Crohn's disease - extra-intestinal manifestations

Crohn's disease is a well-known inflammatory condition of the gastrointestinal tract. Approximately 40% of patients experience at least one extra-intestinal manifestation of the condition; the skin being the most common site. Other common locations include the eyes, joints, and hepatobiliary system.  Extra-intestinal manifestations precede the formal diagnosis of Crohn's disease in about 25% of patients.

Although the underlying aetiology of Crohn's remains fundamentally unknown, the largely accepted theory involves exposure to “triggers” (microbial, environmental, immunological) in a genetically susceptible person. The chronic inflammatory component of Crohn's disease is likely driven by altered activation of both Th1 and Th17 immune pathways with elevated levels of interleukins 23 and 17.

• The onset of Crohn's can occur from childhood up to the seventh decade; most cases are diagnosed between 15-30 years of age
• Gastrointestinal symptoms are diverse and includes any or a combination of - abdominal pain, diarrhoea, blood and/or mucous in the stools, weight loss, fatigue, fever, and bowel obstruction secondary to stricture formation

Overview

Approximately 40% of patients experience at least one extra-intestinal manifestation of the disease. These can be divided into cutaneous and non-cutaneous extra-intestinal manifestations 

Non-cutaneous extra-intestinal manifestations 

Can be found in almost any body system with the eyes, musculoskeletal and hepatobiliary systems, being the most commonly affected. 

• Eyes - episcleritis, scleritis, uveitis
• Musculoskeletal - arthralgia, IBD-related arthritis (peripheral, ankylosing spondylitis, sacroililtis), enthesitis, dactylitis
• Hepatobiliary - primary sclerosing cholangitis, autoimmune hepatitis, pancreatitis

Cutaneous extra-intestinal manifestations

These are divided into four groups:

• Specific lesions - histopathological findings consistent with Crohn's on biopsy
• Reactive lesions - inflammatory lesions that do not share the same histopathological findings
• Associated lesions - likely develop due to shared HLA-gene types or secondary to a chronic inflammatory response
• Treatment-induced - particularly with anti-TNF therapies used to treat Crohn's disease 

Specific lesions

• Cutaneous lesions occur due to direct extension of bowel disease to the skin - although Crohn's is well known for its ability to affect any part of the GI tract, from the oral mucosa to the anus, most of the disease is non-contiguous and restricted to the ileum and colon. Perianal fissures/fistulas are found in one-third of patients with Crohn's and is generally more indicative of colonic involvement. Patients may also develop skin tags in the perianal area

• Metastatic Crohn's disease - skin lesions at sites distant to the gastrointestinal tract with histological features of Crohn's showing non-caseating granulomas and dilated lymphatics. Due to the localised nature of the granulomas, the histopathological features can be missed:

• Orofacial granulomatosis (OFG) - characterised by persistent or recurrent enlargement of the tissues of the orofacial area. This can be idiopathic or associated with Crohn's. Childhood onset of OFG carries a higher risk of developing Crohn's

• Genital swelling - females present with swelling of the labia on one or both sides. Males develop swelling of the penis and scrotum. The lymphoedema tends to get more severe with each flare, which can result in permanent distortion of the normal anatomy of the genitalia

• Other sites - lesions tend to be red-purple plaques or nodules occasionally with an ulcerated component. The most common sites include the intertriginous area, extremities, and face

Reactive lesions

These are inflammatory lesions that do not share the same histopathological findings but are believed to share similar pathogenesis with Crohn's disease, perhaps due to impaired function of neutrophils or altered cellular immunity.

• Pyoderma gangrenosum (PG) - although more commonly associated with ulcerative colitis, PG can arise in Crohn's disease. Lesions classically start as tender papulopustules with a surrounding erythematous-violaceous rim. The area then undergoes necrosis, leading to ulceration. Lesions tend to heal with significant scarring
• Sweet syndrome - although associated with IBD, Sweet's is more commonly associated with haematological disease. Lesions typically arise as tender, erythematous, oedematous papules and plaques that favour the head, neck, and upper extremities. Systemic findings, including fever, are common

Associated lesions 

Likely arise due to shared HLA-gene types or secondary to a chronic inflammatory response. The presence and severity of the cutaneous manifestations listed below generally parallels intestinal disease activity.

• Erythema nodosum - a fairly common cutaneous finding associated with Crohn's disease, with reports ranging from 6% to 15% of patients affected. The typical clinical presentation includes a female patient with tender erythematous nodules overlying the anterior tibia

• Oral lesions - are also a common occurrence. Features include gingival or mucosal swelling, cobblestoning of the buccal mucosa, aphthous ulcers, and angular cheilitis

Treatment-induced

• The cutaneous manifestations of anti-TNF treatment do not correlate with disease activity status. It has been estimated that 5-10% of patients with IBD treated with an anti-TNF drugs develop anti-TNF-induced skin lesions. Eczematous and psoriasiform skin changes are the most common findings

• FBC - anaemia can arise due to blood loss, malabsorption, or malnutrition. An increased platelet count may suggest active inflammation. Leucocytosis may be present 
• Serum inflammatory markers - CRP and ESR may be raised if there is active inflammation or an infectious complication
• U&Es - may be abnormal as a result of dehydration / an electrolyte imbalance 
• LFT's - a low serum albumin may indicate a protein-losing enteropathy
• Serum ferritin, vitamin B₁₂, folate, and vitamin D levels - there can be nutritional deficiencies due to malabsorption or intestinal losses
• Faecal calprotectin - if raised may suggest active inflammation