Approach to Skin Lesions in Patients with Inflammatory Bowel Diseases

Introduction 

Inflammatory bowel disease (IBD) includes ulcerative colitis (UC) and Crohn’s disease (CD). This group of chronic inflammatory diseases has many extra-intestinal manifestations. Skin is the second most common extra-intestinal organ affected after the musculoskeletal system.¹ The prevalence of cutaneous manifestations among IBD patients is estimated to be 15%. Some manifestations are more common in UC while others are in CD.² This review provides a practical approach to the cutaneous manifestations among IBD patients to help guide investigation and management when patients with IBD are referred for a dermatology consult. The cutaneous manifestations of IBD are summarized in Table 1.

Table 1: Cutaneous manifestations of inflammatory bowel diseases (IBD); courtesy of Dr Abdulhadi Jfri, MD

This review divides the cutaneous manifestations of IBD into four major subgroups:

I. Cutaneous extension of the disease: 

Metastatic Crohn’s disease is an unusual presentation of CD that manifests with non-specific violaceous papules or nodules that can ulcerate anywhere on the body but are most commonly found in intertriginous areas, but can also be seen on the abdomen and the extremities. Such lesions require pathological confirmation showing non-caseating granulomas similar to the underlying CD to make a diagnosis.³ Peri-anal fistulae are a contiguous extension of CD and can be a presenting manifestation. Other contiguous lesions include knife-cut ulcerations of the inguinal folds that are considered to be the most common presenting cutaneous sign in adults.⁴ Genital edema that leads to lymphangiectasias is considered the most common presenting sign in pediatric patients.⁵

II. Nutritional deficiencies:

Patients with IBD often suffer from multiple nutritional deficiencies related to chronic inflammation, dietary restrictions (especially during flares), and surgical resection. These nutritional deficiencies can also result from malabsorption and diarrhea. 

The most common nutritional deficiency among IBD patients is the acquired form of acrodermatitis enteropathica due to zinc deficiency. It presents with periorificial and acral scaly erythematous patches and plaques that lead to crusted vesiculobullous erosive psoriasiform and pustular lesions and may be associated with diffuse non-scarring alopecia. Additional nutritional-related dermatoses may include: pellagra, due to vitamin B3 deficiency, which presents with photosensitivity and photo-distributed hyperpigmentation, sebaceous hyperplasia and stomatitis; scurvy, due to a vitamin C deficiency, which presents with hyperkeratotic papules, twisted corkscrew hairs with perifollicular hemorrhage and inflamed gums that bleed easily; purpura, due to a vitamin K deficiency; stomatitis/glossitis/angular cheilitis from any of the vitamin B deficiencies; and xeroderma (or dry skin and eczematous patches) due to essential fatty acid deficiency.^6,7

III. Oral manifestations:

Oral findings in IBD are varied and include: aphthous stomatitis (reactive with disease flare up), linear fissures of buccal vestibule, mucosal cobble-stoning (seen with CD and represents coalescing mucosal granulomatous nodules), angular cheilitis, pyostomatitis vegetans (oral pustules and erosions in a snail-track arrangement), pyodermatitis-pyostomatitis vegetans and granulomatous cheilitis or persistent swelling of buccal mucosa which is observed more in patients with CD.⁸

IV. Associations:

Several associated dermatoses that are observed among IBD patients are depicted in Figure 1 and further described below. 

Some of these associated dermatoses tend to correlate with disease activity, while others may occur in well-controlled patients. Erythema nodosum is the most common associated cutaneous lesion in IBD and is seen more often in females with active colitis; it presents as multiple tender erythematous subcutaneous nodules on the extremities, typically on the anterior lower legs.⁹ Pyoderma gangrenousm (PG), the second most common cutaneous lesion in IBD, occurs more frequently with UC and does not appear to correlate with disease activity. PG can appear anywhere on the body, but mostly present on the extremities following trauma. Lesions manifest as painful single or multiple violaceous papule/pustules that ulcerate with gun-metal grey undermined borders and which heal with cribriform scars.⁹ Another cutaneous association with IBD is hidradenitis suppurativa (HS). In a 2019 meta-analysis and systematic review involving five case-control studies, 2 cross-sectional studies, and 1 cohort study with a total of 93 601 unique participants, analysis demonstrated associations of HS with CD (pooled OR, 2.12; 95% CI, 1.46-3.08) and UC (pooled OR, 1.51; 95% CI, 1.25-1.82). IBD patients tend to have more perianal involvement compared to non-IBD patients with HS.¹⁰

Neutrophilic dermatoses including Sweets syndrome, which presents with acute fever and painful nodules and plaques on the upper body, usually presents in conjunction with an active flare up of IBD.¹¹ Bowel-associated dermatosis-arthritis syndrome (BADAS) may also present with papulopustular papules on the extremities, also in the setting of active IBD.¹²

Cutaneous vasculitis is also seen in association with IBD with or without disease activity. This includes cutaneous small vessels vasculitis (CSVV)¹³ presenting with palpable purpura evolving into hemorrhagic blisters or cutaneous polyarteritis nodosa (PAN)¹⁴ characterized by purpura, nodules, ulcers, and livedo reticularis. 

Mounting evidence suggests an association between EBA and IBDs, such as UC and CD. IBD has been shown to be present in approximately 30% of EBA patients.¹⁵ EBA presents with fragile skin blisters which heal with scarring and milia in areas of friction such as hands, elbows, knees, and ankles.¹⁶ Bullous pemphigoid (BP) has been thought to be drug induced in the setting of IBD due to the use of mesalamine or sulfasalazine. However, a population-based case-control study involving a total of 5,263 BP patients and 21,052 age-, gender-, and hospital visit number-matched controls from the National Health Insurance Research Database of Taiwan (1997-2013) confirmed that the association between UC and IBD treatment was not associated with development of BP. BP presents as tense blisters overlying a preceding or concomitant pruritic urticarial plaque.¹⁷ The prevalence of linear IgA bullous dermatosis (LABD) was found to be 7.1% in patients with UC compared to 0.05% in the general population.¹⁸

A significant association exists between IBD and psoriasis as shown in a recent meta-analysis that included over 7.7 million patients. Patients with psoriasis had an increased risk of CD (RR, 2.53; 95% CI, 1.65-3.89) and UC (RR, 1.71; 95% CI, 1.55-1.89).¹⁹ Another association which may be medication-induced is the “paradoxical” palmoplantar pustular psoriasis which can be associated with tumour necrosis factor alpha (TNFα) inhibitors. In a review and analysis of 127 case of patients receiving TNFα inhibitors for the treatment of rheumatoid arthritis, ankylosing spondylitis and CD [70 patients on infliximab (55.1%), 35 on etanercept (27.6%), and 22 on adalimumab (17.3%)], there was a documented induction and exacerbation of palmoplantar pustular psoriasis in 40% of these cases, and plaque-type psoriasis in 33.1% of the cases.²⁰

Although lichen nitidus is a rare skin condition that presents as skin-coloured asymptomatic flat-topped monomorphic papules, it has also been reported to be associated with CD. This is especially true of the extensive variant.²¹ Other associations include erythema annulare centrifugum (EAC), erythema elevatum diutinum (EED), cutaneous lesions of secondary amyloidosis, and coexistence of other autoimmune diseases such as vitiligo. Erythema ab igne, related to repeated use of heating pads to relieve abdominal pain during disease flares, can be seen on various body areas particularly the abdomen.²¹

The prolonged use of immunosuppressive agents, such as azathioprine and prednisone, and biologics can also increase the risk of skin cancers among IBD patients. The risk of nonmelanoma skin cancers (NMSC) increased more than two-fold in patients with IBD who were taking thiopurines (HR 2.28, 95% CI 1.5-3.5).²² In a meta-analysis comprised of 12 studies involving over 172,000 patients, IBD was associated with a 37% increase in the risk of melanoma (12 studies: RR, 1.37; 95% CI, 1.10-1.70) compared to the general population.²³

Figure 1: Associated dermatoses with inflammatory bowel disease (IBD); courtesy of Dr Abdulhadi Jfri, MD

Conclusion 

In conclusion, cutaneous findings in patients with IBD have various etiologies, including disease associations, vitamin deficiencies, cutaneous complications, and complications of medical or surgical therapies. The recognition of these clinical cutaneous findings in IBD patients is important for the proper diagnosis and management.