What are the extra intestinal manifestations of ulcerative colitis and how are they managed?

Extra-Intestinal Manifestations of Ulcerative Colitis

Up to 50% of patients with ulcerative colitis will develop at least one extra-intestinal manifestation during their disease course, with these complications significantly impacting quality of life and, in some cases like primary sclerosing cholangitis and venous thromboembolism, being potentially life-threatening. 1

Overview and Clinical Significance

Extra-intestinal manifestations (EIMs) can present before the diagnosis of UC is established, making awareness of these conditions critical for early recognition. 1 The probability of developing EIMs increases with disease duration and in patients who already have one EIM. 1 Some manifestations such as peripheral arthritis and erythema nodosum parallel intestinal disease activity, while others including ankylosing spondylitis, uveitis, primary sclerosing cholangitis, and pyoderma gangrenosum run an independent course. 1

Complex EIMs should be managed through multidisciplinary team meetings involving specialists in the affected organ systems. 1

Major Categories of Extra-Intestinal Manifestations

1. Musculoskeletal Manifestations (Most Common)

Joint involvement is the second most common EIM in UC, occurring in approximately 20% of all patients. 1

Peripheral Arthropathy

Type I peripheral arthropathy:

• Pauci-articular, affecting less than five large joints asymmetrically 1, 2
• Typically involves weight-bearing joints (ankles, knees, hips) and occasionally wrists, elbows, and shoulders 1
• Acute and self-limiting (resolves within weeks rather than months) 1
• Directly associated with intestinal disease activity 1, 2
• Observed in 4-17% of UC patients 1, 2

Type II peripheral arthropathy:

• Symmetrical and polyarticular, affecting more than five small joints 1, 2
• Independent of UC activity and can persist for months to years 1, 2
• Observed in approximately 2.5% of UC patients 1, 2

Diagnosis is based on clinical findings of painful swollen joints (synovitis) with exclusion of rheumatoid arthritis, osteoarthritis, and connective tissue diseases. 1

Axial Arthropathy

Radiological evidence of sacroiliitis occurs in 20-50% of patients with UC, but progressive ankylosing spondylitis occurs in only 1-10% of patients. 1

• Diagnosis is made according to modified Rome criteria 1
• MRI is the gold standard for early detection, as it can identify inflammation before bone lesions become visible on plain radiography 2
• MRI sequences including T1-weighted spin-echo, short tau inversion recovery (STIR), and fat-saturated T2-weighted sequences are recommended for patients aged less than 40 years with inflammatory back pain lasting more than 3 months 1
• HLA-B27 is found in 25-75% of patients with UC and ankylosing spondylitis, but only in 7-15% of patients with isolated sacroiliitis 1, 2
• HLA-B27 testing is unreliable as a diagnostic test in IBD due to lower prevalence than in idiopathic AS 1

2. Dermatologic Manifestations

Erythema nodosum:

• Affects extensor surfaces of the lower extremities, particularly anterior tibial areas, with symmetrical distribution 1
• Closely related to disease activity 1
• Treatment parallels that of underlying UC, typically requiring systemic corticosteroids 1
• In resistant or recurrent cases, immunomodulation or anti-TNF therapy may be used 1

Pyoderma gangrenosum:

• Runs an independent course from intestinal disease activity 1
• Requires specific therapy beyond UC treatment 3

3. Ophthalmologic Manifestations

• Iritis/uveitis are more common in women 1
• Run an independent course from intestinal disease activity 1
• Require specific ophthalmologic management 3

4. Hepatobiliary Manifestations

Primary sclerosing cholangitis (PSC):

• Life-threatening complication 1
• Runs an independent course from intestinal disease activity 1
• More common in males 1
• Associated with increased risk of pouchitis in patients who undergo ileal pouch-anal anastomosis 1
• Extraintestinal manifestations occur in approximately 27% of UC patients, with PSC being a significant contributor 4

5. Hematologic Manifestations

Anemia:

• Found in 21% of all UC patients 1
• Most common forms are iron deficiency anemia, anemia of chronic disease, and combination of both 1

Diagnostic criteria for iron deficiency:

• Without active disease: serum ferritin < 30 μg/L 1
• With inflammation: serum ferritin up to 100 μg/L may still indicate iron deficiency 1
• Ferritin 30-100 μg/L suggests combination of iron deficiency and anemia of chronic disease 1

Venous thromboembolism:

• Life-threatening complication requiring vigilance 1

6. Other Manifestations

• Renal manifestations (urinary tract involvement) 5
• Pulmonary manifestations 5
• Pancreatic manifestations 5

Management Approach

General Principles

For EIMs that parallel intestinal disease activity (Type I peripheral arthropathy, erythema nodosum, oral aphthous ulcers, episcleritis), treating the underlying UC flare is the first-line approach. 1, 2

For EIMs that run an independent course (ankylosing spondylitis, uveitis, PSC, pyoderma gangrenosum, Type II peripheral arthropathy), specific therapy beyond UC treatment is required. 1, 3

Specific Treatment Algorithms

Type I Peripheral Arthropathy

1. First-line: Treat the underlying UC flare, which typically resolves joint symptoms within weeks 2
2. NSAIDs or systemic corticosteroids if needed for symptom control 2

Type II Peripheral Arthropathy

1. First-line: NSAIDs or systemic corticosteroids 2
2. Consider immunomodulators or anti-TNF therapy for refractory cases 3

Axial Arthropathy

1. First-line: NSAIDs for symptom control 2
2. For patients refractory to or intolerant of NSAIDs: Anti-TNF agents (infliximab, adalimumab, golimumab) 2
3. Treatment decisions should be shared with a rheumatologist 2
4. The efficacy and safety of anti-TNF agents in ankylosing spondylitis are well established 2

Anemia

Iron supplementation is recommended in all UC patients when iron deficiency anemia is present. 1

Total iron requirement estimation:

• Hemoglobin 10-12 g/dL (women) or 10-13 g/dL (men): 1000 mg if body weight < 70 kg, 1500 mg if ≥ 70 kg 1
• Hemoglobin 7-10 g/dL: 1500 mg if body weight < 70 kg, 2000 mg if ≥ 70 kg 1

Important Clinical Pitfalls

Common pitfall: Assuming all arthropathy in UC patients will improve with UC treatment alone. Type II peripheral arthropathy and axial arthropathy require specific management independent of intestinal disease control. 1, 2

Common pitfall: Relying on HLA-B27 testing for diagnosis of axial arthropathy in UC patients. Due to lower prevalence than in idiopathic AS, it is unreliable as a diagnostic test in IBD. 1

Common pitfall: Using plain radiography alone for early axial arthropathy diagnosis. MRI can identify non-radiographic sacroiliitis before bone changes are visible on plain films. 1, 2

Common pitfall: Underdiagnosing anemia. All UC patients should be screened with full blood count, serum ferritin, and CRP levels. 1

Common pitfall: Failing to recognize that patients with one EIM are at increased risk for developing additional EIMs, requiring heightened surveillance. 1

Risk Factors for EIMs

• Extensive UC (pancolitis) 1
• Longer disease duration 1
• Presence of one EIM increases risk for others 1
• Non-smoking status 1
• NSAID use 1
• Primary sclerosing cholangitis (increases risk of pouchitis post-surgery) 1