulcerative colitis.[2,3,6,9] Disease location also appears to influence risk. Patients with more extensive ulcerative colitis and colonic involvement in Crohn's disease are more likely to have joint complications.[3] There may also be subsets of IBD patients at increased risk for joint problems. For example, cigarette smoking and appendectomy were found to increase the risk of spondyloarthropathies in patients with ulcerative colitis.[10]

Issues in Diagnosis

The diagnosis of joint-related complications in IBD is based largely on the overall clinical picture and the exclusion of other disease processes. It is important to consider osteonecrosis, particularly in patients previously treated with corticosteroids. Septic arthritis should always be considered in the differential diagnosis. In addition, other intestinal disorders are associated with joint manifestations, including: Whipple's disease, Behcet's syndrome, and gluten-sensitive enteropathy.[11] Radiographs of the spine and sacroiliac joints can show the chronic changes associated with ankylosing spondylitis and sacroiliitis, such as syndesmophytes and sacroiliac erosions. In a study[12] in which Crohn's disease patients underwent computed tomography (CT) evaluation, 29% showed changes consistent with sacroiliitis whereas only 3% of those patients had symptoms of low back pain, suggesting that radiologic changes appear before symptoms.

Treatment

There are multiple therapeutic options for the management of seronegative spondyloarthropathy associated with IBD. Nonsteroidal anti-inflammatory drugs have traditionally been used to treat both axial and peripheral arthropathies. A small, open-label study[13] of a cyclooxygenase-2 inhibitor conducted in IBD patients with peripheral arthritis showed improvement in 41% of patients, with minimal side effects. These drugs are not optimal for treating IBD patients, as they may be associated with disease exacerbation.[14] In patients with spondyloarthropathies, sulfasalazine administered at doses of 3 g per day has been shown to significantly improve patients' overall assessment of their symptoms, and is therefore an option for patients taking aminosalicylates.[15] Methotrexate also has some effect in patients with ankylosing spondylitis and peripheral arthritis.[16] Multiple studies have also examined the effect of antitumor necrosis factor-alpha antibodies in the treatment of ankylosing spondylitis.[16–21] Infliximab, adalimumab, and etanercept have demonstrated rapid improvement in symptoms in the majority of patients with ankylosing spondylitis. On the basis of these studies, these medications should be considered in patients with IBD and significant axial arthropathies.

Osteoporosis

Patients with IBD are at increased risk for developing osteoporosis, secondary to the disease process itself, as well as secondary to the medications commonly used for treatment (such as corticosteroids). The fracture risk in IBD patients is 40% greater than that of the general population.[22] All IBD patients older than age 65, with a history of glucocorticoid use for more than 3 months' duration, should undergo bone mineral density scan.[23] Plain radiographs of the peripheral joints can show effusions and changes of osteoporosis, but typically demonstrate no evidence of erosion. Regular exercise and adequate calcium and vitamin D intake should be ensured with supplementation as necessary. Avoidance of tobacco, excess alcohol, and minimizing corticosteroid use are essential.[23] Bisphosphonates are effective in increasing bone mineral density in patients with osteoporosis and should be used in those with known osteoporosis, atraumatic fractures, and in patients who cannot withdraw from corticosteroids after 3 months.[24]

Dermatologic Manifestations

Erythema nodosum and pyoderma gangrenosum are the inflammatory cutaneous disorders most commonly associated with IBD. These 2 skin manifestations occur in 3%–12% of patients with IBD.[2,9,25] Erythema nodosum is more common among women with IBD and in patients with Crohn's disease; it typically appears as painful, red, subcutaneous nodules on extensor surfaces and mirrors disease activity (Figure 1).[7] Biopsy shows focal panniculitis. Pyoderma gangrenosum typically presents as ulcerated lesions that appear independent of disease activity, and is more difficult to treat (Figure 2).[26] Results of biopsy reveal a sterile abscess. Pyoderma gangrenosum can be induced or worsened by trauma and may appear around stoma or skin biopsy sites, a process referred to as pathergy.[7]

Figure 1.

Erythema nodosum. (Courtesy of Mayo Clinic Department of Dermatology)

Figure 2.

Pyoderma gangrenosum. (Courtesy of Mayo Clinic Department of Dermatology)

Erythema nodosum responds well to steroids and treatment of the underlying bowel disease.[27] Refractory cases may respond to infliximab.[28] Pyoderma gangrenosum is generally more resistant to treatment, and rapid aggressive therapy is recommended. Options include high-dose oral or intravenous steroids, cyclosporine, oral and topical tacrolimus, and mycophenolate mofetil.[27] Pyoderma gangrenosum also responds well to infliximab, which is a favorable option for patients who do not respond quickly to high-dose corticosteroids or are unable to be weaned off corticosteroids.[29]

Aphthous stomatitis appears as shallow tender ulcers in the oral cavity that can be associated with IBD. These lesions typically respond well to treatment of the underlying condition. Viral lesions such as herpes simplex should also be considered.[30]

Ocular Manifestations

Ocular manifestations of IBD should be considered in patients presenting with tearing, burning, itching, pain, or vision changes. Eye complications occur in approximately 3% of patients with IBD, and are more frequent in ulcerative colitis than in Crohn's disease.[3,25] The major eye complications include episcleritis, scleritis, and uveitis.[31] Episcleritis is inflammation of the vascular layer directly beneath the conjunctiva that presents with acute redness of 1 or both eyes, with burning, itching, and pain to palpation (Figure 3). Scleritis is a more serious disorder, and is caused by inflammation of deeper scleral vessels; it presents with redness and pain, and may involve vision changes (Figure 4). Uveitis includes inflammation of the iris, vitreous, choroids, or retina. Patients typically present with acute redness, pain, and vision changes.

Figure 3.

Episcleritis. (Courtesy of Mayo Clinic Department of Ophthalmology)

Figure 4.

Scleritis. (Courtesy of Mayo Clinic Department of Ophthalmology)

IBD patients who present with the symptoms described above should be suspected of having 1 of these common ocular complications. Patients with significant symptoms or any vision changes should be referred immediately to an ophthalmologist. These conditions usually respond well to treatment of the underlying bowel disease. Patients with episcleritis may also respond to topical steroids. Scleritis and uveitis are more likely to respond to systemic treatment and should be managed in conjunction with treatment by a specialist.[31]

Conclusion

Extraintestinal manifestations of IBD are important to consider in the management of patients with Crohn's disease and ulcerative colitis. They are most commonly associated with active bowel disease, but can also occur prior to bowel disease or during periods of remission. Although management typically involves control of the active disease, there are treatment options for those patients who continue to be symptomatic despite treatment of their bowel disease. A multispecialty approach to the care of these patients can be helpful in optimizing management.