Inflammatory bowel disease (IBD) is a chronic immune-mediated disorder comprised of Crohn disease and ulcerative colitis. Ulcerative colitis affects the large intestines, whereas Crohn disease may affect any part of the gastrointestinal tract (GIT). IBD is a multisystem condition that predominantly affects the gastrointestinal, musculoskeletal, ocular, and cutaneous systems. The complications that arise outside the intestinal inflammation of IBD are known as extraintestinal manifestations (EIMs) of IBD. Regularly, these manifestations result in significant morbidity in IBD patients, even more so than the intestinal disease itself. EIMs present in 5% to 50% of all IBD patients.
The severity and occurrence of EIMs and their correlation with intestinal-IBD activity vary. Most EIMs are directly associated with an ongoing intestinal flare. This includes aphthous ulcers, pauciarticular arthritis, erythema nodosum (EN), and episcleritis. Other EIMs like ankylosing spondylitis(AS) and uveitis are independent of intestinal disease activity. Single or multiple EIMs may arise before or after the intestinal manifestations or diagnosis of IBD. Studies have revealed that the presence of a single EIM increases the likelihood of developing additional EIMs.
Musculoskeletal Manifestations
Musculoskeletal manifestations are the most common IBD EIMs (arising in about 40% of IBD patients). These arthropathies manifest mainly as either axial or peripheral spondyloarthritis (SpA). Peripheral SpAs are further categorized into two types. Pauciarticular (Type 1) peripheral arthritis presents as acute, asymmetrical arthritis involving six or fewer joints (mainly the large joints). It is self-limited, with episodes lasting less than 10 weeks. It correlates with intestinal-IBD activity. Hence, the treatment of IBD results in the improvement of symptoms. Polyarticular (Type 2) peripheral arthritis presents as symmetric arthritis involving the small joints. It is unrelated to IBD activity and hence may precede the IBD diagnosis. Dactylitis, enthesitis, and the above peripheral arthropathies are differentiated clinically. Axial arthropathies include AS and sacroiliitis. Ankylosing spondylitis occurs in 5 to 10% of IBD patients. It presents in young adults with morning stiffness, low back pain that aggravates with rest, and spine abnormalities on imaging. It has a progressive course and is associated with HLA-B27 in affected individuals. Sacroiliitis occurs in 25% of IBD patients. Axial arthropathies are less frequent than peripheral arthropathies and occur independently of intestinal-IBD activity. They arise more frequently in males as compared with females. Treatment of musculoskeletal manifestations of IBD comprises a combination of physiotherapy, corticosteroids (intraarticular/systemic), anti-inflammatory, and anti-tumor necrosis factor medication.
Cutaneous Manifestations
Cutaneous manifestations of IBD occur in up to 15% of IBD patients. The most common conditions include EN, pyoderma gangrenosum, Sweet syndrome, and oral aphthous lesions. EN frequently arises as tender raised subcutaneous nodules on the lower extremities. These nodules appear red/purple, measuring 1-5 cm in size, and occurs more commonly in females than males. EN is a self-limited condition that coincides with intestinal-IBD activity and improves with IBD treatment. Specific treatment options for mild EN include leg elevation, compression stockings, analgesic, and anti-inflammatory medication.
Severe disease is uncommon with IBD and should prompt investigation for infectious causes of EN. Pyoderma gangrenosum is a relatively rare manifestation seen in 0.4% to 2% of IBD patients. Pyoderma gangrenosum arises at sites of trauma, a phenomenon called pathergy and follows an unpredictable and severe course. It may arise anywhere. However, the most commonly involved sites are the extensor surfaces of the lower limbs. There may be one or more lesions comprising of erythematous pustules or nodules that may rapidly spread, resulting in deep purulent ulcers. Histopathological examination of the lesion reveals a sterile culture, diffuse neutrophil infiltration with dermolysis. Since most patients with PG have underlying IBD, treatment of IBD results in the resolution of symptoms. Sweet’s syndrome, also known as acute febrile neutrophilic dermatosis, is a rare cutaneous manifestation of IBD that presents as tender, papulosquamous exanthema or nodules involving the limbs, trunk, or face. It may also present with systemic signs and symptoms like fever, arthritis, leukocytosis, and conjunctivitis. It generally correlates with intestinal-IBD activity but may precede the diagnosis. Histopathological exam of the lesion reveals the presence of neutrophilic infiltrate. The condition responds effectively to topical or systemic corticosteroid treatment. Oral lesions associated with IBD commonly affect individuals with Crohn disease. These lesions arise due to oral inflammation and ulceration and correlate with intestinal disease activity. Common conditions include aphthous lesions, periodontitis, and pyostomatitis vegetans. Treatment requires adequate IBD treatment with topical steroids for oral lesions.
Ocular Manifestations
About 2% to 5% of patients with IBD present with ocular manifestations, making eyes the third most common extraintestinal tissue apart from joints and skin affected by IBD. The most common ocular manifestations include episcleritis, scleritis, and uveitis. Episcleritis presents with sensations of ocular burning, irritation, pain, and redness. Episcleritis should be differentiated from scleritis clinically as the latter is a serious condition that presents with severe ocular pain and tenderness. In severe cases, scleritis may present with visual impairment that requires urgent referral to the ophthalmologist to avoid permanent vision loss. Less severe cases benefit from topical steroid therapy, and IBD treatment as episcleritis and scleritis correlate with intestinal disease activity. In comparison, uveitis may precede IBD diagnosis and occurs independently of intestinal-IBD activity. It presents as ocular pain, photophobia, blurred vision, and headache. Slit-lamp examination reveals the presence of peri-limbic edema and inflammatory changes in the anterior chamber. Like scleritis, uveitis requires prompt treatment with topical or systemic corticosteroids to prevent complications like vision loss and evaluation by an ophthalmologist.
Hepatobiliary Manifestations
IBD results in hepatobiliary manifestations in about 50% of patients during their illness. These manifestations include primary sclerosing cholangitis (PSC), autoimmune/granulomatous hepatitis, fatty liver disease, cholestasis, gallstone formation, and autoimmune pancreatitis. PSC is the most common hepatobiliary manifestation of IBD, as 75% of PSC patients are diagnosed with IBD.
PSC results in inflammation and fibrosis of the intra- and extrahepatic biliary tract. It presents with RUQ pain, fever, fatigue, jaundice, itching, and weight loss. Liver function tests reveal a cholestatic pattern with magnetic resonance cholangiography revealing the presence of multiple segmental bile duct strictures and dilatations resulting in the classic ‘beads-on-a-string’ appearance. Advanced disease inevitably leads to cirrhosis, portal hypertension, and hepatic failure. PSC progresses independent of intestinal-IBD activity, and hence IBD treatment does not improve the condition. Treatment of PSC includes ursodeoxycholic acid, endoscopic retrograde cholangiopancreatography with dilatation of bile ducts, or hepatic transplantation. In patients with Crohn disease, severe ileitis or ileal resection results in bile salt malabsorption that contributes to gallstone formation.
Other Manifestations
Urological manifestations of IBD include nephrolithiasis with possible urinary outflow obstruction. Nephrolithiasis is most commonly seen in patients with Crohn disease due to ileal malabsorption/ileal resection. The resulting fat malabsorption in the gut predisposes to calcium oxalate kidney stone formation. Dehydration due to diarrheal episodes in IBD patients further exacerbates renal stone formation. Patients with IBD are at an increased risk of developing thromboembolic disorders. These disorders occur independent of the intestinal disease activity and result from the IBD-related chronic systemic inflammation that leads to atherosclerosis.
Most common disorders include ischemic heart disease, stroke, deep vein thrombosis, and pulmonary embolism. The presence of any of the signs and symptoms of these conditions requires prompt management to prevent mortality. IBD also predisposes to metabolic bone disorders resulting in low bone mass in up to 14 to 42% of affected patients. The etiology for bone loss is multifactorial. It may be contributed primarily by the IBD pathogenesis or secondary to poor calcium absorption or side effects of IBD treatment resulting in low bone mass and fractures. IBD has also been associated with interstitial pneumonia and interstitial nephritis. However, the exact prevalence of these EIMs is unknown.
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